Final Report Summary - 03K (Oral Off-patent Oncology Drugs for Kids)
Executive Summary:
There is an urgent need for appropriate oral formulations of anticancer drugs for the treatment of paediatric malignancies in children of all ages. The goal of the O3K consortium is to develop oral liquid formulations of Cyclophosphamide and Temozolomide, important chemotherapeutics which have been identified in the list of paediatric needs by European MEdicines Agency (EMEA/197972/2007).
Both off-patent drugs are widely used orally for the treatment of childhood cancer. However, the currently available tablets (Cyclophosphamide) and capsules (Temozolomide) are not suitable for use in a paediatric setting, particularly in infants and young children, as it is often impractical for them to be swallowed. This is a major health concern since these children do not readily have direct and safe access to these curative drugs.
O3K conducts the pharmaceutical, clinical and pharmacological studies required for the development of these oral liquid formulations. Upon completion of the project, a dossier containing data required for application for a Paediatric Use Marketing Authorisation (PUMA) will be filed for both products. O3K will provide access to curative drugs for all children with cancer, improving compliance, ensuring safety for both patient and environment and allowing the development of essential ambulatory treatments.
In accordance with ICH guidelines, the development of these agents leads to improved quality and safety of paediatric drug formulations. The O3K project involves 9 partners (including 5 institutions and 3 SMEs providing significant expertise in clinical and pharmacological research relating to paediatric oncology along with 1 parents organisation) from three European member states (UK, Italy and France).
Initially, pharmaceutical development started using a new drug delivery technology named “Oralance Technology”.
Thus, for pharmaceutical and safety reasons, it was decided to give up the Oralance technology in the O3K development. It has been decided to redirect the formulation plan and the formulation plan was then focused on the development of a dispersible/soluble tablet which could be dissolved in a glass of water prior to administration.
Development of cyclophosphamide
A new formulation of cyclophosphamide (soluble tablets) has been successfully developed. The stability studies are ongoing. The IMPD is in preparation: the 3 months stability results will be added.
The clinical trial protocol has been submitted to the regulatory authorities and to ethical committee (approved by the ethical committee), and the Clinical trial is a part of the paediatric investigation plan which is in advanced evaluation by the PDCO at the European Medicine Agency (>day 60 report)..
Development of temozolomide
Several alternatives for the galenic preparation of temozolomide have been tested.
However, to date, there is no galenic formulation for a liquid preparation of temozolomide that fulfils the requirements (for the patient and for the environment).
The pharmaceutical development of temozolomide has been stopped at this step.
Project Context and Objectives:
The new EU Regulation on medicinal products for paediatric use (EC1901/2006) came into force on January 26th 2007. This regulation aims to improve the health of children in Europe by:
o Stimulating research and development of medicines for use in children
o Ensuring that medicines used to treat children are appropriately tested and authorised
o Improving the availability of information on the use of medicines in children
The absence of suitable authorised medicinal products to treat paediatric diseases is an issue that has been of concern for many years. Consequently, healthcare professionals (i.e MDs, Nurses) frequently resort to the preparation and administration of unlicensed formulations by manipulation of adult dosage forms.
The new EU regulation introduced major changes to the marketing authorisation required for patented as well as for off-patent drugs. Among them, the specific Paediatric Use Marketing Authorisation (PUMA) intends to stimulate research and development of off-patent products to improve their use in children. In particular, there is an urgent need for appropriate paediatric formulations of several oral off-patent drugs in order to allow accurate dosing, safe use and enhanced patient compliance.
The needs of additional information for the use of off-patent medicines in children have been identified and listed by the EMEA paediatric expert group (EMEA/496777/2006), and revised on June 2007 (EMEA/197972/2007). This list includes 27 off-patent oncology products. Nine of them are oral drugs that need age-appropriate formulation.
The goal of the Oral, Off-patent, Oncology drugs for Kids (O3K) project is to develop child-appropriate liquid formulations of cyclophosphamide and temozolomide, using this new technology. Temozolomide (TMZ) and cyclophosphamide (CPM) are widely used for the treatment of paediatric cancer and both drugs are included in the list of paediatric needs established by the EMEA.
Two liquid formulations of Cyclophosphamide and Temozolomide for daily oral administration in children will be developed with the goal to further submit a Paediatric Use Marketing Authorisation (PUMA) for both compounds. This will allow the administration of the exact dose along with a good bioavailability and improved compliance at all ages.
The O3K objectives are:
1. to secure the feasibility of developing the new oral formulations in terms of pharmaceutical aspects and to perform this work under the good manufacturing practices
2. to perform the non clinical, clinical and pharmacological development of a drinkable suspension of temozolomide for the purpose of a submission for a Paediatric Use Marketing Authorisation in the EU
3. to perform the non clinical, clinical and pharmacological development of a drinkable solution of cyclophosphamide for the purpose of a submission for a Paediatric Use Marketing Authorisation in the EU
Progress beyond the state-of-the-art
• Drug development is needed in paediatric oncology
Childhood cancers represent a rare disease accounting for less than 1% of the total number of cancer cases in humans. Across the whole of Europe, approximately 16 000 new cases of childhood cancer are diagnosed in children under the age of 19 each year (http://info.cancerresearchuk.org/news/pressreleases/2007/january/278356). Despite the high cure rates now being achieved for certain tumour types (e.g. 80% five year survival rates for Wilms tumour and acute lymphoblastic leukaemia), , cancer remains the major cause of death from disease beyond the age of 1 year with approximately 3000 children dying from cancer each year in Europe.
During the last 30 years, access to innovative therapies developed by pharmaceutical companies has been extremely limited for children in Europe, one reason being that Paediatric Oncology does not represent a large, and hence financially attractive, area for drug marketing. Most of the anticancer drugs currently used in children have been developed by academic groups through prospective clinical trials using the drugs and formulations available for use in adults. This allowed the generation of clinical and pharmacological paediatric data for compounds that eventually went off-patent. However, there are still data missing for many off-patent oncology drugs, due to the lack of commitment by pharmaceutical companies. In particular, age-appropriate oral formulations of many important anticancer drugs have not been developed.
• An increasing use of oral chemotherapy for the treatment of paediatric malignancies
o Oral chemotherapy is used on a daily basis to treat paediatric malignancies, and even more in the future
o Some drugs are indicated for oral use only. For example, oral temozolomide has gained popularity for the treatment of refractory brain tumours in children, 6-mercaptopurine is a major component of maintenance chemotherapy for acute lymphoblastic leukaemia and procarbazine has been an important drug for Hodgkin’s disease for many years. In addition busulfan is used at high dose before haematopoietic stem cell transplantation in place of total body irradiation in children, with an intravenous form of busulfan not available until very recently.
o Anticancer drugs currently administered intravenously are given orally in order to allow protracted administration or ambulatory treatment. Daily oral etoposide is used for the palliative treatment of a variety of many solid tumours. For the use of metronomic therapy, cycloclophosphamide is given orally at low daily doses, thus allowing the prolonged exposure to optimal low concentrations believed to be cytotoxic to tumour endothelial cells.
o Oral chemotherapy facilitates ambulatory treatments and provides flexibility, improved quality of life, and reduced financial cost. Oral chemotherapy is especially attractive for the treatment of children, particularly in the setting of disease relapse.
o Many innovative targeted compounds that will eventually be indicated in children are given orally, at low daily doses, for protracted administration. For example, there is evidence to suggest that oral targeted drugs such as EGFR inhibitors (erlotinib, gefitinib), mTOR inhibitors and antiangiogenic compounds (sorafenib and sunitinib) may have antitumour activity against paediatric malignancies.
• Appropriate oral formulations for children are not available for most of these compounds and this has major consequences
o Most oral anticancer drugs are only available in tablet or capsule form at inappropriate dosages for a paediatric population. In practice, many children cannot swallow adult tablets or are averse to the taste of adult medicines, especially those below the age of six years.
o This has been clearly established by the EMEA classification of dosage forms (reflection paper “formulations of choice for the paediatric population” (EMEA/CHMP/PEG/194810/2005) which states:
- “a major concern is at what age children can safely swallow solid oral dosage forms such as tablets or capsules. Again this is generally a factor of age and health status but there are significant inter-patient differences around an average of about 6 years”.
- “oral tablets and capsules are not applicable for preterm newborn infants, term newborn infants, infants and toddlers. Oral capsule is applicable with problems for children between 2 and 5 years and oral tablet is probably applicable, but not preferred for children between 2 and 5 years. Oral tablet and capsule have a good applicability only for children 6 to 11”
o The prescribed dose for a child may be less than the smallest available formulation dosage, which has been design to fit adults needs. Although most tablets are scored, the requisite dose may still be less than in half the tablet, in particular for the youngest children. In these situations the tablets have to be fractioned or the capsules opened and the contents divided. This practice may result in substantial inaccuracy in dosing and may potentially jeopardize the effectiveness of treatment. Doctors and other health care specialists trying to treat children appropriately face a difficult dilemma: giving nothing or trying to adapt an adult medicine to paediatric use . Clinical practices to deal with the dosing issues are not easy to standardize, and heterogeneity of drug exposure from a patient to another one may impact the efficacy of the treatment. In addition, health care providers have to deal with the tablets or capsules that are available. For example, when a compound is to be given daily, the entire dose for one week is given on 4 or 5 days.
o In other situations, intravenous formulation may be given in the form of a drinkable solution. However, this may increase the risk of serious adverse reactions or inappropriate dosing due to poor or inconsistent bioavailability.
o Oral administration of anticancer drugs is a major concern in children under the age of three years. This is particularly important as paediatric malignancies in children under the age of three represent 30% of all paediatric cancers.
The New Oral drinkable formulations will allow easiness of use and flexibility of administration doses depending on the age and body surface of kids.
➢ Cyclophosphamide :
A CPM IV dosage form is available on the market (Endoxan®) and the IV formulation is very simple at 20mg/ml. This IV dosage form is widely used orally in children (off label use) with a good acceptability.
Using cyclophosphamide is safe for the environment since this is an inactive pro-drug that requires liver enzymatic by CYP450 to generate alkylating moieties.
Then, we propose to develop a drinkable solution of cyclophosphamide, with an easy and fast reconstitution.
The drinkable solution of cyclophosphamide will be developed with the following objectives:
- to develop a drinkable solution allowing easiness of use and flexibility of administration doses depending on the age and body surface of kids.
- to guarantee good tolerance of the formulation using well tolerated and agreed excipients for paediatrics
- to insure physical and chemical stability during storage and use as well as relevant safety of handling and use in ambulatory treatment situations
- to control accuracy and reproducibility of doses delivery with a suitable formulation and appropriate dosing device
- to have a manufacturing process allowing industrial scale for commercial supply
- to guarantee regulatory compliance
The goal is to have appropriate physical properties of the dosage form for a reliable manufacturing process.
Depending on the critical parameters encountered (reconstitution time and physical characteristics of powder for reliable process, stability of cyclophosphamide), 4 development options are envisaged:
- A simple distribution of the API in vials together with aroma
- A dry blend formulation combining API with excipients
- A powder granulation formulation consisting in associating excipients to the API under humid conditions followed by a drying phase.
- An orodispersible tablet formulation having the property to dissolve immediately (within one minute) when in contact with water.
- This last one has been selected.
➢ Temozolomide:
Considering the current state of pharmaceutical knowledge on temozolomide, a drinkable suspension of temozolomide consisting of a coated granulate powder has been proposed. Indeed, the marketed capsules have common excipients and are manufactured according to a classical process. However, the critical parameter regarding Temozolomide will be to develop a dosage allowing to prevent any contact and environmental risk during administration but which releases without delay Temozolomide when in stomach. In other words, Temozolomide should not be released immediately when the formulation is reconstituted in water but should be release at the stomach stage.
The drinkable suspension of temozolomide will be developed with the same objectives than cyclophosphamide and to be safe for the environment.
The main point of the paediatric suspension development is to avoid or slow down the release of temozolomide from the granulates into water after reconstitution of the suspension, but maintain immediate release during administration in the stomach at the site of absorption.
Project Results:
3.1. Overview of the expected and achieved results related to WP2: Preclinical and pharmaceutical development for clinical evaluation
Oralance (Partner 5) is WP2 leader but Oralance left the consortium on 29/03/20010 and NEGOSITEK (Partner 8) became WP2 leader
Work Package 2 included the following steps:
- Pre-formulation studies
- Formulation
- Analytics
- Technical Trials and manufacturing
- Clinical Batches Supply
- NODS and clinical batches follow up during commercial development
Initially, pharmaceutical development started using a new drug delivery technology named “Oralance Technology”.
1°) Pre-formulation studies
This first step included a full physicochemical and biopharmaceutical assessment on both APIs as well as a screening of ingredients regarding solubility and compatibility of active ingredients. The next steps were physical stability (mainly API crystalline form and polymorphism risk study) in the ingredients as well as chemical stability.
Pre-formulation study was incomplete but allowed to show that it is possible to incorporate cyclophosphamide and temozolomide in Suppocire CM or its oral equivalent (Gelucire 39/01).
2°) Formulation
Formulation work was planned in 2 steps, the first being the NODS formulation and the second one related to the clinical formulation:
NODS formulation
NODS formulation work consisted in studying the formulation and process parameters allowing incorporating cyclophosphamide and temozolomide into the NODS matrix. Oralance showed that it was possible, at small scale (tens of grams) to incorporate (entrapment ratio) 10% of cyclophosphamide or 20% of temozolomide in a NODS Suppocire CM matrix.
A very few trials were made on cyclophosphamide only to demonstrate feasibility of entrapment. Oralance worked essentially on temozolomide.
Based on these first results, some scales up trials (at hundred grams scale) have been performed before starting the technology transfer at Elaiapharm (the subcontractor’s site).
Clinical Formulation
Clinical formulation work consisted of studying the association of NODS to other excipients (dilutants, lubricants, suspending agents...) in order to reach a powder formulation ready for reconstitution with water forming a homogeneous aqueous drinkable suspension.
The key defined parameters for a suitable formulation were:
- Appropriate powder mixture flowability properties
- Ease and rapid reconstitution of the suspension with water addition
- Homogeneity of dosing
- Safety for environment (no temozolomide at the NODS surface)
- Satisfactory physical stability (no sticking phenomenon) under accelerated stability studies (30°C and 40°C).
We obtained some formulation prototypes showing preliminary satisfactory results in terms of reconstitution when stored at 4°C or room temperature. However, when stored at 30 and 40°C, we observed sticking phenomena coming from the low melting point of NODS. Therefore, additional trials have been requested to Oralance for reducing sticking behaviour. Oralance worked on a different washing process for the NODS using ethanol. In addition, upon request of Negositek and Dr. Veronique Andrieu (Marseille University) made trials with the Gelucire 43/01 having a higher melting point.
The sticking phenomena were improved but not fully corrected and we encountered problems of API entrapment ratio as well as yield variability.
The entrapment ratio and yield variability was really a concern as it showed that the formulation and process were not reproducible and not under control. In addition, Oralance did not succeed to improve these parameters.
Furthermore, in vitro dissolution studies also showed variability in the API release kinetic and the curve profiles allowed us to suspect the presence of temozolomide at the NODS surface. An investigation was made using Raman spectrometry at a contract analytical services company (Drugabilis) but the results could not allow to clearly demonstrating the absence of API at the NODS surface. Therefore, the present clinical formulation prototype is not reliable.
In summary, formulations studies allowed to obtain some prototypes but those are not appropriate for a clinical study.
Although Oralance considered its formulation ready to go in clinical, Negositek stated clearly that the present formulation candidature cannot go further for technical, quality, safety and regulatory reasons.
3°) Analytics
Regarding analytics studies, Oralance worked only on temozolomide.
Analytical methods for API and NODS assay were tested but these methods were not fully validated.
4°) Technical Trials and Manufacturing
Technical NODS trials were performed at Elaiapharm on a placebo batch and on an active batch containing Omeprazol as an active tracer in replacement of temozolomide. Indeed, as temozolomide is a very expensive active, we did not want to launch any technical trial at real scale as long as the formulation and process be under control.
No technical batch for regulatory stability study was performed.
5°) Clinical Batches Supply
Given that no clinical formulation is available so far, no any clinical batch could be produced.
Conclusion
Deliverables of Work Package 2 were not reached at M18 for pharmaceutical and safety reasons. However, given the situation, Negositek and Keocyt were asked by the Project Coordinator to investigate and prepare the implementation of a new development plan using other formulation approach than the NODS one.
Negositek identified and proposed solutions for pursuing the project without using NODS technology.
A new development work started for cyclophosphamide in collaboration with Elaiapharm.
We decided to redirect the formulation plan and use fast track development methodology. Thus, in order to win time and because the drugs are well known, formulation work was undertaken without any pre-formulation study. However, we had to find an agreed subcontracting company for handling cytotoxic products. There are few companies having suitable capabilities for the manufacture of cytotoxic products. We rapidly identified Elaiapharm and we implemented a collaboration contract to perform the new formulation development of the two drugs.
Cyclophosphamide trials were more advanced than temozolomide ones. Priority has been given to the cyclophosphamide development.
CYCLOPHOSPHAMIDE
Cyclophosphamide aqueous solution
At first, the formulation work was oriented to a cyclophosphamide aqueous solution. Trials were performed to identify the relevant pH and concentrations for good stability of cyclophosphamide in solution. Unfortunately, the different trials demonstrated that there is no way to obtain a good stability of cyclophosphamide in aqueous solution.
Dispersible tablet
The formulation plan was then focused on the development of a dispersible tablet which could be dissolved in a glass of water prior to administration. Various formulations were tested according to two manufacturing processes: humid granulation and direct compression.
1) Formulation with Cellulose as diltutant
Different tablet formulations have been developed for three Cyclophosphamide strengths and tested according to their pharmaceutical characteristics:
- Compressibility
- Hardness
- Disintegration
- Dissolution
The choice of the dosage form and the composition of tablets were made taking into account the recommendations of the EMEA guideline EMEA/CHMP/ PEG/194810/2005.
All excipients are commonly used and are conform to the corresponding monographs of the current European Pharmacopoeia. Lactose which is widely used in tablet formulation was avoided because of the risk of lactose intolerance.
An interesting formulation candidate has been identified for performing stability studies and first stability studies were launched at Elaiapharm.
A new development site was rapidly found for the project because Elaiapharm was bought by Lundbeck Company which decided to close the cytotoxic area. Manufactures and analytical know how were transferred in a few months to Bertin Pharma
o Stability
Stability results of tablet batches with three doses of Cyclophosphamide manufactured by Elaiapharm at T0 and after one month show that there was a degradation of the active substance. Because the tablet packaging was permeable, it was concluded that degradation of Cyclophosphamide was due to the presence of humidity or water during the stability study.
ICH long term stability studies started on three batches of dispersible tablets: one batch per dose.
It is to be noticed that, according to the different Summary of Product Characteristics, the current Cyclophosphamide marketed formulations are to be stored below 25°C.
However, the stability data show a significant increase of impurities especially the monochloro impurity after 3 months of storage at 25°C / 60% RH.
Monochloro impurity increases in presence of water. At this stage, cyclophosphamide dispersible tablets were packaged in PVC/PVDC blister which is not a high protective packaging with regard to water.
Therefore, in order to guarantee proper stability of the tablets, we decided to launch new stability studies in different more protective packaging.
-PVC/PVDC blisters (present reference)
- Aluminium/Aluminium blisters
- Glass bottles
- Polyethylene bottles with desiccant cap.
It is to be noticed that glass bottles and Aluminium/Aluminum blisters are already used for marketed dispersible tablets.
• Initial level of monochloro impurity at T0 is from 0.15% to 0.28% depending on the dosage strengths
• Endoxan monochloro impurity level is 0.17% at T0 and about 0.1% (analytical precision) at T1 month
• Dispersible tablets
• Decrease of cyclophosphamide (2 to 10%) in all packagings except in Glass bottles
• Increase of monochloro impurity above specification (>1%) except for Glass bottles (0,62%)
• Appearence of new impurities
• The observed degradation seems to be related mainly to excipients interaction rather than water
• Stablity results in glass bottles at T5°C also show monocholoro evolution,
• Present formulation is not appropriate
In addition, in order to anticipate any specific stability issue with cyclophosphamide, in parallel of new packaging investigation, it has been decided to launch, as a back up plan, a compatibility study screening a wide range of excipients which are appropriate for dispersible tablets formulations.
2) Formulation without Cellulose as dilutant
In parallel and because of the negative stability results of the Cyclophosphamide tablets, a compatibility study with a wide range of excipients was launched in order to identify what excipients should be avoided with regard to cyclophosphamide degradation. For securing the compatibility study reliability, it was decided to assess potential active/excipients interactions with 2 different analytical techniques:
- Differential Scanning Calorimetry
- HPLC assay of Cyclophosphamide
The origin of the degradation of Cyclophosphamide in the previous tablet formulation has been identified because of the presence of one excipient (Cellulose microcrystalline).
Appropriate excipients for the new formulation of dispersible tablets of cyclophosphamide were chosen and several new tablet prototypes show good compressibility and proper dissolution.
Several analytical determinations were performed among with compared uniformity and monochloro impurity. Based on these analyses, the best formulation candidate was identified. This formulation is based on mannitol as main component. It is composed with mannitol 400 and 200 association.
Several trials aiming to reduce the amount of mannitol in the formulation have been performed. The goal of these new trials was to investigate the possibility to reduce mannitol ratio to a maximum of 30 %.
In case results of the new trial would be not satisfactory we would choose the identified mannitol formulation for starting clinical program.
Three compositions were tested based on the association of mannitol 200 and other components:
• Mannitol 200 (Pearlitol® 200) and isomalt (GaleniQ® 721)
• Mannitol 200 (Pearlitol® 200), isomalt (Pearlitol® 200) and lactose (flowlac® 100)
• Mannitol 200 (Pearlitol® 200) and maltose (Advantose® 100)
Trials have been performed to reduce mannitol amount. The compositions tested present a bad uniformity in comparison to the association of two mannitols.
Thus, it was decided to keep the formulation combining the two mannitols as it was the best one in term of dosage uniformity. Three dosage strengths were manufactured (5, 20 and 50 mg).
In addition, It has been decided to avoid sodium saccharinate, following PIP assessment recommendations for this excipient.
The selected composition was manufactured on a higher batch size for checking homogeneity and process parameters.
Conclusion
The obtained blend is homogeneous. It was selected for the tabletting of the three dosage strengths: 5, 20 and 50 mg.
Packaging step
Each batch was manually packaged in brown glass bottles (100 ml, LGA supplier):
No sticking, no other problem occured during the tabletting of the three dosage strengths. The three batches comply with uniformity of dosage unit test, which is the critical point particularly for low dosage strength. The three batches were selected for stability study .
CONCLUSION
New formulation trials have been performed to obtain cyclophosphamide soluble tablet without microcrystalline cellulose, as an incompatibility between this excipient and cyclophosphamide was demonstrated.
A new formulation has been developed using grades of mannitol presenting different particle size distribution. This new formulation complies with content uniformity of dosage units, which is the critical point of the lowest tablet strenght. The composition is presented in table 30
Table 30: Composition of soluble tablets of Cyclophosphamide
Quantity (%)
Cyclophosphamide 6.25
Mannitol (Pearlitol® 400 DC) 52.30
Mannitol (Pearlitol® 200 SD) 33.70
Croscarmellose sodique (Vivasol®) 6.25
Magnesium stearate (MF2V®) 1.50
Total 100.00
Based on this homothetic composition, three batches have been manufactured, corresponding to the three dosages strengths. They have been packaged in glass bottles for stability study.
The HPLC analytical methods were validated with regard to the different parameters : specificity, system suitability, linearity, accuracy, stability of solutions and limit of quantification were demonstrated.
Batch Analysis
At present, 3 batches of cyclophosphamide soluble tablets were manufactured for clinical studies and stability purpose, at the following dosage strengths:
- 5 mg
- 20 mg
- 50 mg
Characterization of impurities
The only Cyclophosphamide impurity which is detectable in the finished product is the Monochloro impurity which is a synthesis and a degradation impurity.
Stability
ICH long term stability studies started on three batches of soluble tablets: one batch per dose. The stability studies are ongoing. They will stop after 36 months.
Cyclophosphamide drug substance must be stored in a cool place and the storage conditions of the current marketed tablet formulation Endoxan® is below 25°C.
Thus, stability studies regarding the new soluble tablet formulation were launched under two conditions during 36 months: (ANNEXES)
- 5°C
- 25°C/60% RH
The retest period for Cyclophosphamide drug substance is 36 months, to be kept at 2-8°C.
Based on the above preliminary results of stability, there is a good chemical stability at 5 and 25°C of the three batches of Cyclophosphamide tablets for the three strengths. The results of pharmacotechnical tests are satisfactory. There is a change in the appearance for the two higher dosage forms at 25°C.
So a retest period of 12 months with the following labeling statement: “store between 2°C and 8°C”, was proposed.
The retest period will be updated according to the results obtained along the ongoing stability studies.
3 months stability studies are ongoing and the results allowed us to submit an updated IMPD.
TEMOZOLOMIDE
A temozolomide suspension formulation plan was launched in Bertin Pharma. As the objective was to avoid any direct external contact with temozolomide, a protective barrier on the drug is necessary. Thus, after granulation, the obtained granules were coated with different polymers.
Given the very expensive cost of temozolomide, first trials were performed with theophylline which was used as a tracer before trials with temozolomide.
The technical requirement was to avoid immediate direct release of temozolomide from granules when put in water. A lot of different granules formulations were tested using one and several coating barriers and combining various polymers (hydrophilic, lipophilic, pH sensitive polymers etc...).
Conclusion of Theophylline trials:
Theophylline was tested as a tracer in substitution of Temozolomide for the preliminary feasibility study. The goal of this study was to formulate granules having no release of the active ingredient after reconstitution in water before administration, and presenting an immediate release profile after oral administration in the gastric environment.
Different formulation trials have been performed using combinations of soluble and insoluble polymer to produce unilayer and bilayer coated granules.
In addition, the influence process parameters as well as particle size of granules was studied.
Granules were assessed under in use conditions (reconstitution of the suspension in water) and in dissolution conditions at 2 pH (1.2 and 6.8).
No formulation allowed us to reach the first objective being to avoid immediate release of Theophylline in the suspension fro preventing safety issue during use.
However, even if Theophylline physicochemical properties are close to Temozolomide ones, it is not the same molecule and its particle size is much smaller.
Thus, we decided to perform 2 granulate trials with Temozolomide.
Temozolomide granulates
We tested 2 formulations whose compositions are mentioned below:
Batch 100612 was granulated with copovidone whereas batch 100613 used Eudragit EPO to.
Physical characteristics of these batches were measured in terms of density as well as particle size.
A higher particle size could be obtained using 10% of copovidone and Eudragit EPO as granulation solution compared to copovidone alone.
In vitro dissolution was performed on both batches (dissolution medium volume 500 ml, stirring 75 rpm, temperature 37°C) according to 3 different conditions: Water, pH 1.2 pH 6.8.
Under in vitro dissolution conditions, Temozolomide is fully released from the granules in the different pH conditions.
Batches 100612 and 100613 were also studied under in use conditions: reconstitution of the suspension in water at two concentrations 6 mg/ml and 20 mg/ml. Temozolomide release and appearance of the reconstituted suspensions were observed.
A partial immediate release of Temozolomide occurs within the minutes after reconstitution of the suspensions in water. The saturation concentration of Temozolomide is reached after 4 hours for the two tested batches at a concentration of 20 mg/ml. The slight decrease of Temozolomide concentration between 25 hours and 75 hours combined with the yellowish appearance of the suspensions are likely related to a slight degradation of Temozolomide over time in aqueous solution.
Based on the above results we can observe that:
We did not succeed to avoid immediate release of Temozolomide from the granules whatever the formulation approach or the pH conditions
Temozolomide is not stable over time when in aqueous solution.
Therefore, we concluded that it is not possible to develop a Temozolomide suspension which can be safe and stable after dispersion in water over a long period of time.
Temozolomide dispersible tablets
Given these facts, we decided to change the formulation strategy. As Temozolomide is not stable in water over time, we had to design a formulation to be dispersed in water just at the time of the administration. Thus, we investigated the possibility of developing dispersible tablets. Dispersible tablets, as solid dosage forms, present the advantage of being stable during storage over time and can be easily combined in several dosage strengths to reach the suitable dose.
Those tablets are to be dispersed in water at the time of use to lead to an oral suspension allowing easy administration in children.
First trials were performed in order to assess technical feasibility of Temozolomide dispersible tablets.
In a first step three different dispersible tablets formulations were tested:
A good compressibility was observed based on mannitol 400 (batch D110011): a wide range on hardness can be reached (from 30 to 150 N). The better hardness is about 60 N corresponding to a low friability (0.3%) and dispersion duration (30 sec).
In a second step, the tabletting properties of a mannitol 400 based formulation was studied using different punches sizes in order to assess robustness of the process as well as the possibility of covering a wide range of different dosage strength.
Conclusion
We observed a good behaviour of the formulation during tabletting. A large range of hardness was obtained: 40N to higher than 200N for the tested punches.
Very good results were also obtained in disintegration and dispersion time for each hardness and punches.
Hardness between 60-80N gave optimal results with low friability and good dispersion duration.
Therefore, we demonstrated the feasibility of a dispersible tablet formulation with Temozolomide.
Based on these encouraging results, we are now working on the development of a dispersible tablet guarantying safety during conditions of use for the health and environment.
With a dispersible tablet, which is a solid dosage form, we avoid the risk of contamination during storage and handling. However, we have to make sure that Temozolomide will not be release immediately when tablet is dispersed in water for environmental reasons.
Thus, the next step would be to perform a protective coating of Temozolomide active ingredient before incorporating it into the tablet formulation. Active ingredient coating is already use in the pharrmaceutical industry using the so called fluid bed technology which was developed years ago by Glatt company.
Our objective would be to coat temozolomide active ingredient with a hydrophobic polymer at a low concentration in order to create a direct barrier during the time of reconstitution and administration which dissolve few minutes later when the suspension arrives in the stomach.
In the previous formulations approach using granulates, the polymer coating was applied onto the granules but was not in direct contact with Temozolomide. In addition, the objective was to have a stable reconstituted suspension during time over several days.
In the case of dispersible tablets the coating layer will be applied directly on the surface of temozolomide active ingredient and we do not need Temozolomide be retained for a long time.
From a process perspective, we already demonstrated the feasibility of making a dispersible tablet with temozolomide. We could now develop the temozolomide coating step using fluid technology.
But it has been decided to stop the pharmaceutical development plan of temozolomide and to put together all resources in the cyclophosphamide development plan.
3.2. Overview of the expected and achieved results related to WP3: Formulation, supply and regulatory
Keocyt (partner 6) is WP3 leader.
Objectives:
- To optimise Clinical formulation in order to reach commercial robustness and regulatory compliant formulation for Marketing Authorization, secure clinical & commercial supply, including supply of active ingredients
- To lead regulatory activities
Keocyt was involved in the following tasks:
- Contribution to the Pharmaceutical Development plan elaboration, task led by Negositek
- Contribution, together with Negositek, to the identification of subcontractors, negotiation, implementation of contracts / technical and quality requirements, and follow up of subcontracted tasks
- Scientific and regulatory advice on clinical and commercial formulations and industrial process tasks
- Investigation and sourcing of active ingredients and packaging items
- Supervision of manufacturing the different batches that wre used for technical, stability tests and clinical trial supply.
All these tasks were performed in close relationship with Negositek as well as the IGR Project Coordinator.
Summary of progress towards objectives and details for each task:
Work Package 3 included the following steps:
⇒ Commercial formulation development
⇒ Commercial process development
⇒ Cyclophosphamide and temozolomide sourcing
⇒ Industrial transfer and validation
⇒ ICH stability studies
⇒ Global quality/regulatory documentation management for the CMC Part
1°) Commercial formulation development
This work consisted in adjusting clinical formulation by optimizing the composition in terms of aroma and preservatives as well as other parameters for assuring a reliable scale up for commercial supply.
Given that clinical formulation was not yet available because the first stability data are not available at the end of the project (M36), no work could be initiated on the commercial formulation.
2°) Commercial process development
No study was performed as long as clinical and commercial formulations are not completely defined. However the process of manufacturing is rather simple and should not show any issue once coming to manufacturing commercial quantities. CMO to manufacture commercial batches is identified. Scale up will be easy.
3°) Cyclophosphamide and Temozolomide sourcing
Sourcing the two API temozolomide and cyclophosphamide are key in the project. Such a sourcing has been done by Keocyt. Suppliers have been identified and selected for both compounds based on pricing and quality criteria. In addition, Keocyt obtained from both suppliers chemical documentation describing main route of synthesis, impurities, and analytical methods. Indeed, eDMF exist for both APIs. Keocyt has ordered an audit of these documents by independent experts that concluded to the fact that the APIs were of high quality and that documentations provided by suppliers were of quality enough to be acceptable by EMA for registration (of the IMPD and finally when filing for the registration dossier of the finished product).
We already have acquired more than a kilo of both APIs.
A supply agreement has been reached for clinical supply and a commercial commitment from both parties are under finalization to make sure APIs will be available when the two products will be on the market (considering that commercial supply would not start before 2013).
Beside these two suppliers, we have identified back up suppliers if needed and will continue to screen potential suppliers especially European ones at acceptable prices.
4°) Industrial transfer and validation
This activity will be initiated after process development is completed.
5°) ICH stability studies
These studies are Ongoing.
6°) Global quality/regulatory documentation management
The Paediatric Investigation Plan was submitted on 09/05/2011 to the European Medicines Agency (EMEA). After validation, procedures for PIP started on the 15/06/2011. The day 60 (the 12/08/2011), the summary report was sent by the PDCO. The requests are encouraging and no blocking.
Many meeting were held by Keocyt on regulatory matters using sometimes the expertise of Pharmes (regulatory consultancy company which costs are supported by Keocyt) to define regulatory requirements and build different proposals for the development. In addition to Pharmes, Keocyt asked several advices from experts such as Dr. Veronique Andrieu (Vice President of the registration commission at AFSSAPS) for pharmaceutical matters and Pr. Georges Houin (expert at AFSSAPS) for pharmacokinetic approach.
NODS
Negositek, IGR and Keocyt have elaborated a Paediatric Investigation Plan for both NODS® cyclophosphamide and NODS® temozolomide. The PIP procedure has been suspended due to the changes formulation.
Key requirements for IMPD were defined but the dossier was not written as Oralance did not provide sufficient data for an IMPD submission.
Soluble/dispersible tablets of cyclophosphamide
IMPD has been provided by Keocyt and submitted by IGR according to Keocyt, at the same time as the protocol to competent authority using the VHP, on 1st March 2011. The VHP submission has been accepted by all countries, except Italy, on 6th March 2011. The VHP was rejected.
The resubmission of our VHP application needs:
- positive results of the 3 months stability study
- Approval by PDCO of the PIP since VHP is willing to follow the PDCO/ EMA opinion.
Thus the VHP is submitted once the PIP is fully approved i.e. at the end of November.
Negositek, IGR and Keocyt have elaborated a new Paediatric Investigation Plan for cyclophosphamide soluble tablet.
A Pre submission TC with EMA for the PIP took place on 29th March. The PIP has been submitted on 10 th May 2011. After validation, procedures for PIP started on the 15/06/2011. The day 60 (the 12/08/2011), the summary report was sent by the PDCO. The PDCO day 60 report was very encouraging with no blocking questions.
3.3. Overview of the expected and achieved results related to WP4: Clinical studies
IGR (partner 1) is WP4 leader
Project leader: Prof Gilles Vassal, IGR, France
Key Objective:
To perform clinical studies with the two new oral formulations (prepared in WP2 and supplied for clinical trials by WP3), i.e. drinkable solution of cyclophosphamide and drinkable suspension of temozolomide.
3.3.1. Clinical trial setting
➢ Temozolomide
According to the Annex 1, a first template of both protocols have been written and reviewed by all principal investigators, work package coordinators:
➢ Pharmacokinetic and safety study of an oral liquid formulation of temozolomide – NODS®temozolomide – in children with malignant brain tumour.
This study was designed as a prospective trial with 2 cohorts:
In cohort 1, a cross-over randomised trial to test bioequivalence of both formulations (NODS® temozolomide versus Temodal® capsules).
Are eligible children of 3 years and more, able to swallow intact capsules and with newly diagnosed glioma or relapsed/refractory malignant tumour for whom a treatment by oral temozolomide is indicated. Patients will be treated with temozolomide 200 mg/m²/day orally for 5 consecutive days every 28 days as follow:
Cycle 2 and further: Treatment will be pursued with Temodal® capsules or NODS® temozolomide at 200 mg/m² (if no grade 3 or 4 toxicity occurs after cycle 1) according to PK results and feasibility.
In cohort 2, a descriptive pharmacokinetic study (treatment with NODS® temozolomide only).
Children of less than 3 years are eligible with newly diagnosed glioma or relapsed/refractory malignant tumour for whom a treatment by oral temozolomide is indicated. Patients will receive NODS®temozolomide at a dose of 150 mg/m²/day for 5 consecutive days on cycle 1. The dose will be increased on cycle 2 and further to 200 mg/m²/day, for 5 consecutive days every 28 days, if no grade 3 or 4 toxicity occurs after cycle 1. Pharmacokinetics parameters will be measured at Day 1.
A total of 42 patients will be studied as follow:
24 children of 3 years and more
12 children of less than 3 years
6 additional patients in case of drop-outs.
A final EMEA scientific advice for both formulations has been obtained on 10-13/12/2007.The two Paediatric Investigation Plans (one for NODS®temozolomide and one for NODS®cyclophosphamide) were submitted on 27/02/2009 to the European Medicines Agency (EMEA). After validation, procedures for both PIPs started on the 30/04/2009. The day 60 (the 26/06/2009), the summary report was sent by the PDCO.
The major issue was the request of bioequivalence studies in adults for both compounds prior to evaluation in children in order to address the relative bioavailability/bioequivalence of the new formulation compared with the existing tablets formulation before performing a pharmacokinetic/safety trial in children (without bioequivalence).
In addition, there are no strong and large adults data with the NODS formulation (incorporating other active principles) that would have help to show sufficient safety and PK data in humans. Indeed, the NODS Omeprazole data in adults provided by Oralance were not sufficiently reliable.
Following the summary report, a telephone conference was held on 07/09/2009 to discuss several items with the PDCO and EMEA.
Based on those requests, 2 new synopses (bioequivalence in adults) were designed and the first paediatric synopsis were redesigned:
➢ 2 bioequivalence studies in adults to determine the relative bioavailability of NODS® formulation compared to tablets formulation in adults
Those studies were designed as prospective, cross-over randomised trials to assess the relative bioavailability of NODSÒformulation compared to capsules/tablets formulation in adults.
A. NODS®Temozolomide
Are eligible patients with relapsed/refractory brain tumour for whom a treatment by oral temozolomide is indicated. Patients will be treated with temozolomide 200 mg/m²/day orally for 5 consecutive days every 28 days.
Cycle 2 and further: Treatment will continue with Temodal® capsules 200 mg/m².
A total of 40 patients will be studied.
B. NODS®Cyclophosphamide
Are eligible patients with recurrent or refractory malignant disease for whom a treatment with oral cyclophosphamide is indicated. Patients will be treated with NODS®Cyclophosphamide 100 mg/m²/day for 14 consecutive days.
Cycle 2 and further: Treatment will continue with Endoxan® tablets 100 mg/m².
A total of 40 patients will be studied.
Considering the difficulties encountered with the TMZ and the delay in the project, it was proposed to switch from the NODS-CPM to another simple liquid formulation of cyclophosphamide: a drinkable solution with an easy and fast reconstitution.
1) Cyclophosphamide
The question of a need of bioequivalence study as requested with this new formulation has risen. This request was linked to the fact that NODS was a new formulation and no preclinical or clinical data were provided in the PIPs. With the CPM simple oral solution, it might be possible not to perform the bioequivalence in adults. Indeed, an IV CPM form is widely used by oral administration in children. Those data are not published in the literature, but it would be possible to collect clinical data (safety) from patient files.
In this context, the exemption of the bioequivalence study in adults was formulated:
The bioequivalence/bioavailability study will be performed directly in children. The study was redesigned as a prospective cross-over randomised trial with 2 cohorts to determine the relative bioavailability of oral cyclophosphamide compared to cyclophosphamide tablets (Endoxan®) to establish bioequivalence:
In cohort 1, 30 children aged more than 6 years will be recruited. Patients will be treated with oral cyclophosphamide 50 mg/m² for 28 consecutive days as follow:
Cycle 1:
Group 1
N=15 Group 2
N=15
Day 1
(PK sampling) cyclophosphamide oral solution
50 mg/m² Endoxan® tablets
50 mg/m²
Day 2
(PK sampling) Endoxan® tablets
50 mg/m² cyclophosphamide oral solution
50 mg/m²
Day 3
(PK sampling) Endoxan® tablets
50 mg/m² Endoxan® tablets
50 mg/m²
Day 4 – 28 Endoxan® tablets
50 mg/m² Endoxan® tablets
50 mg/m²
Cycle 2 and further: Treatment will be pursued with cyclophosphamide tablets or oral solution 25 mg/m² in addition to vinorelbine IV on days 1, 8 and 15 according to PK results.
In cohort 2, 24 children aged less than 6 years will be recruited. Patients will be treated with oral cyclophosphamide 50 mg/m²/day for 28 consecutive days as follow:
Cycle 1:
Group 1
N=12 Group 2
N=12
Day 1
(PK sampling) Cyclophosphamide oral solution
50 mg/m² Intravenous cyclophosphamide
50 mg/m² over 1h
Day 2
(PK sampling) Intravenous cyclophosphamide
50 mg/m² over 1h Cyclophosphamide oral solution
50 mg/m²
Day 3 – 28 Cyclophosphamide oral solution
50 mg/m² Cyclophosphamide oral solution
50 mg/m²
Cycle 2 and further: Treatment will continue with cyclophosphamide oral solution
25 mg/m² in addition with vinorelbine IV on days 1, 8 and 15.
2) Temozolomide
Concerning the temozolomide, the decision either to go on with the NODS or to go on the alternative solution was postponed due to the lack of data.
On March 29 th, 2011 a pre submission Teleconference MEETING with EMA was held for the PIP application of orodispersible Tablets (oroDT) of cyclophosphamide.
The study will be designed with 2 cohorts as follows:
In cohort 1, the orodispersible tablet of cyclophosphamide will be compared to the currently marketed tablets in children older than 6 years, i.e. patients able to swallow intact tablets, who are due to receive an oral cyclophosphamide – based treatment for their malignant disease. This will establish the bioequivalence of the new formulation as compared to the old one. This will be a bridging study as advised by SAWP.
In cohort 2, the absolute bioavailability of orodispersible tablet of cyclophosphamide will be established by comparing the oral to the IV forms, in children younger than 6 years of age, i.e. unable to swallow intact tablets, who are due to receive a cyclophosphamide based chemotherapy for their malignant disease. This will serve as a scientific basis for the dose recommendation of the oral new formulation as opposed to the empirically-based old available tablets without any relevant pharmacological data in the young paediatric population. Absolute bioavailability of orodispersible tablet of cyclophosphamide will be established according to EMA guidelines (CPMP/EWP/QWP/1401/98).
The intent is to improve oral treatment for children with cancer who are due to receive protracted daily administration of cyclophosphamide by running an absolute bioavailability study in children.
The study will be run as a prospective cross-over randomised trial with 2 cohorts with the following objectives:
- to determine the bioequivalence of an oral liquid solution compared to tablets formulation of cyclophosphamide in children aged 6 years and more able to swallow intact tablets (cohort 1)
- to determine the absolute bioavailability of an oral liquid solution compared to intravenous form of cyclophosphamide in children aged less than 6 years (cohort 2).
In cohort 1, the oral liquid solution of cyclophosphamide will be compared to the currently marketed Endoxan® tablets in children older than 6 years, i.e. patients able to swallow intact tablets, who are due to receive an oral cyclophosphamide – based treatment for their malignant disease. This will establish the bioequivalence of the new formulation as compared to the old one.
Are eligible children aged 6-18 years, able to swallow intact capsules and with recurrent or refractory solid tumour for which prolonged daily administration of cyclophosphamide is indicated. Patients will be treated with cyclophosphamide 100 mg/m² for 3 consecutive days as follow:
– – Group 1
– N=15 – Group 2
– N=15
– Day 1
– (PK sampling) – Cyclophosphamide-liquid
– 100 mg/m² – Cyclophosphamide-tablets
– 100 mg/m²
– Day 2
– (PK sampling) – Cyclophosphamide-tablets
– 100 mg/m² – Cyclophosphamide-liquid
– 100 mg/m²
– Day 3
– (PK sampling) – Cyclophosphamide-tablets
– 100 mg/m² – Cyclophosphamide-tablets
– 100 mg/m²
– Day 4 – 10 – – No treatment – No treatment
– Day 11 – 28 – – Cyclophosphamide-liquid
– 50 mg/m² – Cyclophosphamide-liquid
– 50 mg/m²
Patients will be treated from day 11 to 28 with the orodispersible cyclophosphamide at 50 mg/m²/day assuming pharmacokinetic results are compatible with bioequivalence.
Pharmacokinetic sampling will be performed during three consecutive days. The 3rd day of pharmacokinetic will allow the assessment of intra-patient variability of pharmacokinetics which is insufficiently documented and the effect of induction of metabolism which has previously been reported with cyclophosphamide
Cycle 2 and beyond:
According to the clinician's decision and according to the pharmacokinetic results, treatment will continue with the orodispersible cyclophosphamide at a dose of 50 mg/m²/day given as single agent or at a dose of 25 mg/m²/day when given in combination with vinorelbine 25 mg/m² (administrated as an IV infusion on days 1, 8 and 15).
In cohort 2, the absolute bioavailability of the drinkable solution of cyclophosphamide will be established by comparing to the IV forms, in children younger than 6 years of age, i.e. unable to swallow intact tablets, who are due to receive a cyclophosphamide based chemotherapy for their malignant disease.. Absolute bioavailability of drinkable solution of cyclophosphamide will be established according to EMEA guidelines (CPMP/EWP/QWP/1401/98).
Are eligible children between 6 months and six years of age with recurrent or refractory malignant disease for whom prolonged daily administration of cyclophosphamide is indicated. Patients will be treated with cyclophosphamide 100 mg/m² for 2 consecutive days as follow:
– – Group 1
– N=9 – Group 2
– N=9
– Day 1
– (PK sampling) – Intravenous cyclophosphamide
– 100 mg/m² over 1h – Cyclophosphamide-liquid
– 100 mg/m²
– Day 2
– (PK sampling) – Cyclophosphamide-liquid
– 100 mg/m² – Intravenous cyclophosphamide
– 100 mg/m² over 1h
– Day 3-9– – No treatment – No treatment
– Day 10-28– – Cyclophosphamide-liquid
– 25 mg/m² – Cyclophosphamide-liquid
– 25 mg/m²
Patients will be treated from day 10 to 28 with the orodispersible cyclophosphamide at 50 mg/m²/day assuming pharmacokinetic results indicate adequate bioavailability
Cycle 2 and beyond:
According to the clinician's decision and according to the pharmacokinetic results, treatment will continue with the orodispersible cyclophosphamide at a dose of 50 mg/m²/day given as single agent or at a dose of 25 mg/m²/day when given in combination with vinorelbine 25 mg/m² (administrated as an IV infusion on days 1, 8 and 15).
➢ Regulatory point
We withdrew our PIP application for the development of a pediatric oral formulation of NODS cyclophosphamide in May 2010.
Indeed, we have decided early 2010 to abandon the project to formulate cyclophosphamide in NODS particles due to pharmaceutical issues.
We have developed an orodispersible tablet (three dosages) of cyclophosphamide in order to address the need for age appropriate formulation of this widely used drug, a need that has been addressed in the priority list.
Thus we do have a completely different product as compared to the first PIP we submitted. However, the needs and the rationale are the same.
A pre submission Teleconference meeting with EMA for the PIP application of orodispersible Tablets (oroDT) of cyclophosphamide was held on March 29 th, 2011.
The Paediatric Investigation Plan (for cyclophosphamide orodispersible) was submitted on 09/05/2011 to the European Medicines Agency (EMEA). After validation, procedures for PIP started on the 15/06/2011. The day 60 (the 12/08/2011), the summary report was sent by the PDCO.
The PDCO day 60 report was very encouraging with no blocking questions.
The protocol has been submitted to the French ethical committee and has been approved on the 05/04/2011.
➢ Temozolomide
As presented several alternatives for the galenic preparation of temozolomide have been tested
However, to date, there is no galenic formulation for a liquid preparation of temozolomide that fulfils the requirements (for the patient and for the environment).
We do not have a formulation of temozolomide ready to go for clinical development,
➢ Operational and administrative aspects :
The clinical trial will be sponsored and run by the academic partners involved.
The O3K CPM trial has been submitted to ITCC network and has been accepted by ITCC Clinical Trial Committee on 28/01/2011. The opening of new countries and centres can make easier and accelerate the inclusions of patients in the study. The CPM’s trial has been proposed to 2 other countries: The Netherlands and Germany (members of ITCC network). The objective is to assure the recruitment in less than 18 months.
Sponsoring will be set up according to a co-sponsoring agreement that has already been implemented to run three academia-sponsored phase I and II trials of the European consortium for Innovative Therapies for Children with Cancer (http://www.itcc-consortium.org). There will be a coordinating sponsor and four co-sponsors.
Five co-sponsors will be in charge of administrative process in each of the three member states:
Università Cattolica del Sacro Cuore (P3) for Italy
Newcastle university (P2) for the United Kingdom
IGR for France (P1)
ERASMUS for the Netherlands
Universitätsklinikum Freiburg for Germany
Their role will be to set up the sponsoring administrative process in each country (i.e preparation of the specific national part of the dossier; submission to the regulatory national regulatory and ethic committee (s)) for both studies). Each partner will be in charge of writing the information sheet and consent forms, and asking parents association for review.
A co-sponsorship agreement will be established and signed in between the five institutions.
Thirty one centres will participate to the CPM clinical trials:
- 11 centres in France which are part of the Pharmacology Group of the French Society of Paediatric Oncology, running phase I, phase II trials and pharmacology studies together
- 9 centres in the United Kingdom which are part of the CCLG and have been selected to run phase I, phase II and pharmacology studies nationally.
- 5 centres in Italy which are part of AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica), running phase I, phase II trials and pharmacology studies.
- 3 centres in Germany which are part of ITCC running phase I, phase II trials and pharmacology studies
- 3 centres in Netherlands which are part to ITCC running phase I, phase II trials and pharmacology studies
UNAPECLE (P9) will review the protocol, information sheet and the patient diary. In addition, UNAPECLE will watch closely over the ethical issues during the project to assure that those issues are properly addressed.
➢ Ethical part:
1. Ethical aspects within the project
Due to the specific population of our O3K project (children between 6 months and 18 years) , the EC asked us in November 2007, to revise our ethical part according to the guidelines and recommendation, and to demonstrate our understanding and implementation of ethics in relation to our project.
According to the ESR (evaluation summary report) of European Commission, we added an Independent Ethics Standing Committee (IESC) in the Annex 1 of the project composed of 3 independent experts (3 in ethics UK, It, Fr).
Experts should not be members of parents organisation, and totally independent of partners. There will be one ethics expert from each member state.
Mission of the IESC :
➢ Review of the protocol before submission to National Ethics Committees
➢ Review of the Patient information package (information sheet, consent form, booklet)
➢ Every 6 months, the IESC will state whether or not ethical issues were raised at the individual level. Every 6 months, the IESC will receive from the sponsor the list of registered patients with relevant information (how patients agreed to participate to the trial, how and who asked for their participation...)
The IESC was constituted and met for the first time on 12/01/2009
The members of the IESC are:
_Chantal Aubert-Fourmy (French ethical expert, coordinator of the paediatric committee of the CNCP (Conférence nationale de comités de protection des personnes),
- Mary Dixon-Woods (Professor of Medical sociology, University of Leicester UK)
- Dr Marina Cicerone (member of the Ethical Committee at the Catholic University of Rome)
Chantal Aubert-Fourmy worked on the French information sheets
She advised to set up 4 information sheets (IS):
- One IS per parent
- One IS for major patient (similar than parents)
- One IS for children [12-17[ (similar than parents)
- One IS for children [6-12] (suitable document)
- One IS for children < 6 (illustrated and simplified document)
Those sheets will be then translated in each language of the member state participating to the trials.
3.4. Overview of the expected and achieved results related to WP5: Pharmacokinetic evaluation
University of Newcastle (Partner 2) is WP5 leader
Project leader: Gareth Veal, Newcastle, UK
Key Objective
To define the bioequivalence of cyclophosphamide when administered as a drinkable solution in a paediatric population. This will involve a direct comparison of the pharmacokinetics of this agent when administered by the currently accepted best practices (cyclophosphamide – i.v. infusion and oral administration of tablets)
Work description
A limited number of blood samples will be collected prior to and following administration of a drinkable solution of cyclophosphamide in paediatric populations. In addition, to directly compare pharmacokinetics of the drinkable formulations with current standard practice, samples will also be collected following administration of intravenous cyclophosphamide and oral cyclophosphamide tablets. The defined collection times will be optimally selected based on pharmacokinetic datasets obtained from previously studied paediatric patient populations. Limited sampling approaches will be used whenever possible so as to minimise the inconvenience to the patients and to minimise total blood volumes being taken from young children.
Plasma will be immediately separated from blood samples and stored at -20°C until shipment to the appropriate analytical reference laboratory. In addition to the collection of samples for pharmacokinetic analysis, information relating to the exact timing of drug administration, dose of drug administered, pharmacokinetic sampling times and concomitant therapies will also be collected.
All samples for cyclophosphamide analysis should be sent directly to the analytical reference laboratory in Newcastle (Dr Gareth Veal, Northern Institute for Cancer Research, Newcastle University) following collection. This immediate processing and transport of clinical samples is required in order to perform the dosages for the interim analysis concerning the first 8 patients in cohort 1.
Cyclophosphamide and metabolites will be assayed in plasma using a recently developed liquid chromatography tandem mass spectrometry (LC/MS/MS) method. This method has been optimised and validated as part of the WP5 programme, in a lead up to the analysis of clinical samples. All samples will be analysed to quantify concentrations of cyclophosphamide and its major metabolites dechloroethylcyclophosphamide (DCCP), ketocyclophosphamide (KetoCP) and carboxyphosphamide (CXCP). This assay has been fully validated (linear range: 0.05 – 10.0 µg/ml) and has recently been used successfully to analyse samples from cyclophosphamide pharmacokinetic studies involving approximately 25 children (>200 samples analysed). These studies will build on previously published data from the group in Newcastle relating to cyclophosphamide pharmacokinetics in children (Yule et al., 2004; Chinnaswamy et al., 2011).
Pharmacokinetic parameters will be calculated using non-compartmental analysis. The following pharmacokinetic parameters will be reported:
− Cyclophosphamide : Tmax, Cmax, absorption half-life, elimination half-life, AUCt (AUC measured at last point), AUC∞ (AUC extrapolated to infinity), Clearance/F corrected for BSA , Volume of distribution/F corrected for BSA
− Carboxyphosphamide (CX): Tmax, Cmax, AUCt (AUC measured at last point), AUC∞ (AUC extrapolated to infinity) ratio to cyclophosphamide AUC
− Dechloroethylcyclophosphamide (DCCP) : Tmax, Cmax, AUCt (AUC measured at last point), AUC∞ (AUC extrapolated to infinity), ratio to cyclophosphamide AUC
− Ketocyclophosphamide (KETO) : Tmax, Cmax, AUCt (AUC measured at last point), AUC∞ (AUC extrapolated to infinity), ratio to cyclophosphamide AUC
Statistical analysis will describe the main pharmacokinetic parameters as means, SD, 95% Confidence interval, medians, minimum and maximum. In addition, Clearance/F, Volume of distribution/F and elimination half-life will be calculated using a non-compartmental method.
AUC∞ is the most reliable reflection of the extent of absorption. Individual bioavailability (F) will be defined as the ratio of AUC∞ of cyclophosphamide after a drinkable solution of cyclophosphamide to that of IV cyclophosphamide. Absolute bioavailability will be expressed as mean, SD, 95% confidence interval, median, minimum and maximum. Considering available data in adults and the wide interpatient variability, it is expected that F will lie within an interval of 60 to 100% with a substantial inter-patient variation.
Individual AUC∞ ratios for the measured metabolites will be calculated and expressed as mean, SD, 95% confidence interval, median, minimum and maximum. Those ratios will help to identify the potential impact of first-pass intestinal and hepatic metabolism.
To describe the pharmacokinetics and metabolism of cyclophosphamide following administration, a population based analysis using NONMEM will be performed to better identify the covariates explaining the inter-patient variability.
An assay has been optimised and fully validated to allow the quantification of cyclophosphamide and its metabolites in clinical samples obtained from children with cancer. No analysis of clinical samples has been started because no patients have been recruited to the clinical study.
3.5. Project management during the period
Consortium management tasks and their achievement
o Ensure the proper scientific management of the project in order to strengthen and support the participants to achieve the objectives, complete the milestones in time and deliver the deliverables.
o Make sure that the consortium’s contractual duties are carried out. Advise and guide the Participants to comply with the EU regulations and their contractual and legal requirements. Abide by the "good practice" of resources management as presented in the Financial Guidelines.
o Set-up an effective communication infrastructure and foster the integrative process within the consortium.
o Manage the processes for the capture and the protection of intellectual property, including confidential information and patents properly.
The following tasks were performed during the period:
3.5.1. Consortium management tasks and their achievement
Management of legal issues:
o A consortium agreement was established, discussed with partners and their legal departments, agreed and signed by all partners´ legal departments.
Communication Management:
o Key aspects were communicated to or discussed with the Scientific Officer of the European Commission
o Regular Phone conferences with the Coordinator and relevant partners were carried out to discuss actual progress within the project.
Project Controlling (including Reporting):
o To oversee the compliance of the project with the EU provisions (grant agreement and its annexes) and the Consortium Agreement
o To prepare templates concerning the extent, structuring and the description depth of information on the status of the project and the progress
o To manage the due-process submission of reports (according to the reporting guidelines for FP7)
o To coordinate the submission of deliverables and milestones particularly with the WP leaders
o To monitor and regularly present the status and progress to the board.
o The consortium successfully managed a defaulting partner (Oralance) which was taken out of the consortium in respect to all EU guidelines and procedure. During this period, the Scientific Officer (Mr Donnely) was kept informed of all actions and decision in a timely fashion.
o In addition, the Coordinator and the partners responding in a timely fashion to all reports and documents asked by the DG research in the evaluation process of the submitted amendment.
Finance Management:
Activities were as follows:
o The pre-financing payments were coordinated and transferred to the participants
o Monitor costs vs. budgets on an periodic basis
o Report on financial issues as required by the reporting guidelines
o Support all partners with issuing and obtaining Form Cs in due time
o Close cooperation with the administration departments of the involved parties and with the financial officer at the European Commission
Meeting Organisation:
Organisation of effective meetings of the Consortium:
o Several teleconference meetings with partners (board meeting, WP meeting)
o Extraordinary general assemblies
Organisation comprises the following tasks:
o support with the meeting preparation for the WP leaders (focus, templates, structuring)
o follow-up of points agreed at the meetings, therefore writing and circulation of minutes and monitoring of pursuance.
Deviations and management:
March 29th 2010, the O3K Consortium considers that ORALANCE was a defaulting party, and thus, was asked to leave the consortium, as defined by the consortium agreement, in full respect of the FP7 rules and guidelines.
On May 11th2010, a request for an amendment was sent to the European commission that includes:
Modification of duration
The duration of the O3K project specified in Article 3 of the grant agreement is modified as follows: New duration: 36 + 18 = 54 months
Addition of one beneficiary
Andrieu Consultant International, to provide the Project with the needed pharmaceutical and regulatory expertise needed to move forward the project.
End date of participation:
The participation of the following beneficiaries is terminated from the date specified in the following table: ORALANCE, legal Form: liability company 29th of march 2010
Termination at the initiative of the consortium and approved by the partner (letter on April 21st, 2010)
Different amendments with description of work have been sent in November 2010, March 2011 and May 2011
3.5.2. Changes in the consortium, if any
- Decision of University from Leicester (P7) to withdraw from the project
The University of Leicester (Partner 7) was an O3K partner with the goal to sponsor the clinical trials in the UK. Due to national decision in the UK, the CCLG Trials Centre in Leicester was closed and the University of Leicester was no longer in a situation to sponsor the O3K Trials. Partner 7 decided to leave the O3K consortium. The consortium decided to move the responsibility of sponsoring the trials in the UK to Newcasttle, partner 2.
- Oralance: the company has gone into receivership (December the 28th) and the consortium was informed by mail on the 17/01/2010. In order to be as transparent as possible, we informed our EC officer (Mr Donnely) on19/01/2010.
On March 29th, 2010, after the implementation of the process stated in the consortium agreement and with respect to EU FP7 rules, the O3K Consortium unanimously considered that ORALANCE was a defaulting party, and thus, Oralance was asked to leave the consortium, as defined by the consortium agreement.
Addition of one or more beneficiary (ies)
Full name and legal form of the beneficiary Start date of participation
Institute Of Child Health, Research Organisation established at 30 Guilford Street, London WC1N 1EH, represented by its Director, Professor Andrew Copp and his deputy, Professor Peter Scambler 1st of April 2010
Andrieu Consultant International (FR 48 494 939 796) established in France (le Valencay 2, 122 rue du commandant Rolland, 13008 Marseille), represented by Veronique ANDRIEU (Manager). February 28th 2010
Changes in responsibilities
Not applicable.
On a WP level
As Oralance left the consortium, Negositek became WP2 work package leader
3.5.3. List of project meetings, dates and venues:
2 types of coordination meeting are foreseen during the project
- General Assembly meetings gathering all the consortium
- Project board meetings gathering IGR, Keocyt, Newcastle and Negositek
-
Organisation comprises the following tasks:
o support with the meeting preparation for the WP leaders (focus, templates, structuring)
o Follow-up of points agreed at the meetings, therefore writing and circulation of minutes and monitoring of pursuance.
O3K meetings:
Date Place
Kick-off meeting 15/09/2008 Villejuif
Project board 30/10/2008 Phone meeting
Project board 19/11/2008 Phone meeting
Project board 11/12/2008 Phone meeting
Project board 21/01/2009 Phone meeting
Project board 24/02/2009 Phone meeting
Project board 16/04/2009 Phone meeting
Project board 13/05/2009 Phone meeting
Project board 27/06/2009 Phone meeting
Project board 27/08/2009 Phone meeting
WP2 meeting (with P1, P5, P6, P8) 09/09/2009 Villejuif
WP2 meeting (with P1, P5, P6, P8) 08/10/2009 Labège
General Assembly 12/10/2009 Villejuif
WP2 meeting (with P1, P5, P6, P8) 06/11/2009 Labège
WP2 meeting (with P1, P5, P6, P8) 04/12/2009 Phone meeting
WP1/WP2/WP3 meeting 31/12/2009 Villejuif
CPM pharmaceutical meeting 04/02/2010 Villejuif and phone meeting
Extraordinary General Assembly 1st 17/02/2010 Villejuif
Extraordinary General Assembly 2nd 29/03/2010 Villejuif and phone meeting
Extraordinary General Assembly 3nd 30/06/2010 Villejuif and phone meeting
Project board 13/07/2010 Phone meeting
Project board 18/10/2010 Phone meeting
WP2 meeting 06/12/2010 Bertin pharma
Project board 17/12/2010 Phone meeting
Project board 17/01/2011 Phone meeting
WP2 meeting (with P1, P5, P6, P8) 9/03/2011 Phone meeting
WP2 meeting (with P1, P5, P6, P8) 15/03/2011 Phone meeting
WP2 18/03/2011 Phone meeting
WP2 meeting (with P1, P5, P6, P8) 13/04/2011 Phone meeting
Extraordinary General Assembly 4st 26/04/2011 Villejuif and phone meeting
Project board 14/06/2011 Phone meeting
WP2 meeting (with P1, P5, P6, P8) 30/06/2011 Villejuif
3.5.4. Problems which have occurred and solutions provided
As a brief reminder,
01/09/2008: Start of the project with agreement on retroactivity procedure. We consequently all together decided to operate and incur costs before having the GA signed (9 months).
07/05/2009 by IGR and 09/06/2009 by EC: Grant Agreement is signed
18-19/06/2009: Reception of the 1st EC contribution & funds sent to partners. Thus, it took 9 months to receive funding for the project. Since, per the project, the first 6 months of activity were mainly dedicated to the development of the two pharmaceutical formulations by Oralance, the project could only start in fact in June 2099 instead of September 1st, 2008.
17/02/2010 Extraordinary General Assembly (we present the external expert report on Oralance’s work)
02/2010: Regular exchanges with the EC officer to maintain perfect transparency
More specifically, several problems arose during the first period.
- The negotiation of the O3K consortium agreement was longer than foreseen because of the long process of negotiations of some partners. This delay involved a delay in the payment to the consortium of the first advance received from the European Commission. We consequently all together decide to operate and incur costs before having the funding. However, due to its financial situation ORALANCE could not start working on the project before receiving funds.
- Early December 2009, there was a disagreement in between K. Ioualalen (ORALANCE, WP2 project leader) who considered that both the NODS-TMZ formulation and the clinical formulation were validated, and the Project board who considered there were still major issues to be solved.
To allow the Project Board to evaluate documents and to assure its relevance with technical and regulatory requirements, Gilles Vassal asked Véronique Andrieu (Ph. D in pharmaceutical sciences, Pharm. D) an external expert with a strong expertise in galenics and regulatory issues working at the French Drug Agency, to state on the TMZ data. Her evaluation concluded that the NODS-TMZ data do not fulfil the requirement for an IMPD submission and that the results are not sufficient in terms of safety, concentration, and reproducibility to go forward on the project
The final decision, not to continue the cyclophosphamide development with the NODS technology, was taken by the entire consortium during the Extraordinary General Assembly on February 17th.
We proposed during the extraordinary general assembly that took place on the 17/02/2010 to switch the development of NODS-cyclophosphamide and NODS –temozolomide into an alternative formulation of both drugs to propose a liquid oral formulation that will fit the paediatric needs. This was the major goal of the project.
▪ For Cyclophosphamide, two orientations have been chosen: Cyclophosphamide Aqueous solution and dispersible tablets.
▪ For Temozolomide, the formulation work was undertaken according to 2 different approaches:
- Suspension formulation
- Dispersible tablets
Cyclophosphamide trials were more advanced than temozolomide ones. Priority has been given to the cyclophosphamide development;
However, after several attempts, the chemical bottlenecks in developing a liquid formulation of temozolomide were not solved and it has been decided to stop the pharmaceutical development plan of temozolomide and to put together all resources in the cyclophosphamide development plan.
On April 2010, we submitted a request for extension of 18 months to finish the project. This extensionwas requested to run the full clinical development with the new galenic formulation, as specified on
27th April 2010 GA report.
This issue was discussed with Dr Ruxandra Draghia –Akly In July 2010 And she proposed a go/no go decision process
It was agreed we will first complete the pharmaceutical development with the new galenic formulation
and then define the appropriate extension to run and finish the program. The request for an extension
was to be submitted within 12 months of the end of project.
This annex amendment requests an extension of 9 months (with no request for additional budget) and includes all the preliminary data that we have generated until this date, May 2011.
As discussed in mail correspondence with Alexandru Costescu on April 15 th and approved by the consortium on April 26th, an additional 9 months extension could be agreed as needed by the conduct of the clinical trial.
It was agreed that a report will be provided at M42 for a go/no go decision to extend the project for an additional 9 months..
We were notified in May 2011 that this amendment was not accepted and we were told in June 2011 that DG research wanted an evaluation by 3 external experts. The consortium prepared and sent all documentations required.
To speed up the evaluation (indeed the decision of an external evaluation was taken at M34 of the project), it was decided in agreement with the scientific officer to hold an on-site meeting with experts on August the 17th 2011. .
On August 16th 2011, we were notified by email by A Costescu that he cancelled the meeting which was already organised;
on the 31st of august 2011, ie the last day of the M36, Gilles Vassal, the scientific coordinator, sent a letter to the entire consortium in order to specify that:
• An external evaluation of our requested amendment was ongoing
• Only two ongoing activities will continue because they could not be stopped and they were crucial for the continuation of the project if the outcome of the evaluation were positive:
o stability studies to generate the necessary information for the IMPD and the preparation of the clinical batches
o the PIP evaluation process which was at the stage of day 60 report
AT that time, no other activity was ongoing within the consortium since we were waiting for starting the clinical trial. Partners were diligently asked not to start any new activities which cost would be inferred to the O3K funding
Outcomes of the O3K cyclophosphamide project beyond M36
• The PIP was approved by EMA and PDCO in December 2011 and published in January 2012
• The stability studies were positive at 1 months, 3 months and 6 months
• The clinical batches were prepared and were available in May 2012
• The final clinical trial protocol including the IMPD was approved in France by the national competent authority and the ethic committee in July, 2012.
• The cyclophosphamide trial was ready to be launched in 30 July 2012.
• A patent of the new cyclophosphamide formulation was submitted in November 2012.
Potential Impact:
O3K will have important strategic impacts on economy, European competitiveness, and societal problems.
Thanks to the European Regulation for Paediatric use of Medicinal products, paediatric drug development becomes an economically attractive domain.
The ultimate goal of the O3K project, to be taken forward upon completion of the project, is to commercialise and to distribute two new medicinal products for children with cancer in Europe. In addition, by establishing the proof-of-concept of the use of drinkable suspension to develop age appropriate formulations of anticancer drugs, other compounds, including those of the EMEA list, may be developed. Moreover, this technology could be used to develop age-appropriate formulations for innovative targeted compounds developed by Big Pharmaceutical companies. Indeed, the specific paediatric needs for these innovative compounds will have to be addressed according to the EU Regulation on the Paediatric use of Medicinal Products. Altogether, this will adequately answer the needs for old products, as well as new products, and potentially create a healthy economic activity in the field of orphan drugs.
Thus, O3K will reinforce European competitiveness on several points:
By bringing together a network of paediatric oncology clinical investigating centres, (4 institutions committed to sponsor and develop clinical research in paediatric oncology, 2 pharmacology research laboratories with internationally recognised expertise in the field of paediatric oncology), 3 SMEs dedicated to drug development and 1 Parents Organisation, the O3K project will synergize research & development initiatives and create a critical mass of expertise and skills in the field of paediatric oncology and pharmacology research at the European level. The O3K project is a well-focussed project and is likely to generate in the mid term innovative and economically healthy activities.
The consequences are, first, a better working collaboration, financial and technical compatibilities and thereby a harmonisation of European research. By using new technologies and a significant level of oncology expertise, the O3K will advance the European role in drug development in children and strengthen a new R&D domain, namely drug research for children.
Concerning the solving of societal problems, more than 16000 children develop cancer each year in Europe. Despite improved survival rates with currently used multimodality treatments, cancer remains a life-threatening disease in children and represents the primary cause of death by disease in children over 1 year of age with more than 4 000 children dying of cancer each year in Europe. This is a major human health issue for the paediatric population. Safe and efficacious drugs are needed, as outlined by the EU regulation, to improve further cure and quality of life of children with cancer. The O3K project will contribute to the success of the EU Paediatric Medicines Regulation by providing child-appropriate formulations for two off-patent drugs.
The major impact will be for children and parents. The new child-appropriate formulations in oncology will improve safety, quality of life of children and their family and security of the environment. Development of ambulatory treatment with well-studied oral chemotherapy will be feasible and will help to improve quality of life of children, parents and family.
Long term impacts: The two drugs will be marketed and distributed. It is expected that an economically healthy activity will be generated from the O3K project.
There is an urgent need for appropriate oral formulations of anticancer drugs for the treatment of paediatric malignancies in children of all ages. The goal of the O3K consortium is to develop oral liquid formulations of Cyclophosphamide and Temozolomide, important chemotherapeutics which have been identified in the list of paediatric needs by European MEdicines Agency (EMEA/197972/2007).
Both off-patent drugs are widely used orally for the treatment of childhood cancer. However, the currently available tablets (Cyclophosphamide) and capsules (Temozolomide) are not suitable for use in a paediatric setting, particularly in infants and young children, as it is often impractical for them to be swallowed. This is a major health concern since these children do not readily have direct and safe access to these curative drugs.
O3K conducts the pharmaceutical, clinical and pharmacological studies required for the development of these oral liquid formulations. Upon completion of the project, a dossier containing data required for application for a Paediatric Use Marketing Authorisation (PUMA) will be filed for both products. O3K will provide access to curative drugs for all children with cancer, improving compliance, ensuring safety for both patient and environment and allowing the development of essential ambulatory treatments.
In accordance with ICH guidelines, the development of these agents leads to improved quality and safety of paediatric drug formulations. The O3K project involves 9 partners (including 5 institutions and 3 SMEs providing significant expertise in clinical and pharmacological research relating to paediatric oncology along with 1 parents organisation) from three European member states (UK, Italy and France).
Initially, pharmaceutical development started using a new drug delivery technology named “Oralance Technology”.
Thus, for pharmaceutical and safety reasons, it was decided to give up the Oralance technology in the O3K development. It has been decided to redirect the formulation plan and the formulation plan was then focused on the development of a dispersible/soluble tablet which could be dissolved in a glass of water prior to administration.
Development of cyclophosphamide
A new formulation of cyclophosphamide (soluble tablets) has been successfully developed. The stability studies are ongoing. The IMPD is in preparation: the 3 months stability results will be added.
The clinical trial protocol has been submitted to the regulatory authorities and to ethical committee (approved by the ethical committee), and the Clinical trial is a part of the paediatric investigation plan which is in advanced evaluation by the PDCO at the European Medicine Agency (>day 60 report)..
Development of temozolomide
Several alternatives for the galenic preparation of temozolomide have been tested.
However, to date, there is no galenic formulation for a liquid preparation of temozolomide that fulfils the requirements (for the patient and for the environment).
The pharmaceutical development of temozolomide has been stopped at this step.
Project Context and Objectives:
The new EU Regulation on medicinal products for paediatric use (EC1901/2006) came into force on January 26th 2007. This regulation aims to improve the health of children in Europe by:
o Stimulating research and development of medicines for use in children
o Ensuring that medicines used to treat children are appropriately tested and authorised
o Improving the availability of information on the use of medicines in children
The absence of suitable authorised medicinal products to treat paediatric diseases is an issue that has been of concern for many years. Consequently, healthcare professionals (i.e MDs, Nurses) frequently resort to the preparation and administration of unlicensed formulations by manipulation of adult dosage forms.
The new EU regulation introduced major changes to the marketing authorisation required for patented as well as for off-patent drugs. Among them, the specific Paediatric Use Marketing Authorisation (PUMA) intends to stimulate research and development of off-patent products to improve their use in children. In particular, there is an urgent need for appropriate paediatric formulations of several oral off-patent drugs in order to allow accurate dosing, safe use and enhanced patient compliance.
The needs of additional information for the use of off-patent medicines in children have been identified and listed by the EMEA paediatric expert group (EMEA/496777/2006), and revised on June 2007 (EMEA/197972/2007). This list includes 27 off-patent oncology products. Nine of them are oral drugs that need age-appropriate formulation.
The goal of the Oral, Off-patent, Oncology drugs for Kids (O3K) project is to develop child-appropriate liquid formulations of cyclophosphamide and temozolomide, using this new technology. Temozolomide (TMZ) and cyclophosphamide (CPM) are widely used for the treatment of paediatric cancer and both drugs are included in the list of paediatric needs established by the EMEA.
Two liquid formulations of Cyclophosphamide and Temozolomide for daily oral administration in children will be developed with the goal to further submit a Paediatric Use Marketing Authorisation (PUMA) for both compounds. This will allow the administration of the exact dose along with a good bioavailability and improved compliance at all ages.
The O3K objectives are:
1. to secure the feasibility of developing the new oral formulations in terms of pharmaceutical aspects and to perform this work under the good manufacturing practices
2. to perform the non clinical, clinical and pharmacological development of a drinkable suspension of temozolomide for the purpose of a submission for a Paediatric Use Marketing Authorisation in the EU
3. to perform the non clinical, clinical and pharmacological development of a drinkable solution of cyclophosphamide for the purpose of a submission for a Paediatric Use Marketing Authorisation in the EU
Progress beyond the state-of-the-art
• Drug development is needed in paediatric oncology
Childhood cancers represent a rare disease accounting for less than 1% of the total number of cancer cases in humans. Across the whole of Europe, approximately 16 000 new cases of childhood cancer are diagnosed in children under the age of 19 each year (http://info.cancerresearchuk.org/news/pressreleases/2007/january/278356). Despite the high cure rates now being achieved for certain tumour types (e.g. 80% five year survival rates for Wilms tumour and acute lymphoblastic leukaemia), , cancer remains the major cause of death from disease beyond the age of 1 year with approximately 3000 children dying from cancer each year in Europe.
During the last 30 years, access to innovative therapies developed by pharmaceutical companies has been extremely limited for children in Europe, one reason being that Paediatric Oncology does not represent a large, and hence financially attractive, area for drug marketing. Most of the anticancer drugs currently used in children have been developed by academic groups through prospective clinical trials using the drugs and formulations available for use in adults. This allowed the generation of clinical and pharmacological paediatric data for compounds that eventually went off-patent. However, there are still data missing for many off-patent oncology drugs, due to the lack of commitment by pharmaceutical companies. In particular, age-appropriate oral formulations of many important anticancer drugs have not been developed.
• An increasing use of oral chemotherapy for the treatment of paediatric malignancies
o Oral chemotherapy is used on a daily basis to treat paediatric malignancies, and even more in the future
o Some drugs are indicated for oral use only. For example, oral temozolomide has gained popularity for the treatment of refractory brain tumours in children, 6-mercaptopurine is a major component of maintenance chemotherapy for acute lymphoblastic leukaemia and procarbazine has been an important drug for Hodgkin’s disease for many years. In addition busulfan is used at high dose before haematopoietic stem cell transplantation in place of total body irradiation in children, with an intravenous form of busulfan not available until very recently.
o Anticancer drugs currently administered intravenously are given orally in order to allow protracted administration or ambulatory treatment. Daily oral etoposide is used for the palliative treatment of a variety of many solid tumours. For the use of metronomic therapy, cycloclophosphamide is given orally at low daily doses, thus allowing the prolonged exposure to optimal low concentrations believed to be cytotoxic to tumour endothelial cells.
o Oral chemotherapy facilitates ambulatory treatments and provides flexibility, improved quality of life, and reduced financial cost. Oral chemotherapy is especially attractive for the treatment of children, particularly in the setting of disease relapse.
o Many innovative targeted compounds that will eventually be indicated in children are given orally, at low daily doses, for protracted administration. For example, there is evidence to suggest that oral targeted drugs such as EGFR inhibitors (erlotinib, gefitinib), mTOR inhibitors and antiangiogenic compounds (sorafenib and sunitinib) may have antitumour activity against paediatric malignancies.
• Appropriate oral formulations for children are not available for most of these compounds and this has major consequences
o Most oral anticancer drugs are only available in tablet or capsule form at inappropriate dosages for a paediatric population. In practice, many children cannot swallow adult tablets or are averse to the taste of adult medicines, especially those below the age of six years.
o This has been clearly established by the EMEA classification of dosage forms (reflection paper “formulations of choice for the paediatric population” (EMEA/CHMP/PEG/194810/2005) which states:
- “a major concern is at what age children can safely swallow solid oral dosage forms such as tablets or capsules. Again this is generally a factor of age and health status but there are significant inter-patient differences around an average of about 6 years”.
- “oral tablets and capsules are not applicable for preterm newborn infants, term newborn infants, infants and toddlers. Oral capsule is applicable with problems for children between 2 and 5 years and oral tablet is probably applicable, but not preferred for children between 2 and 5 years. Oral tablet and capsule have a good applicability only for children 6 to 11”
o The prescribed dose for a child may be less than the smallest available formulation dosage, which has been design to fit adults needs. Although most tablets are scored, the requisite dose may still be less than in half the tablet, in particular for the youngest children. In these situations the tablets have to be fractioned or the capsules opened and the contents divided. This practice may result in substantial inaccuracy in dosing and may potentially jeopardize the effectiveness of treatment. Doctors and other health care specialists trying to treat children appropriately face a difficult dilemma: giving nothing or trying to adapt an adult medicine to paediatric use . Clinical practices to deal with the dosing issues are not easy to standardize, and heterogeneity of drug exposure from a patient to another one may impact the efficacy of the treatment. In addition, health care providers have to deal with the tablets or capsules that are available. For example, when a compound is to be given daily, the entire dose for one week is given on 4 or 5 days.
o In other situations, intravenous formulation may be given in the form of a drinkable solution. However, this may increase the risk of serious adverse reactions or inappropriate dosing due to poor or inconsistent bioavailability.
o Oral administration of anticancer drugs is a major concern in children under the age of three years. This is particularly important as paediatric malignancies in children under the age of three represent 30% of all paediatric cancers.
The New Oral drinkable formulations will allow easiness of use and flexibility of administration doses depending on the age and body surface of kids.
➢ Cyclophosphamide :
A CPM IV dosage form is available on the market (Endoxan®) and the IV formulation is very simple at 20mg/ml. This IV dosage form is widely used orally in children (off label use) with a good acceptability.
Using cyclophosphamide is safe for the environment since this is an inactive pro-drug that requires liver enzymatic by CYP450 to generate alkylating moieties.
Then, we propose to develop a drinkable solution of cyclophosphamide, with an easy and fast reconstitution.
The drinkable solution of cyclophosphamide will be developed with the following objectives:
- to develop a drinkable solution allowing easiness of use and flexibility of administration doses depending on the age and body surface of kids.
- to guarantee good tolerance of the formulation using well tolerated and agreed excipients for paediatrics
- to insure physical and chemical stability during storage and use as well as relevant safety of handling and use in ambulatory treatment situations
- to control accuracy and reproducibility of doses delivery with a suitable formulation and appropriate dosing device
- to have a manufacturing process allowing industrial scale for commercial supply
- to guarantee regulatory compliance
The goal is to have appropriate physical properties of the dosage form for a reliable manufacturing process.
Depending on the critical parameters encountered (reconstitution time and physical characteristics of powder for reliable process, stability of cyclophosphamide), 4 development options are envisaged:
- A simple distribution of the API in vials together with aroma
- A dry blend formulation combining API with excipients
- A powder granulation formulation consisting in associating excipients to the API under humid conditions followed by a drying phase.
- An orodispersible tablet formulation having the property to dissolve immediately (within one minute) when in contact with water.
- This last one has been selected.
➢ Temozolomide:
Considering the current state of pharmaceutical knowledge on temozolomide, a drinkable suspension of temozolomide consisting of a coated granulate powder has been proposed. Indeed, the marketed capsules have common excipients and are manufactured according to a classical process. However, the critical parameter regarding Temozolomide will be to develop a dosage allowing to prevent any contact and environmental risk during administration but which releases without delay Temozolomide when in stomach. In other words, Temozolomide should not be released immediately when the formulation is reconstituted in water but should be release at the stomach stage.
The drinkable suspension of temozolomide will be developed with the same objectives than cyclophosphamide and to be safe for the environment.
The main point of the paediatric suspension development is to avoid or slow down the release of temozolomide from the granulates into water after reconstitution of the suspension, but maintain immediate release during administration in the stomach at the site of absorption.
Project Results:
3.1. Overview of the expected and achieved results related to WP2: Preclinical and pharmaceutical development for clinical evaluation
Oralance (Partner 5) is WP2 leader but Oralance left the consortium on 29/03/20010 and NEGOSITEK (Partner 8) became WP2 leader
Work Package 2 included the following steps:
- Pre-formulation studies
- Formulation
- Analytics
- Technical Trials and manufacturing
- Clinical Batches Supply
- NODS and clinical batches follow up during commercial development
Initially, pharmaceutical development started using a new drug delivery technology named “Oralance Technology”.
1°) Pre-formulation studies
This first step included a full physicochemical and biopharmaceutical assessment on both APIs as well as a screening of ingredients regarding solubility and compatibility of active ingredients. The next steps were physical stability (mainly API crystalline form and polymorphism risk study) in the ingredients as well as chemical stability.
Pre-formulation study was incomplete but allowed to show that it is possible to incorporate cyclophosphamide and temozolomide in Suppocire CM or its oral equivalent (Gelucire 39/01).
2°) Formulation
Formulation work was planned in 2 steps, the first being the NODS formulation and the second one related to the clinical formulation:
NODS formulation
NODS formulation work consisted in studying the formulation and process parameters allowing incorporating cyclophosphamide and temozolomide into the NODS matrix. Oralance showed that it was possible, at small scale (tens of grams) to incorporate (entrapment ratio) 10% of cyclophosphamide or 20% of temozolomide in a NODS Suppocire CM matrix.
A very few trials were made on cyclophosphamide only to demonstrate feasibility of entrapment. Oralance worked essentially on temozolomide.
Based on these first results, some scales up trials (at hundred grams scale) have been performed before starting the technology transfer at Elaiapharm (the subcontractor’s site).
Clinical Formulation
Clinical formulation work consisted of studying the association of NODS to other excipients (dilutants, lubricants, suspending agents...) in order to reach a powder formulation ready for reconstitution with water forming a homogeneous aqueous drinkable suspension.
The key defined parameters for a suitable formulation were:
- Appropriate powder mixture flowability properties
- Ease and rapid reconstitution of the suspension with water addition
- Homogeneity of dosing
- Safety for environment (no temozolomide at the NODS surface)
- Satisfactory physical stability (no sticking phenomenon) under accelerated stability studies (30°C and 40°C).
We obtained some formulation prototypes showing preliminary satisfactory results in terms of reconstitution when stored at 4°C or room temperature. However, when stored at 30 and 40°C, we observed sticking phenomena coming from the low melting point of NODS. Therefore, additional trials have been requested to Oralance for reducing sticking behaviour. Oralance worked on a different washing process for the NODS using ethanol. In addition, upon request of Negositek and Dr. Veronique Andrieu (Marseille University) made trials with the Gelucire 43/01 having a higher melting point.
The sticking phenomena were improved but not fully corrected and we encountered problems of API entrapment ratio as well as yield variability.
The entrapment ratio and yield variability was really a concern as it showed that the formulation and process were not reproducible and not under control. In addition, Oralance did not succeed to improve these parameters.
Furthermore, in vitro dissolution studies also showed variability in the API release kinetic and the curve profiles allowed us to suspect the presence of temozolomide at the NODS surface. An investigation was made using Raman spectrometry at a contract analytical services company (Drugabilis) but the results could not allow to clearly demonstrating the absence of API at the NODS surface. Therefore, the present clinical formulation prototype is not reliable.
In summary, formulations studies allowed to obtain some prototypes but those are not appropriate for a clinical study.
Although Oralance considered its formulation ready to go in clinical, Negositek stated clearly that the present formulation candidature cannot go further for technical, quality, safety and regulatory reasons.
3°) Analytics
Regarding analytics studies, Oralance worked only on temozolomide.
Analytical methods for API and NODS assay were tested but these methods were not fully validated.
4°) Technical Trials and Manufacturing
Technical NODS trials were performed at Elaiapharm on a placebo batch and on an active batch containing Omeprazol as an active tracer in replacement of temozolomide. Indeed, as temozolomide is a very expensive active, we did not want to launch any technical trial at real scale as long as the formulation and process be under control.
No technical batch for regulatory stability study was performed.
5°) Clinical Batches Supply
Given that no clinical formulation is available so far, no any clinical batch could be produced.
Conclusion
Deliverables of Work Package 2 were not reached at M18 for pharmaceutical and safety reasons. However, given the situation, Negositek and Keocyt were asked by the Project Coordinator to investigate and prepare the implementation of a new development plan using other formulation approach than the NODS one.
Negositek identified and proposed solutions for pursuing the project without using NODS technology.
A new development work started for cyclophosphamide in collaboration with Elaiapharm.
We decided to redirect the formulation plan and use fast track development methodology. Thus, in order to win time and because the drugs are well known, formulation work was undertaken without any pre-formulation study. However, we had to find an agreed subcontracting company for handling cytotoxic products. There are few companies having suitable capabilities for the manufacture of cytotoxic products. We rapidly identified Elaiapharm and we implemented a collaboration contract to perform the new formulation development of the two drugs.
Cyclophosphamide trials were more advanced than temozolomide ones. Priority has been given to the cyclophosphamide development.
CYCLOPHOSPHAMIDE
Cyclophosphamide aqueous solution
At first, the formulation work was oriented to a cyclophosphamide aqueous solution. Trials were performed to identify the relevant pH and concentrations for good stability of cyclophosphamide in solution. Unfortunately, the different trials demonstrated that there is no way to obtain a good stability of cyclophosphamide in aqueous solution.
Dispersible tablet
The formulation plan was then focused on the development of a dispersible tablet which could be dissolved in a glass of water prior to administration. Various formulations were tested according to two manufacturing processes: humid granulation and direct compression.
1) Formulation with Cellulose as diltutant
Different tablet formulations have been developed for three Cyclophosphamide strengths and tested according to their pharmaceutical characteristics:
- Compressibility
- Hardness
- Disintegration
- Dissolution
The choice of the dosage form and the composition of tablets were made taking into account the recommendations of the EMEA guideline EMEA/CHMP/ PEG/194810/2005.
All excipients are commonly used and are conform to the corresponding monographs of the current European Pharmacopoeia. Lactose which is widely used in tablet formulation was avoided because of the risk of lactose intolerance.
An interesting formulation candidate has been identified for performing stability studies and first stability studies were launched at Elaiapharm.
A new development site was rapidly found for the project because Elaiapharm was bought by Lundbeck Company which decided to close the cytotoxic area. Manufactures and analytical know how were transferred in a few months to Bertin Pharma
o Stability
Stability results of tablet batches with three doses of Cyclophosphamide manufactured by Elaiapharm at T0 and after one month show that there was a degradation of the active substance. Because the tablet packaging was permeable, it was concluded that degradation of Cyclophosphamide was due to the presence of humidity or water during the stability study.
ICH long term stability studies started on three batches of dispersible tablets: one batch per dose.
It is to be noticed that, according to the different Summary of Product Characteristics, the current Cyclophosphamide marketed formulations are to be stored below 25°C.
However, the stability data show a significant increase of impurities especially the monochloro impurity after 3 months of storage at 25°C / 60% RH.
Monochloro impurity increases in presence of water. At this stage, cyclophosphamide dispersible tablets were packaged in PVC/PVDC blister which is not a high protective packaging with regard to water.
Therefore, in order to guarantee proper stability of the tablets, we decided to launch new stability studies in different more protective packaging.
-PVC/PVDC blisters (present reference)
- Aluminium/Aluminium blisters
- Glass bottles
- Polyethylene bottles with desiccant cap.
It is to be noticed that glass bottles and Aluminium/Aluminum blisters are already used for marketed dispersible tablets.
• Initial level of monochloro impurity at T0 is from 0.15% to 0.28% depending on the dosage strengths
• Endoxan monochloro impurity level is 0.17% at T0 and about 0.1% (analytical precision) at T1 month
• Dispersible tablets
• Decrease of cyclophosphamide (2 to 10%) in all packagings except in Glass bottles
• Increase of monochloro impurity above specification (>1%) except for Glass bottles (0,62%)
• Appearence of new impurities
• The observed degradation seems to be related mainly to excipients interaction rather than water
• Stablity results in glass bottles at T5°C also show monocholoro evolution,
• Present formulation is not appropriate
In addition, in order to anticipate any specific stability issue with cyclophosphamide, in parallel of new packaging investigation, it has been decided to launch, as a back up plan, a compatibility study screening a wide range of excipients which are appropriate for dispersible tablets formulations.
2) Formulation without Cellulose as dilutant
In parallel and because of the negative stability results of the Cyclophosphamide tablets, a compatibility study with a wide range of excipients was launched in order to identify what excipients should be avoided with regard to cyclophosphamide degradation. For securing the compatibility study reliability, it was decided to assess potential active/excipients interactions with 2 different analytical techniques:
- Differential Scanning Calorimetry
- HPLC assay of Cyclophosphamide
The origin of the degradation of Cyclophosphamide in the previous tablet formulation has been identified because of the presence of one excipient (Cellulose microcrystalline).
Appropriate excipients for the new formulation of dispersible tablets of cyclophosphamide were chosen and several new tablet prototypes show good compressibility and proper dissolution.
Several analytical determinations were performed among with compared uniformity and monochloro impurity. Based on these analyses, the best formulation candidate was identified. This formulation is based on mannitol as main component. It is composed with mannitol 400 and 200 association.
Several trials aiming to reduce the amount of mannitol in the formulation have been performed. The goal of these new trials was to investigate the possibility to reduce mannitol ratio to a maximum of 30 %.
In case results of the new trial would be not satisfactory we would choose the identified mannitol formulation for starting clinical program.
Three compositions were tested based on the association of mannitol 200 and other components:
• Mannitol 200 (Pearlitol® 200) and isomalt (GaleniQ® 721)
• Mannitol 200 (Pearlitol® 200), isomalt (Pearlitol® 200) and lactose (flowlac® 100)
• Mannitol 200 (Pearlitol® 200) and maltose (Advantose® 100)
Trials have been performed to reduce mannitol amount. The compositions tested present a bad uniformity in comparison to the association of two mannitols.
Thus, it was decided to keep the formulation combining the two mannitols as it was the best one in term of dosage uniformity. Three dosage strengths were manufactured (5, 20 and 50 mg).
In addition, It has been decided to avoid sodium saccharinate, following PIP assessment recommendations for this excipient.
The selected composition was manufactured on a higher batch size for checking homogeneity and process parameters.
Conclusion
The obtained blend is homogeneous. It was selected for the tabletting of the three dosage strengths: 5, 20 and 50 mg.
Packaging step
Each batch was manually packaged in brown glass bottles (100 ml, LGA supplier):
No sticking, no other problem occured during the tabletting of the three dosage strengths. The three batches comply with uniformity of dosage unit test, which is the critical point particularly for low dosage strength. The three batches were selected for stability study .
CONCLUSION
New formulation trials have been performed to obtain cyclophosphamide soluble tablet without microcrystalline cellulose, as an incompatibility between this excipient and cyclophosphamide was demonstrated.
A new formulation has been developed using grades of mannitol presenting different particle size distribution. This new formulation complies with content uniformity of dosage units, which is the critical point of the lowest tablet strenght. The composition is presented in table 30
Table 30: Composition of soluble tablets of Cyclophosphamide
Quantity (%)
Cyclophosphamide 6.25
Mannitol (Pearlitol® 400 DC) 52.30
Mannitol (Pearlitol® 200 SD) 33.70
Croscarmellose sodique (Vivasol®) 6.25
Magnesium stearate (MF2V®) 1.50
Total 100.00
Based on this homothetic composition, three batches have been manufactured, corresponding to the three dosages strengths. They have been packaged in glass bottles for stability study.
The HPLC analytical methods were validated with regard to the different parameters : specificity, system suitability, linearity, accuracy, stability of solutions and limit of quantification were demonstrated.
Batch Analysis
At present, 3 batches of cyclophosphamide soluble tablets were manufactured for clinical studies and stability purpose, at the following dosage strengths:
- 5 mg
- 20 mg
- 50 mg
Characterization of impurities
The only Cyclophosphamide impurity which is detectable in the finished product is the Monochloro impurity which is a synthesis and a degradation impurity.
Stability
ICH long term stability studies started on three batches of soluble tablets: one batch per dose. The stability studies are ongoing. They will stop after 36 months.
Cyclophosphamide drug substance must be stored in a cool place and the storage conditions of the current marketed tablet formulation Endoxan® is below 25°C.
Thus, stability studies regarding the new soluble tablet formulation were launched under two conditions during 36 months: (ANNEXES)
- 5°C
- 25°C/60% RH
The retest period for Cyclophosphamide drug substance is 36 months, to be kept at 2-8°C.
Based on the above preliminary results of stability, there is a good chemical stability at 5 and 25°C of the three batches of Cyclophosphamide tablets for the three strengths. The results of pharmacotechnical tests are satisfactory. There is a change in the appearance for the two higher dosage forms at 25°C.
So a retest period of 12 months with the following labeling statement: “store between 2°C and 8°C”, was proposed.
The retest period will be updated according to the results obtained along the ongoing stability studies.
3 months stability studies are ongoing and the results allowed us to submit an updated IMPD.
TEMOZOLOMIDE
A temozolomide suspension formulation plan was launched in Bertin Pharma. As the objective was to avoid any direct external contact with temozolomide, a protective barrier on the drug is necessary. Thus, after granulation, the obtained granules were coated with different polymers.
Given the very expensive cost of temozolomide, first trials were performed with theophylline which was used as a tracer before trials with temozolomide.
The technical requirement was to avoid immediate direct release of temozolomide from granules when put in water. A lot of different granules formulations were tested using one and several coating barriers and combining various polymers (hydrophilic, lipophilic, pH sensitive polymers etc...).
Conclusion of Theophylline trials:
Theophylline was tested as a tracer in substitution of Temozolomide for the preliminary feasibility study. The goal of this study was to formulate granules having no release of the active ingredient after reconstitution in water before administration, and presenting an immediate release profile after oral administration in the gastric environment.
Different formulation trials have been performed using combinations of soluble and insoluble polymer to produce unilayer and bilayer coated granules.
In addition, the influence process parameters as well as particle size of granules was studied.
Granules were assessed under in use conditions (reconstitution of the suspension in water) and in dissolution conditions at 2 pH (1.2 and 6.8).
No formulation allowed us to reach the first objective being to avoid immediate release of Theophylline in the suspension fro preventing safety issue during use.
However, even if Theophylline physicochemical properties are close to Temozolomide ones, it is not the same molecule and its particle size is much smaller.
Thus, we decided to perform 2 granulate trials with Temozolomide.
Temozolomide granulates
We tested 2 formulations whose compositions are mentioned below:
Batch 100612 was granulated with copovidone whereas batch 100613 used Eudragit EPO to.
Physical characteristics of these batches were measured in terms of density as well as particle size.
A higher particle size could be obtained using 10% of copovidone and Eudragit EPO as granulation solution compared to copovidone alone.
In vitro dissolution was performed on both batches (dissolution medium volume 500 ml, stirring 75 rpm, temperature 37°C) according to 3 different conditions: Water, pH 1.2 pH 6.8.
Under in vitro dissolution conditions, Temozolomide is fully released from the granules in the different pH conditions.
Batches 100612 and 100613 were also studied under in use conditions: reconstitution of the suspension in water at two concentrations 6 mg/ml and 20 mg/ml. Temozolomide release and appearance of the reconstituted suspensions were observed.
A partial immediate release of Temozolomide occurs within the minutes after reconstitution of the suspensions in water. The saturation concentration of Temozolomide is reached after 4 hours for the two tested batches at a concentration of 20 mg/ml. The slight decrease of Temozolomide concentration between 25 hours and 75 hours combined with the yellowish appearance of the suspensions are likely related to a slight degradation of Temozolomide over time in aqueous solution.
Based on the above results we can observe that:
We did not succeed to avoid immediate release of Temozolomide from the granules whatever the formulation approach or the pH conditions
Temozolomide is not stable over time when in aqueous solution.
Therefore, we concluded that it is not possible to develop a Temozolomide suspension which can be safe and stable after dispersion in water over a long period of time.
Temozolomide dispersible tablets
Given these facts, we decided to change the formulation strategy. As Temozolomide is not stable in water over time, we had to design a formulation to be dispersed in water just at the time of the administration. Thus, we investigated the possibility of developing dispersible tablets. Dispersible tablets, as solid dosage forms, present the advantage of being stable during storage over time and can be easily combined in several dosage strengths to reach the suitable dose.
Those tablets are to be dispersed in water at the time of use to lead to an oral suspension allowing easy administration in children.
First trials were performed in order to assess technical feasibility of Temozolomide dispersible tablets.
In a first step three different dispersible tablets formulations were tested:
A good compressibility was observed based on mannitol 400 (batch D110011): a wide range on hardness can be reached (from 30 to 150 N). The better hardness is about 60 N corresponding to a low friability (0.3%) and dispersion duration (30 sec).
In a second step, the tabletting properties of a mannitol 400 based formulation was studied using different punches sizes in order to assess robustness of the process as well as the possibility of covering a wide range of different dosage strength.
Conclusion
We observed a good behaviour of the formulation during tabletting. A large range of hardness was obtained: 40N to higher than 200N for the tested punches.
Very good results were also obtained in disintegration and dispersion time for each hardness and punches.
Hardness between 60-80N gave optimal results with low friability and good dispersion duration.
Therefore, we demonstrated the feasibility of a dispersible tablet formulation with Temozolomide.
Based on these encouraging results, we are now working on the development of a dispersible tablet guarantying safety during conditions of use for the health and environment.
With a dispersible tablet, which is a solid dosage form, we avoid the risk of contamination during storage and handling. However, we have to make sure that Temozolomide will not be release immediately when tablet is dispersed in water for environmental reasons.
Thus, the next step would be to perform a protective coating of Temozolomide active ingredient before incorporating it into the tablet formulation. Active ingredient coating is already use in the pharrmaceutical industry using the so called fluid bed technology which was developed years ago by Glatt company.
Our objective would be to coat temozolomide active ingredient with a hydrophobic polymer at a low concentration in order to create a direct barrier during the time of reconstitution and administration which dissolve few minutes later when the suspension arrives in the stomach.
In the previous formulations approach using granulates, the polymer coating was applied onto the granules but was not in direct contact with Temozolomide. In addition, the objective was to have a stable reconstituted suspension during time over several days.
In the case of dispersible tablets the coating layer will be applied directly on the surface of temozolomide active ingredient and we do not need Temozolomide be retained for a long time.
From a process perspective, we already demonstrated the feasibility of making a dispersible tablet with temozolomide. We could now develop the temozolomide coating step using fluid technology.
But it has been decided to stop the pharmaceutical development plan of temozolomide and to put together all resources in the cyclophosphamide development plan.
3.2. Overview of the expected and achieved results related to WP3: Formulation, supply and regulatory
Keocyt (partner 6) is WP3 leader.
Objectives:
- To optimise Clinical formulation in order to reach commercial robustness and regulatory compliant formulation for Marketing Authorization, secure clinical & commercial supply, including supply of active ingredients
- To lead regulatory activities
Keocyt was involved in the following tasks:
- Contribution to the Pharmaceutical Development plan elaboration, task led by Negositek
- Contribution, together with Negositek, to the identification of subcontractors, negotiation, implementation of contracts / technical and quality requirements, and follow up of subcontracted tasks
- Scientific and regulatory advice on clinical and commercial formulations and industrial process tasks
- Investigation and sourcing of active ingredients and packaging items
- Supervision of manufacturing the different batches that wre used for technical, stability tests and clinical trial supply.
All these tasks were performed in close relationship with Negositek as well as the IGR Project Coordinator.
Summary of progress towards objectives and details for each task:
Work Package 3 included the following steps:
⇒ Commercial formulation development
⇒ Commercial process development
⇒ Cyclophosphamide and temozolomide sourcing
⇒ Industrial transfer and validation
⇒ ICH stability studies
⇒ Global quality/regulatory documentation management for the CMC Part
1°) Commercial formulation development
This work consisted in adjusting clinical formulation by optimizing the composition in terms of aroma and preservatives as well as other parameters for assuring a reliable scale up for commercial supply.
Given that clinical formulation was not yet available because the first stability data are not available at the end of the project (M36), no work could be initiated on the commercial formulation.
2°) Commercial process development
No study was performed as long as clinical and commercial formulations are not completely defined. However the process of manufacturing is rather simple and should not show any issue once coming to manufacturing commercial quantities. CMO to manufacture commercial batches is identified. Scale up will be easy.
3°) Cyclophosphamide and Temozolomide sourcing
Sourcing the two API temozolomide and cyclophosphamide are key in the project. Such a sourcing has been done by Keocyt. Suppliers have been identified and selected for both compounds based on pricing and quality criteria. In addition, Keocyt obtained from both suppliers chemical documentation describing main route of synthesis, impurities, and analytical methods. Indeed, eDMF exist for both APIs. Keocyt has ordered an audit of these documents by independent experts that concluded to the fact that the APIs were of high quality and that documentations provided by suppliers were of quality enough to be acceptable by EMA for registration (of the IMPD and finally when filing for the registration dossier of the finished product).
We already have acquired more than a kilo of both APIs.
A supply agreement has been reached for clinical supply and a commercial commitment from both parties are under finalization to make sure APIs will be available when the two products will be on the market (considering that commercial supply would not start before 2013).
Beside these two suppliers, we have identified back up suppliers if needed and will continue to screen potential suppliers especially European ones at acceptable prices.
4°) Industrial transfer and validation
This activity will be initiated after process development is completed.
5°) ICH stability studies
These studies are Ongoing.
6°) Global quality/regulatory documentation management
The Paediatric Investigation Plan was submitted on 09/05/2011 to the European Medicines Agency (EMEA). After validation, procedures for PIP started on the 15/06/2011. The day 60 (the 12/08/2011), the summary report was sent by the PDCO. The requests are encouraging and no blocking.
Many meeting were held by Keocyt on regulatory matters using sometimes the expertise of Pharmes (regulatory consultancy company which costs are supported by Keocyt) to define regulatory requirements and build different proposals for the development. In addition to Pharmes, Keocyt asked several advices from experts such as Dr. Veronique Andrieu (Vice President of the registration commission at AFSSAPS) for pharmaceutical matters and Pr. Georges Houin (expert at AFSSAPS) for pharmacokinetic approach.
NODS
Negositek, IGR and Keocyt have elaborated a Paediatric Investigation Plan for both NODS® cyclophosphamide and NODS® temozolomide. The PIP procedure has been suspended due to the changes formulation.
Key requirements for IMPD were defined but the dossier was not written as Oralance did not provide sufficient data for an IMPD submission.
Soluble/dispersible tablets of cyclophosphamide
IMPD has been provided by Keocyt and submitted by IGR according to Keocyt, at the same time as the protocol to competent authority using the VHP, on 1st March 2011. The VHP submission has been accepted by all countries, except Italy, on 6th March 2011. The VHP was rejected.
The resubmission of our VHP application needs:
- positive results of the 3 months stability study
- Approval by PDCO of the PIP since VHP is willing to follow the PDCO/ EMA opinion.
Thus the VHP is submitted once the PIP is fully approved i.e. at the end of November.
Negositek, IGR and Keocyt have elaborated a new Paediatric Investigation Plan for cyclophosphamide soluble tablet.
A Pre submission TC with EMA for the PIP took place on 29th March. The PIP has been submitted on 10 th May 2011. After validation, procedures for PIP started on the 15/06/2011. The day 60 (the 12/08/2011), the summary report was sent by the PDCO. The PDCO day 60 report was very encouraging with no blocking questions.
3.3. Overview of the expected and achieved results related to WP4: Clinical studies
IGR (partner 1) is WP4 leader
Project leader: Prof Gilles Vassal, IGR, France
Key Objective:
To perform clinical studies with the two new oral formulations (prepared in WP2 and supplied for clinical trials by WP3), i.e. drinkable solution of cyclophosphamide and drinkable suspension of temozolomide.
3.3.1. Clinical trial setting
➢ Temozolomide
According to the Annex 1, a first template of both protocols have been written and reviewed by all principal investigators, work package coordinators:
➢ Pharmacokinetic and safety study of an oral liquid formulation of temozolomide – NODS®temozolomide – in children with malignant brain tumour.
This study was designed as a prospective trial with 2 cohorts:
In cohort 1, a cross-over randomised trial to test bioequivalence of both formulations (NODS® temozolomide versus Temodal® capsules).
Are eligible children of 3 years and more, able to swallow intact capsules and with newly diagnosed glioma or relapsed/refractory malignant tumour for whom a treatment by oral temozolomide is indicated. Patients will be treated with temozolomide 200 mg/m²/day orally for 5 consecutive days every 28 days as follow:
Cycle 2 and further: Treatment will be pursued with Temodal® capsules or NODS® temozolomide at 200 mg/m² (if no grade 3 or 4 toxicity occurs after cycle 1) according to PK results and feasibility.
In cohort 2, a descriptive pharmacokinetic study (treatment with NODS® temozolomide only).
Children of less than 3 years are eligible with newly diagnosed glioma or relapsed/refractory malignant tumour for whom a treatment by oral temozolomide is indicated. Patients will receive NODS®temozolomide at a dose of 150 mg/m²/day for 5 consecutive days on cycle 1. The dose will be increased on cycle 2 and further to 200 mg/m²/day, for 5 consecutive days every 28 days, if no grade 3 or 4 toxicity occurs after cycle 1. Pharmacokinetics parameters will be measured at Day 1.
A total of 42 patients will be studied as follow:
24 children of 3 years and more
12 children of less than 3 years
6 additional patients in case of drop-outs.
A final EMEA scientific advice for both formulations has been obtained on 10-13/12/2007.The two Paediatric Investigation Plans (one for NODS®temozolomide and one for NODS®cyclophosphamide) were submitted on 27/02/2009 to the European Medicines Agency (EMEA). After validation, procedures for both PIPs started on the 30/04/2009. The day 60 (the 26/06/2009), the summary report was sent by the PDCO.
The major issue was the request of bioequivalence studies in adults for both compounds prior to evaluation in children in order to address the relative bioavailability/bioequivalence of the new formulation compared with the existing tablets formulation before performing a pharmacokinetic/safety trial in children (without bioequivalence).
In addition, there are no strong and large adults data with the NODS formulation (incorporating other active principles) that would have help to show sufficient safety and PK data in humans. Indeed, the NODS Omeprazole data in adults provided by Oralance were not sufficiently reliable.
Following the summary report, a telephone conference was held on 07/09/2009 to discuss several items with the PDCO and EMEA.
Based on those requests, 2 new synopses (bioequivalence in adults) were designed and the first paediatric synopsis were redesigned:
➢ 2 bioequivalence studies in adults to determine the relative bioavailability of NODS® formulation compared to tablets formulation in adults
Those studies were designed as prospective, cross-over randomised trials to assess the relative bioavailability of NODSÒformulation compared to capsules/tablets formulation in adults.
A. NODS®Temozolomide
Are eligible patients with relapsed/refractory brain tumour for whom a treatment by oral temozolomide is indicated. Patients will be treated with temozolomide 200 mg/m²/day orally for 5 consecutive days every 28 days.
Cycle 2 and further: Treatment will continue with Temodal® capsules 200 mg/m².
A total of 40 patients will be studied.
B. NODS®Cyclophosphamide
Are eligible patients with recurrent or refractory malignant disease for whom a treatment with oral cyclophosphamide is indicated. Patients will be treated with NODS®Cyclophosphamide 100 mg/m²/day for 14 consecutive days.
Cycle 2 and further: Treatment will continue with Endoxan® tablets 100 mg/m².
A total of 40 patients will be studied.
Considering the difficulties encountered with the TMZ and the delay in the project, it was proposed to switch from the NODS-CPM to another simple liquid formulation of cyclophosphamide: a drinkable solution with an easy and fast reconstitution.
1) Cyclophosphamide
The question of a need of bioequivalence study as requested with this new formulation has risen. This request was linked to the fact that NODS was a new formulation and no preclinical or clinical data were provided in the PIPs. With the CPM simple oral solution, it might be possible not to perform the bioequivalence in adults. Indeed, an IV CPM form is widely used by oral administration in children. Those data are not published in the literature, but it would be possible to collect clinical data (safety) from patient files.
In this context, the exemption of the bioequivalence study in adults was formulated:
The bioequivalence/bioavailability study will be performed directly in children. The study was redesigned as a prospective cross-over randomised trial with 2 cohorts to determine the relative bioavailability of oral cyclophosphamide compared to cyclophosphamide tablets (Endoxan®) to establish bioequivalence:
In cohort 1, 30 children aged more than 6 years will be recruited. Patients will be treated with oral cyclophosphamide 50 mg/m² for 28 consecutive days as follow:
Cycle 1:
Group 1
N=15 Group 2
N=15
Day 1
(PK sampling) cyclophosphamide oral solution
50 mg/m² Endoxan® tablets
50 mg/m²
Day 2
(PK sampling) Endoxan® tablets
50 mg/m² cyclophosphamide oral solution
50 mg/m²
Day 3
(PK sampling) Endoxan® tablets
50 mg/m² Endoxan® tablets
50 mg/m²
Day 4 – 28 Endoxan® tablets
50 mg/m² Endoxan® tablets
50 mg/m²
Cycle 2 and further: Treatment will be pursued with cyclophosphamide tablets or oral solution 25 mg/m² in addition to vinorelbine IV on days 1, 8 and 15 according to PK results.
In cohort 2, 24 children aged less than 6 years will be recruited. Patients will be treated with oral cyclophosphamide 50 mg/m²/day for 28 consecutive days as follow:
Cycle 1:
Group 1
N=12 Group 2
N=12
Day 1
(PK sampling) Cyclophosphamide oral solution
50 mg/m² Intravenous cyclophosphamide
50 mg/m² over 1h
Day 2
(PK sampling) Intravenous cyclophosphamide
50 mg/m² over 1h Cyclophosphamide oral solution
50 mg/m²
Day 3 – 28 Cyclophosphamide oral solution
50 mg/m² Cyclophosphamide oral solution
50 mg/m²
Cycle 2 and further: Treatment will continue with cyclophosphamide oral solution
25 mg/m² in addition with vinorelbine IV on days 1, 8 and 15.
2) Temozolomide
Concerning the temozolomide, the decision either to go on with the NODS or to go on the alternative solution was postponed due to the lack of data.
On March 29 th, 2011 a pre submission Teleconference MEETING with EMA was held for the PIP application of orodispersible Tablets (oroDT) of cyclophosphamide.
The study will be designed with 2 cohorts as follows:
In cohort 1, the orodispersible tablet of cyclophosphamide will be compared to the currently marketed tablets in children older than 6 years, i.e. patients able to swallow intact tablets, who are due to receive an oral cyclophosphamide – based treatment for their malignant disease. This will establish the bioequivalence of the new formulation as compared to the old one. This will be a bridging study as advised by SAWP.
In cohort 2, the absolute bioavailability of orodispersible tablet of cyclophosphamide will be established by comparing the oral to the IV forms, in children younger than 6 years of age, i.e. unable to swallow intact tablets, who are due to receive a cyclophosphamide based chemotherapy for their malignant disease. This will serve as a scientific basis for the dose recommendation of the oral new formulation as opposed to the empirically-based old available tablets without any relevant pharmacological data in the young paediatric population. Absolute bioavailability of orodispersible tablet of cyclophosphamide will be established according to EMA guidelines (CPMP/EWP/QWP/1401/98).
The intent is to improve oral treatment for children with cancer who are due to receive protracted daily administration of cyclophosphamide by running an absolute bioavailability study in children.
The study will be run as a prospective cross-over randomised trial with 2 cohorts with the following objectives:
- to determine the bioequivalence of an oral liquid solution compared to tablets formulation of cyclophosphamide in children aged 6 years and more able to swallow intact tablets (cohort 1)
- to determine the absolute bioavailability of an oral liquid solution compared to intravenous form of cyclophosphamide in children aged less than 6 years (cohort 2).
In cohort 1, the oral liquid solution of cyclophosphamide will be compared to the currently marketed Endoxan® tablets in children older than 6 years, i.e. patients able to swallow intact tablets, who are due to receive an oral cyclophosphamide – based treatment for their malignant disease. This will establish the bioequivalence of the new formulation as compared to the old one.
Are eligible children aged 6-18 years, able to swallow intact capsules and with recurrent or refractory solid tumour for which prolonged daily administration of cyclophosphamide is indicated. Patients will be treated with cyclophosphamide 100 mg/m² for 3 consecutive days as follow:
– – Group 1
– N=15 – Group 2
– N=15
– Day 1
– (PK sampling) – Cyclophosphamide-liquid
– 100 mg/m² – Cyclophosphamide-tablets
– 100 mg/m²
– Day 2
– (PK sampling) – Cyclophosphamide-tablets
– 100 mg/m² – Cyclophosphamide-liquid
– 100 mg/m²
– Day 3
– (PK sampling) – Cyclophosphamide-tablets
– 100 mg/m² – Cyclophosphamide-tablets
– 100 mg/m²
– Day 4 – 10 – – No treatment – No treatment
– Day 11 – 28 – – Cyclophosphamide-liquid
– 50 mg/m² – Cyclophosphamide-liquid
– 50 mg/m²
Patients will be treated from day 11 to 28 with the orodispersible cyclophosphamide at 50 mg/m²/day assuming pharmacokinetic results are compatible with bioequivalence.
Pharmacokinetic sampling will be performed during three consecutive days. The 3rd day of pharmacokinetic will allow the assessment of intra-patient variability of pharmacokinetics which is insufficiently documented and the effect of induction of metabolism which has previously been reported with cyclophosphamide
Cycle 2 and beyond:
According to the clinician's decision and according to the pharmacokinetic results, treatment will continue with the orodispersible cyclophosphamide at a dose of 50 mg/m²/day given as single agent or at a dose of 25 mg/m²/day when given in combination with vinorelbine 25 mg/m² (administrated as an IV infusion on days 1, 8 and 15).
In cohort 2, the absolute bioavailability of the drinkable solution of cyclophosphamide will be established by comparing to the IV forms, in children younger than 6 years of age, i.e. unable to swallow intact tablets, who are due to receive a cyclophosphamide based chemotherapy for their malignant disease.. Absolute bioavailability of drinkable solution of cyclophosphamide will be established according to EMEA guidelines (CPMP/EWP/QWP/1401/98).
Are eligible children between 6 months and six years of age with recurrent or refractory malignant disease for whom prolonged daily administration of cyclophosphamide is indicated. Patients will be treated with cyclophosphamide 100 mg/m² for 2 consecutive days as follow:
– – Group 1
– N=9 – Group 2
– N=9
– Day 1
– (PK sampling) – Intravenous cyclophosphamide
– 100 mg/m² over 1h – Cyclophosphamide-liquid
– 100 mg/m²
– Day 2
– (PK sampling) – Cyclophosphamide-liquid
– 100 mg/m² – Intravenous cyclophosphamide
– 100 mg/m² over 1h
– Day 3-9– – No treatment – No treatment
– Day 10-28– – Cyclophosphamide-liquid
– 25 mg/m² – Cyclophosphamide-liquid
– 25 mg/m²
Patients will be treated from day 10 to 28 with the orodispersible cyclophosphamide at 50 mg/m²/day assuming pharmacokinetic results indicate adequate bioavailability
Cycle 2 and beyond:
According to the clinician's decision and according to the pharmacokinetic results, treatment will continue with the orodispersible cyclophosphamide at a dose of 50 mg/m²/day given as single agent or at a dose of 25 mg/m²/day when given in combination with vinorelbine 25 mg/m² (administrated as an IV infusion on days 1, 8 and 15).
➢ Regulatory point
We withdrew our PIP application for the development of a pediatric oral formulation of NODS cyclophosphamide in May 2010.
Indeed, we have decided early 2010 to abandon the project to formulate cyclophosphamide in NODS particles due to pharmaceutical issues.
We have developed an orodispersible tablet (three dosages) of cyclophosphamide in order to address the need for age appropriate formulation of this widely used drug, a need that has been addressed in the priority list.
Thus we do have a completely different product as compared to the first PIP we submitted. However, the needs and the rationale are the same.
A pre submission Teleconference meeting with EMA for the PIP application of orodispersible Tablets (oroDT) of cyclophosphamide was held on March 29 th, 2011.
The Paediatric Investigation Plan (for cyclophosphamide orodispersible) was submitted on 09/05/2011 to the European Medicines Agency (EMEA). After validation, procedures for PIP started on the 15/06/2011. The day 60 (the 12/08/2011), the summary report was sent by the PDCO.
The PDCO day 60 report was very encouraging with no blocking questions.
The protocol has been submitted to the French ethical committee and has been approved on the 05/04/2011.
➢ Temozolomide
As presented several alternatives for the galenic preparation of temozolomide have been tested
However, to date, there is no galenic formulation for a liquid preparation of temozolomide that fulfils the requirements (for the patient and for the environment).
We do not have a formulation of temozolomide ready to go for clinical development,
➢ Operational and administrative aspects :
The clinical trial will be sponsored and run by the academic partners involved.
The O3K CPM trial has been submitted to ITCC network and has been accepted by ITCC Clinical Trial Committee on 28/01/2011. The opening of new countries and centres can make easier and accelerate the inclusions of patients in the study. The CPM’s trial has been proposed to 2 other countries: The Netherlands and Germany (members of ITCC network). The objective is to assure the recruitment in less than 18 months.
Sponsoring will be set up according to a co-sponsoring agreement that has already been implemented to run three academia-sponsored phase I and II trials of the European consortium for Innovative Therapies for Children with Cancer (http://www.itcc-consortium.org). There will be a coordinating sponsor and four co-sponsors.
Five co-sponsors will be in charge of administrative process in each of the three member states:
Università Cattolica del Sacro Cuore (P3) for Italy
Newcastle university (P2) for the United Kingdom
IGR for France (P1)
ERASMUS for the Netherlands
Universitätsklinikum Freiburg for Germany
Their role will be to set up the sponsoring administrative process in each country (i.e preparation of the specific national part of the dossier; submission to the regulatory national regulatory and ethic committee (s)) for both studies). Each partner will be in charge of writing the information sheet and consent forms, and asking parents association for review.
A co-sponsorship agreement will be established and signed in between the five institutions.
Thirty one centres will participate to the CPM clinical trials:
- 11 centres in France which are part of the Pharmacology Group of the French Society of Paediatric Oncology, running phase I, phase II trials and pharmacology studies together
- 9 centres in the United Kingdom which are part of the CCLG and have been selected to run phase I, phase II and pharmacology studies nationally.
- 5 centres in Italy which are part of AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica), running phase I, phase II trials and pharmacology studies.
- 3 centres in Germany which are part of ITCC running phase I, phase II trials and pharmacology studies
- 3 centres in Netherlands which are part to ITCC running phase I, phase II trials and pharmacology studies
UNAPECLE (P9) will review the protocol, information sheet and the patient diary. In addition, UNAPECLE will watch closely over the ethical issues during the project to assure that those issues are properly addressed.
➢ Ethical part:
1. Ethical aspects within the project
Due to the specific population of our O3K project (children between 6 months and 18 years) , the EC asked us in November 2007, to revise our ethical part according to the guidelines and recommendation, and to demonstrate our understanding and implementation of ethics in relation to our project.
According to the ESR (evaluation summary report) of European Commission, we added an Independent Ethics Standing Committee (IESC) in the Annex 1 of the project composed of 3 independent experts (3 in ethics UK, It, Fr).
Experts should not be members of parents organisation, and totally independent of partners. There will be one ethics expert from each member state.
Mission of the IESC :
➢ Review of the protocol before submission to National Ethics Committees
➢ Review of the Patient information package (information sheet, consent form, booklet)
➢ Every 6 months, the IESC will state whether or not ethical issues were raised at the individual level. Every 6 months, the IESC will receive from the sponsor the list of registered patients with relevant information (how patients agreed to participate to the trial, how and who asked for their participation...)
The IESC was constituted and met for the first time on 12/01/2009
The members of the IESC are:
_Chantal Aubert-Fourmy (French ethical expert, coordinator of the paediatric committee of the CNCP (Conférence nationale de comités de protection des personnes),
- Mary Dixon-Woods (Professor of Medical sociology, University of Leicester UK)
- Dr Marina Cicerone (member of the Ethical Committee at the Catholic University of Rome)
Chantal Aubert-Fourmy worked on the French information sheets
She advised to set up 4 information sheets (IS):
- One IS per parent
- One IS for major patient (similar than parents)
- One IS for children [12-17[ (similar than parents)
- One IS for children [6-12] (suitable document)
- One IS for children < 6 (illustrated and simplified document)
Those sheets will be then translated in each language of the member state participating to the trials.
3.4. Overview of the expected and achieved results related to WP5: Pharmacokinetic evaluation
University of Newcastle (Partner 2) is WP5 leader
Project leader: Gareth Veal, Newcastle, UK
Key Objective
To define the bioequivalence of cyclophosphamide when administered as a drinkable solution in a paediatric population. This will involve a direct comparison of the pharmacokinetics of this agent when administered by the currently accepted best practices (cyclophosphamide – i.v. infusion and oral administration of tablets)
Work description
A limited number of blood samples will be collected prior to and following administration of a drinkable solution of cyclophosphamide in paediatric populations. In addition, to directly compare pharmacokinetics of the drinkable formulations with current standard practice, samples will also be collected following administration of intravenous cyclophosphamide and oral cyclophosphamide tablets. The defined collection times will be optimally selected based on pharmacokinetic datasets obtained from previously studied paediatric patient populations. Limited sampling approaches will be used whenever possible so as to minimise the inconvenience to the patients and to minimise total blood volumes being taken from young children.
Plasma will be immediately separated from blood samples and stored at -20°C until shipment to the appropriate analytical reference laboratory. In addition to the collection of samples for pharmacokinetic analysis, information relating to the exact timing of drug administration, dose of drug administered, pharmacokinetic sampling times and concomitant therapies will also be collected.
All samples for cyclophosphamide analysis should be sent directly to the analytical reference laboratory in Newcastle (Dr Gareth Veal, Northern Institute for Cancer Research, Newcastle University) following collection. This immediate processing and transport of clinical samples is required in order to perform the dosages for the interim analysis concerning the first 8 patients in cohort 1.
Cyclophosphamide and metabolites will be assayed in plasma using a recently developed liquid chromatography tandem mass spectrometry (LC/MS/MS) method. This method has been optimised and validated as part of the WP5 programme, in a lead up to the analysis of clinical samples. All samples will be analysed to quantify concentrations of cyclophosphamide and its major metabolites dechloroethylcyclophosphamide (DCCP), ketocyclophosphamide (KetoCP) and carboxyphosphamide (CXCP). This assay has been fully validated (linear range: 0.05 – 10.0 µg/ml) and has recently been used successfully to analyse samples from cyclophosphamide pharmacokinetic studies involving approximately 25 children (>200 samples analysed). These studies will build on previously published data from the group in Newcastle relating to cyclophosphamide pharmacokinetics in children (Yule et al., 2004; Chinnaswamy et al., 2011).
Pharmacokinetic parameters will be calculated using non-compartmental analysis. The following pharmacokinetic parameters will be reported:
− Cyclophosphamide : Tmax, Cmax, absorption half-life, elimination half-life, AUCt (AUC measured at last point), AUC∞ (AUC extrapolated to infinity), Clearance/F corrected for BSA , Volume of distribution/F corrected for BSA
− Carboxyphosphamide (CX): Tmax, Cmax, AUCt (AUC measured at last point), AUC∞ (AUC extrapolated to infinity) ratio to cyclophosphamide AUC
− Dechloroethylcyclophosphamide (DCCP) : Tmax, Cmax, AUCt (AUC measured at last point), AUC∞ (AUC extrapolated to infinity), ratio to cyclophosphamide AUC
− Ketocyclophosphamide (KETO) : Tmax, Cmax, AUCt (AUC measured at last point), AUC∞ (AUC extrapolated to infinity), ratio to cyclophosphamide AUC
Statistical analysis will describe the main pharmacokinetic parameters as means, SD, 95% Confidence interval, medians, minimum and maximum. In addition, Clearance/F, Volume of distribution/F and elimination half-life will be calculated using a non-compartmental method.
AUC∞ is the most reliable reflection of the extent of absorption. Individual bioavailability (F) will be defined as the ratio of AUC∞ of cyclophosphamide after a drinkable solution of cyclophosphamide to that of IV cyclophosphamide. Absolute bioavailability will be expressed as mean, SD, 95% confidence interval, median, minimum and maximum. Considering available data in adults and the wide interpatient variability, it is expected that F will lie within an interval of 60 to 100% with a substantial inter-patient variation.
Individual AUC∞ ratios for the measured metabolites will be calculated and expressed as mean, SD, 95% confidence interval, median, minimum and maximum. Those ratios will help to identify the potential impact of first-pass intestinal and hepatic metabolism.
To describe the pharmacokinetics and metabolism of cyclophosphamide following administration, a population based analysis using NONMEM will be performed to better identify the covariates explaining the inter-patient variability.
An assay has been optimised and fully validated to allow the quantification of cyclophosphamide and its metabolites in clinical samples obtained from children with cancer. No analysis of clinical samples has been started because no patients have been recruited to the clinical study.
3.5. Project management during the period
Consortium management tasks and their achievement
o Ensure the proper scientific management of the project in order to strengthen and support the participants to achieve the objectives, complete the milestones in time and deliver the deliverables.
o Make sure that the consortium’s contractual duties are carried out. Advise and guide the Participants to comply with the EU regulations and their contractual and legal requirements. Abide by the "good practice" of resources management as presented in the Financial Guidelines.
o Set-up an effective communication infrastructure and foster the integrative process within the consortium.
o Manage the processes for the capture and the protection of intellectual property, including confidential information and patents properly.
The following tasks were performed during the period:
3.5.1. Consortium management tasks and their achievement
Management of legal issues:
o A consortium agreement was established, discussed with partners and their legal departments, agreed and signed by all partners´ legal departments.
Communication Management:
o Key aspects were communicated to or discussed with the Scientific Officer of the European Commission
o Regular Phone conferences with the Coordinator and relevant partners were carried out to discuss actual progress within the project.
Project Controlling (including Reporting):
o To oversee the compliance of the project with the EU provisions (grant agreement and its annexes) and the Consortium Agreement
o To prepare templates concerning the extent, structuring and the description depth of information on the status of the project and the progress
o To manage the due-process submission of reports (according to the reporting guidelines for FP7)
o To coordinate the submission of deliverables and milestones particularly with the WP leaders
o To monitor and regularly present the status and progress to the board.
o The consortium successfully managed a defaulting partner (Oralance) which was taken out of the consortium in respect to all EU guidelines and procedure. During this period, the Scientific Officer (Mr Donnely) was kept informed of all actions and decision in a timely fashion.
o In addition, the Coordinator and the partners responding in a timely fashion to all reports and documents asked by the DG research in the evaluation process of the submitted amendment.
Finance Management:
Activities were as follows:
o The pre-financing payments were coordinated and transferred to the participants
o Monitor costs vs. budgets on an periodic basis
o Report on financial issues as required by the reporting guidelines
o Support all partners with issuing and obtaining Form Cs in due time
o Close cooperation with the administration departments of the involved parties and with the financial officer at the European Commission
Meeting Organisation:
Organisation of effective meetings of the Consortium:
o Several teleconference meetings with partners (board meeting, WP meeting)
o Extraordinary general assemblies
Organisation comprises the following tasks:
o support with the meeting preparation for the WP leaders (focus, templates, structuring)
o follow-up of points agreed at the meetings, therefore writing and circulation of minutes and monitoring of pursuance.
Deviations and management:
March 29th 2010, the O3K Consortium considers that ORALANCE was a defaulting party, and thus, was asked to leave the consortium, as defined by the consortium agreement, in full respect of the FP7 rules and guidelines.
On May 11th2010, a request for an amendment was sent to the European commission that includes:
Modification of duration
The duration of the O3K project specified in Article 3 of the grant agreement is modified as follows: New duration: 36 + 18 = 54 months
Addition of one beneficiary
Andrieu Consultant International, to provide the Project with the needed pharmaceutical and regulatory expertise needed to move forward the project.
End date of participation:
The participation of the following beneficiaries is terminated from the date specified in the following table: ORALANCE, legal Form: liability company 29th of march 2010
Termination at the initiative of the consortium and approved by the partner (letter on April 21st, 2010)
Different amendments with description of work have been sent in November 2010, March 2011 and May 2011
3.5.2. Changes in the consortium, if any
- Decision of University from Leicester (P7) to withdraw from the project
The University of Leicester (Partner 7) was an O3K partner with the goal to sponsor the clinical trials in the UK. Due to national decision in the UK, the CCLG Trials Centre in Leicester was closed and the University of Leicester was no longer in a situation to sponsor the O3K Trials. Partner 7 decided to leave the O3K consortium. The consortium decided to move the responsibility of sponsoring the trials in the UK to Newcasttle, partner 2.
- Oralance: the company has gone into receivership (December the 28th) and the consortium was informed by mail on the 17/01/2010. In order to be as transparent as possible, we informed our EC officer (Mr Donnely) on19/01/2010.
On March 29th, 2010, after the implementation of the process stated in the consortium agreement and with respect to EU FP7 rules, the O3K Consortium unanimously considered that ORALANCE was a defaulting party, and thus, Oralance was asked to leave the consortium, as defined by the consortium agreement.
Addition of one or more beneficiary (ies)
Full name and legal form of the beneficiary Start date of participation
Institute Of Child Health, Research Organisation established at 30 Guilford Street, London WC1N 1EH, represented by its Director, Professor Andrew Copp and his deputy, Professor Peter Scambler 1st of April 2010
Andrieu Consultant International (FR 48 494 939 796) established in France (le Valencay 2, 122 rue du commandant Rolland, 13008 Marseille), represented by Veronique ANDRIEU (Manager). February 28th 2010
Changes in responsibilities
Not applicable.
On a WP level
As Oralance left the consortium, Negositek became WP2 work package leader
3.5.3. List of project meetings, dates and venues:
2 types of coordination meeting are foreseen during the project
- General Assembly meetings gathering all the consortium
- Project board meetings gathering IGR, Keocyt, Newcastle and Negositek
-
Organisation comprises the following tasks:
o support with the meeting preparation for the WP leaders (focus, templates, structuring)
o Follow-up of points agreed at the meetings, therefore writing and circulation of minutes and monitoring of pursuance.
O3K meetings:
Date Place
Kick-off meeting 15/09/2008 Villejuif
Project board 30/10/2008 Phone meeting
Project board 19/11/2008 Phone meeting
Project board 11/12/2008 Phone meeting
Project board 21/01/2009 Phone meeting
Project board 24/02/2009 Phone meeting
Project board 16/04/2009 Phone meeting
Project board 13/05/2009 Phone meeting
Project board 27/06/2009 Phone meeting
Project board 27/08/2009 Phone meeting
WP2 meeting (with P1, P5, P6, P8) 09/09/2009 Villejuif
WP2 meeting (with P1, P5, P6, P8) 08/10/2009 Labège
General Assembly 12/10/2009 Villejuif
WP2 meeting (with P1, P5, P6, P8) 06/11/2009 Labège
WP2 meeting (with P1, P5, P6, P8) 04/12/2009 Phone meeting
WP1/WP2/WP3 meeting 31/12/2009 Villejuif
CPM pharmaceutical meeting 04/02/2010 Villejuif and phone meeting
Extraordinary General Assembly 1st 17/02/2010 Villejuif
Extraordinary General Assembly 2nd 29/03/2010 Villejuif and phone meeting
Extraordinary General Assembly 3nd 30/06/2010 Villejuif and phone meeting
Project board 13/07/2010 Phone meeting
Project board 18/10/2010 Phone meeting
WP2 meeting 06/12/2010 Bertin pharma
Project board 17/12/2010 Phone meeting
Project board 17/01/2011 Phone meeting
WP2 meeting (with P1, P5, P6, P8) 9/03/2011 Phone meeting
WP2 meeting (with P1, P5, P6, P8) 15/03/2011 Phone meeting
WP2 18/03/2011 Phone meeting
WP2 meeting (with P1, P5, P6, P8) 13/04/2011 Phone meeting
Extraordinary General Assembly 4st 26/04/2011 Villejuif and phone meeting
Project board 14/06/2011 Phone meeting
WP2 meeting (with P1, P5, P6, P8) 30/06/2011 Villejuif
3.5.4. Problems which have occurred and solutions provided
As a brief reminder,
01/09/2008: Start of the project with agreement on retroactivity procedure. We consequently all together decided to operate and incur costs before having the GA signed (9 months).
07/05/2009 by IGR and 09/06/2009 by EC: Grant Agreement is signed
18-19/06/2009: Reception of the 1st EC contribution & funds sent to partners. Thus, it took 9 months to receive funding for the project. Since, per the project, the first 6 months of activity were mainly dedicated to the development of the two pharmaceutical formulations by Oralance, the project could only start in fact in June 2099 instead of September 1st, 2008.
17/02/2010 Extraordinary General Assembly (we present the external expert report on Oralance’s work)
02/2010: Regular exchanges with the EC officer to maintain perfect transparency
More specifically, several problems arose during the first period.
- The negotiation of the O3K consortium agreement was longer than foreseen because of the long process of negotiations of some partners. This delay involved a delay in the payment to the consortium of the first advance received from the European Commission. We consequently all together decide to operate and incur costs before having the funding. However, due to its financial situation ORALANCE could not start working on the project before receiving funds.
- Early December 2009, there was a disagreement in between K. Ioualalen (ORALANCE, WP2 project leader) who considered that both the NODS-TMZ formulation and the clinical formulation were validated, and the Project board who considered there were still major issues to be solved.
To allow the Project Board to evaluate documents and to assure its relevance with technical and regulatory requirements, Gilles Vassal asked Véronique Andrieu (Ph. D in pharmaceutical sciences, Pharm. D) an external expert with a strong expertise in galenics and regulatory issues working at the French Drug Agency, to state on the TMZ data. Her evaluation concluded that the NODS-TMZ data do not fulfil the requirement for an IMPD submission and that the results are not sufficient in terms of safety, concentration, and reproducibility to go forward on the project
The final decision, not to continue the cyclophosphamide development with the NODS technology, was taken by the entire consortium during the Extraordinary General Assembly on February 17th.
We proposed during the extraordinary general assembly that took place on the 17/02/2010 to switch the development of NODS-cyclophosphamide and NODS –temozolomide into an alternative formulation of both drugs to propose a liquid oral formulation that will fit the paediatric needs. This was the major goal of the project.
▪ For Cyclophosphamide, two orientations have been chosen: Cyclophosphamide Aqueous solution and dispersible tablets.
▪ For Temozolomide, the formulation work was undertaken according to 2 different approaches:
- Suspension formulation
- Dispersible tablets
Cyclophosphamide trials were more advanced than temozolomide ones. Priority has been given to the cyclophosphamide development;
However, after several attempts, the chemical bottlenecks in developing a liquid formulation of temozolomide were not solved and it has been decided to stop the pharmaceutical development plan of temozolomide and to put together all resources in the cyclophosphamide development plan.
On April 2010, we submitted a request for extension of 18 months to finish the project. This extensionwas requested to run the full clinical development with the new galenic formulation, as specified on
27th April 2010 GA report.
This issue was discussed with Dr Ruxandra Draghia –Akly In July 2010 And she proposed a go/no go decision process
It was agreed we will first complete the pharmaceutical development with the new galenic formulation
and then define the appropriate extension to run and finish the program. The request for an extension
was to be submitted within 12 months of the end of project.
This annex amendment requests an extension of 9 months (with no request for additional budget) and includes all the preliminary data that we have generated until this date, May 2011.
As discussed in mail correspondence with Alexandru Costescu on April 15 th and approved by the consortium on April 26th, an additional 9 months extension could be agreed as needed by the conduct of the clinical trial.
It was agreed that a report will be provided at M42 for a go/no go decision to extend the project for an additional 9 months..
We were notified in May 2011 that this amendment was not accepted and we were told in June 2011 that DG research wanted an evaluation by 3 external experts. The consortium prepared and sent all documentations required.
To speed up the evaluation (indeed the decision of an external evaluation was taken at M34 of the project), it was decided in agreement with the scientific officer to hold an on-site meeting with experts on August the 17th 2011. .
On August 16th 2011, we were notified by email by A Costescu that he cancelled the meeting which was already organised;
on the 31st of august 2011, ie the last day of the M36, Gilles Vassal, the scientific coordinator, sent a letter to the entire consortium in order to specify that:
• An external evaluation of our requested amendment was ongoing
• Only two ongoing activities will continue because they could not be stopped and they were crucial for the continuation of the project if the outcome of the evaluation were positive:
o stability studies to generate the necessary information for the IMPD and the preparation of the clinical batches
o the PIP evaluation process which was at the stage of day 60 report
AT that time, no other activity was ongoing within the consortium since we were waiting for starting the clinical trial. Partners were diligently asked not to start any new activities which cost would be inferred to the O3K funding
Outcomes of the O3K cyclophosphamide project beyond M36
• The PIP was approved by EMA and PDCO in December 2011 and published in January 2012
• The stability studies were positive at 1 months, 3 months and 6 months
• The clinical batches were prepared and were available in May 2012
• The final clinical trial protocol including the IMPD was approved in France by the national competent authority and the ethic committee in July, 2012.
• The cyclophosphamide trial was ready to be launched in 30 July 2012.
• A patent of the new cyclophosphamide formulation was submitted in November 2012.
Potential Impact:
O3K will have important strategic impacts on economy, European competitiveness, and societal problems.
Thanks to the European Regulation for Paediatric use of Medicinal products, paediatric drug development becomes an economically attractive domain.
The ultimate goal of the O3K project, to be taken forward upon completion of the project, is to commercialise and to distribute two new medicinal products for children with cancer in Europe. In addition, by establishing the proof-of-concept of the use of drinkable suspension to develop age appropriate formulations of anticancer drugs, other compounds, including those of the EMEA list, may be developed. Moreover, this technology could be used to develop age-appropriate formulations for innovative targeted compounds developed by Big Pharmaceutical companies. Indeed, the specific paediatric needs for these innovative compounds will have to be addressed according to the EU Regulation on the Paediatric use of Medicinal Products. Altogether, this will adequately answer the needs for old products, as well as new products, and potentially create a healthy economic activity in the field of orphan drugs.
Thus, O3K will reinforce European competitiveness on several points:
By bringing together a network of paediatric oncology clinical investigating centres, (4 institutions committed to sponsor and develop clinical research in paediatric oncology, 2 pharmacology research laboratories with internationally recognised expertise in the field of paediatric oncology), 3 SMEs dedicated to drug development and 1 Parents Organisation, the O3K project will synergize research & development initiatives and create a critical mass of expertise and skills in the field of paediatric oncology and pharmacology research at the European level. The O3K project is a well-focussed project and is likely to generate in the mid term innovative and economically healthy activities.
The consequences are, first, a better working collaboration, financial and technical compatibilities and thereby a harmonisation of European research. By using new technologies and a significant level of oncology expertise, the O3K will advance the European role in drug development in children and strengthen a new R&D domain, namely drug research for children.
Concerning the solving of societal problems, more than 16000 children develop cancer each year in Europe. Despite improved survival rates with currently used multimodality treatments, cancer remains a life-threatening disease in children and represents the primary cause of death by disease in children over 1 year of age with more than 4 000 children dying of cancer each year in Europe. This is a major human health issue for the paediatric population. Safe and efficacious drugs are needed, as outlined by the EU regulation, to improve further cure and quality of life of children with cancer. The O3K project will contribute to the success of the EU Paediatric Medicines Regulation by providing child-appropriate formulations for two off-patent drugs.
The major impact will be for children and parents. The new child-appropriate formulations in oncology will improve safety, quality of life of children and their family and security of the environment. Development of ambulatory treatment with well-studied oral chemotherapy will be feasible and will help to improve quality of life of children, parents and family.
Long term impacts: The two drugs will be marketed and distributed. It is expected that an economically healthy activity will be generated from the O3K project.