Community Research and Development Information Service - CORDIS

Periodic Report Summary 3 - GANNET53 (A drug strategy targeting heat shock protein 90 to combat metastatic, p53 mutant ovarian cancer.)

Project Context and Objectives:
Epithelial ovarian cancer is the most lethal gynaecologic malignancy. In Europe 66,700 women are diagnosed with ovarian cancer and 41,900 die of the disease every year. Aggressive high-grade serous ovarian carcinoma constitutes the predominant histological subtype and is clinically most relevant accounting for ~85 % of ovarian cancer deaths. Importantly, the preeminent molecular hallmark of high-grade serous ovarian carcinoma is the nearly ubiquitous presence of p53 mutations (> 96% of patients). This strongly suggests that mutant p53 is a central oncogenic driver in the pathogenesis of these tumours.
Resistance to platinum-based chemotherapy is a major treatment obstacle in ovarian cancer patients. Treatment options for patients with platinum-resistant disease are limited and these patients face a particularly dismal prognosis. With current standard therapy options the median progression-free and overall survival in platinum-resistant ovarian cancer (PROC) patients is only 4 and 14 months, respectively. In sum, there is a pressing need for innovative and more effective treatment strategies to improve survival in PROC patients.
Addressing this pressing need, the GANNET53 clinical trial applies a highly innovative treatment concept whose scientific rationale directly grew out from solid basic research findings by members of the GANNET53 consortium (Fig 1). This is a drug strategy that targets the central driver of aggressiveness of these EOC carcinomas, namely mutant p53 protein (mutp53). Degradation of stabilised mutp53 is induced via an Hsp90 (heat shock protein 90) inhibition mechanism. The clinically most advanced second-generation synthetic Hsp90 inhibitor named Ganetespib is used in this trial and applied in a stratified approach in PROC ovarian cancer patients with a high p53 mutation rate.
The GANNET53 trial is a two-part European multi-centre Phase I and Phase II trial. The Phase I trial demonstrated that the combination of Ganetespib 150 mg/m² with Paclitaxel 80 mg/m² once weekly for 3 out of 4 weeks is generally well tolerated with no dose-limiting toxicities (DLTs) in the Phase I trial. Thus, the Independent Data Safety and Monitoring Committee recommended using this Ganetespib dose levels in the Phase II clinical trial. The randomised, two-arm, open-label Phase II trial, determines the efficacy of Ganetespib in combination with weekly Paclitaxel, versus weekly Paclitaxel alone in PROC patients. After inclusion of more than half of the aspired patient number (133 patients have been randomised), active recruitment was stopped in the Phase II trial in September 2016, while patients on treatment are allowed to continue study medication. This decision was primarily taken due to the decision of the company providing Ganetespib to stop the production of Ganetespib. In addition, the GANNET53 Steering Committee had some concerns about the futility of the trial combining Ganetespib with a taxane based on (a) new preclinical in vitro and animal data and in addition on (b) an immature and unplanned efficacy analysis of the current trial (prompted by the temporal limitation of Ganetespib supply). Based on new preclinical research results, the GANNET53 consortium promotes further research on other Ganetespib combinations, particularly with platinum.
An outstanding biobank has been established from the 133 patients included in the randomised Phase II trial. The GANNET53 consortium has collected various biomaterials (FFPEs, fresh-frozen biopsies of the actual relapse, serum, plasma, circulating tumour cells in the blood, ascites, pleural effusions etc.) at screening and at different time points during study treatment. The GANNET53 consortium plans to intensify its translational research studies in order to make the necessary conclusions even from the reduced number of patients included in the randomised Phase II clinical trial.
Project Results:
The GANNET53 project started in October 2013. In the first 8 months all legal, ethical and administrative prerequisites for start of the GANNET53 trial were accomplished.
Two custom-tailored electronic Case Report Forms for Phase I and II, respectively, and a biobank software were devolved for the effective organisation of a large-scale, multi-centre biobank, and real-time tracking of biosamples.
In June 2014, the Phase I dose escalation/de-escalation trial was opened at 5 clinical centres in Austria, Germany, France and Belgium (Fig 2 Recruitment strategy). Patients with platinum-resistant ovarian cancer (PROC) with high-grade serous, high-grade endometrioid, or undifferentiated histology and ≤4 prior chemotherapy regimen were eligible. In total, ten patients were enrolled. The combination of Ganetespib (G) 150 mg/m² with Paclitaxel (P) 80 mg/m² once weekly for 3/4 weeks was well tolerated with no dose-limiting toxicities (DLTs) encountered. The independent Data and Safety Monitoring Committee recommended using 150mg/m² G in the Phase II trial.
The randomised, two-arm, open-label Phase II trial was opened in April 2015. The same inclusion/exclusion criteria as in Phase I applied. Central histopathological review was implemented to ensure eligible histological subtypes. The Phase II trial was conducted at 13 clinical sites in four European countries. Initially it was planned to randomly assign a total of 222 PROC patients in a 2:1 ratio to receive either G+P weekly or P weekly alone (Fig 3 Phase II study design). After inclusion of 133 patients the GANNET53 Steering Committee decided to stop active recruitment of patients in the Phase II trial on 21.09.2016, while patients on treatment are allowed to continue study medication. This decision was primarily taken due to the decision of the company providing G to stop production of G. In addition, some concerns about the futility of combining G with a taxane arose due to (a) new preclinical in-vitro and animal data, and (b) an immature and unplanned efficacy analysis. On 4.12.2017 the Sponsor (IMU, P1) closed the GANNET53 trial as clinical data for endpoint analyses were mature. The Phase II GANNET53 was negative for its primary endpoint Progression-free Survival (PFS). No statistical significant PFS difference among the experimental and the control arm was found. The final clinical data set is currently being analysed in detail.
A unique biobank has been established from the 133 patients included. The GANNET53 consortium has collected sequential biomaterials per patient at screening and at different time points during study treatment (archival formalin-fixed, paraffin-embedded tumour tissues, fresh-frozen biopsies of the actual relapse, serum, plasma, circulating tumour cells in the blood, ascites, pleural effusions etc.). Requested biomaterials were delivered to companion diagnostics partners for further analyses.
Various methodologies for companion diagnostic analysis in the collected biomaterials were established, e.g., a proximity ligation assay to detect protein complexes (Fig 4), approaches to analyse prion-like behaviour of mutant p53 proteins, and a circulating tumour cell enrichment and detection/characterisation system (Fig 5). The GANNET53 consortium plans to intensify its translational research studies to make the necessary conclusions even from the reduced number of patients included in the clinical trial.
The GANNET53 consortium aims to expand G clinical testing to new promising drug combinations. Preclinical data (generated by P11 and P5) showed compelling synergy between G/Carboplatin and G/PARPinhibitor, respectively. Tremendous efforts were undertaken to regain access to G and the consortium succeeded. A new clinical trial, named EUDARIO (Fig 6 EUDARIO trial design), was developed (protocol completed) applying the compelling new combinations in platinum-sensitive EOC patients. An amendment to the GANNET53 grant agreement was submitted to integrate this clinical trial.
Potential Impact:
The major aim of the GANNET53 trial was a significant progression-free survival (PFS) benefit for platinum-resistant ovarian cancer (PROC) patients with aggressive histological subtypes harbouring p53 mutations. The Phase II GANNET53 was negative for its primary endpoint PFS. No statistical significant PFS difference among the experimental and the control arm was found. The final clinical data set is currently being analysed.

Further results achieved:
Established Safety of Ganetespib (G) in a new combination with the taxane Paclitaxel (P):
ο Impact on clinical trials with this new combination in other tumour entities using Paclitaxel as standard therapy, e.g. breast cancer.
Unique biobank of biosamples derived from 133 PROC patients:
ο Big scientific impact, several research projects based on the collected biomaterials are ongoing/will be initiated, e.g., p53 basic research including comparison of exact p53 status at diagnosis and at relapse, analysis of different biomarkers, enables future genome-wide oncogenomics studies to identify additional resistance-mediating molecular changes etc.
Developed innovative software for effective organisation of a large multi-centre biobank and real-time tracking and distribution of biosamples:
ο Application in other tissue-banking networks such as TOC, sale of software, license.
Development of multiple methodologies, e.g. a functional molecular test to detect mutp53-Hsp90 complexes in tumour tissues, approaches to analyse prion-like behaviour of mutant p53 proteins, and a circulating tumour cell enrichment and detection/characterisation system:
ο Scientific impact on the respective research field, license, use in basic-research and potential expansion to other tumour entities
In vivo genetic and pharmacologic proof-of-principle for the mutp53-targeting concept in engineered knock-in mouse models:
ο Potential application in other p53 mutated tumour types.

Further results expected:
• Evaluated life quality of the new experimental therapy based on Hsp90 inhibition in comparison with standard treatment option.
• Evaluated Pharmakokinetic for the G/P combination
• Value of circulating tumour cells (CTCs) for monitoring responsiveness to experimental therapy with G
• Value to predict responsiveness to experimental therapy with G by a functional molecular test to detect mutp53-Hsp90 complexes in tumour tissues.

The GANNET53 consortium aims to expand clinical G testing to new promising drug combinations. Preclinical data (generated by P11) showed compelling synergy between G/Carboplatin and G/PARPinhibitor, respectively. The GANNET53 consortium succeeded to regain access to G. A new clinical trial, named EUDARIO, was developed applying the promising new drug combinations in platinum-sensitive EOC patients. An amendment to the Grant Agreement was submitted to integrate this clinical trial into our DoW. The major aim of the EUDARIO trial is a significant PFS benefit in platinum-sensitive ovarian cancer patients with aggressive histological subtypes harbouring p53 mutations.

The local economies in the four participating EU countries benefit from our clinical trial as an additional source of cash flow and by providing enhanced employment opportunities. Administrative and legal requirements based on the Clinical Trials Directive are implemented and also generate cash flow.

List of Websites:
www.gannet53.eu; http://patients.gannet53.eu

Related information

Reported by

MEDIZINISCHE UNIVERSITAT INNSBRUCK
Austria

Subjects

Life Sciences
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