Community Research and Development Information Service - CORDIS

FP7

GANNET53 Report Summary

Project ID: 602602
Funded under: FP7-HEALTH
Country: Austria

Periodic Report Summary 2 - GANNET53 (A drug strategy targeting stabilised mutant p53 to fight metastatic platinum-resistant 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 the clinical trial protocol was developed and all legal, ethical and administrative prerequisites for start of the GANNET53 Phase I trial were accomplished (lead: Austrian AGO/Innsbruck Medical University).
Two custom-tailored electronic Case Report Forms for Phase I and II and a biobank software were devolved for the effective organisation of a large multi-centre biobank, real-time tracking and distribution of biosamples.
In June 2014, the Phase I dose escalation/de-escalation trial was opened in 5 clinical centres in Austria, Germany, France and Belgium (lead: Centre Anticancereux Léon Bérard, Fig 2 Recruitment strategy). In total, ten patients were enrolled. Patients with platinum-resistant ovarian cancer (PROC) with high-grade serous, high-grade endometrioid, or undifferentiated histology and ≤4 prior chemotherapy regimen were eligible. Primary endpoints were safety and determination of the Ganetespib dose to be used in Phase II.
The dose-limiting toxicity (DLT) observation timeframe of 2 complete cycles was accomplished in all patients on 22.12.2014. No DLT occurred. The combination of Ganetespib 150 mg/m² with Paclitaxel 80 mg/m² once weekly for 3 / 4 weeks was well tolerated with no DLTs in the Phase I trial. Based on safety data reviewed, the independent Data and Safety Monitoring Committee (DSMC) recommended using 150mg/ m² Ganetespib in the Phase II trial and allowed the GANNET53 protocol to move forward without any major concerns.
The randomised, two-arm, open-label Phase II trial was opened in April 2015 (lead: KU Leuven). The same inclusion/exclusion criteria as in Phase I applied. In addition, archival tumour tissue was mandatory inclusion criteria to allow central histopathological review (Charité Berlin) to ensure eligible histological subtypes. The Phase II trial is 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 Ganetespib+Paclitaxel weekly, or Paclitaxel weekly alone (Fig 3 Phase II study design). Primary study endpoint is progression-free survival. On 21.05.2015 the first patient was enrolled in the randomised Phase II clinical trial.
After inclusion of more than half of the aspired patient number (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 Ganetespib to stop production of Ganetespib. In addition, some concerns about the futility of combining Ganetespib with a taxane arose due to (a) new preclinical in-vitro and animal data (lead: Universitaetsmedizin Goettingen), and (b) an immature and unplanned efficacy analysis (prompted by the limited 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. The GANNET53 consortium has collected various biomaterials (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.) at screening and at different time points during study treatment.
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.

Potential Impact:
The major aim of the GANNET53 trial is a significant progression-free survival benefit for platinum-resistant ovarian cancer (PROC) patients with aggressive histological subtypes harbouring p53 mutations.
Further expected results include:
• Improvement in patient reported outcome
• First clinical proof-of-concept that mutp53 is a critical target for cancer therapy in mutp53-dominated tumours
• First clinical proof-of-concept of the innovative mechanism of targeting mutp53 by Hsp90 inhibition
• Established safety of Ganetespib in new combination with the taxane Paclitaxel
• Unique biobank of collected biosamples of PROC patients before and during treatment
• Innovative software for effective organisation of a large multi-centre biobank and real-time tracking and distribution of biosamples
• Functional molecular test to detect mutp53-Hsp90 complexes in tumour tissues, and its value to predict responsiveness to experimental therapy with Ganetespib
• Value of circulating tumour cells (CTCs) for monitoring responsiveness to experimental therapy with Ganetespib
• In vivo genetic and pharmacologic proof-of-principle for the mutp53-targeting concept in engineered knock-in mouse models
In Europe, ovarian cancer is the fifth most commonly diagnosed female cancer. About half of women diagnosed with ovarian cancer will not live beyond five years. The burden of ovarian cancer for the society is not only due to its morbidity and mortality, but also to the treatment impact itself, which has significant side effects and a low response rate in platinum-resistant disease administered in an unselected patient cohort, leading to an enormous burden on healthcare budgets. Our project offers a completely new therapeutic strategy with the potential benefit to markedly prolong survival and improve quality of life. Our approach addresses the obvious urgent social need to expand the therapeutic armamentarium to fight ovarian cancer.
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.
Results from our research project will strongly stimulate the European pharmaceutical industry to perform further investigations and investments on the continuous development and/or improvement of more advanced, rationally designed Hsp90 inhibitors with improved toxicity and efficacy profiles. Furthermore, the proof-of-concept for degrading stabilised mutp53 as a rational target for anticancer treatment will be an enormous stimulus for the development of novel mutp53 targeting drugs in general, leading to the development of new innovative classes of anticancer agents. Since GANNET53 targets mutp53 in ovarian cancer patients and mutp53 proteins are overexpressed in more than 50% of all human cancers, results will carry enormous potential for exploitation in the entire field of oncology.
The implementation of our research project provides a variety of employment opportunities for researchers, clinical staff, supports business, regulatory committees and the related pharmaceutical industry. Three SMEs are participating in the project, each bringing unique expertise and innovation to the task assigned. Exploitation of their results, i.e. innovative software for multi-centre clinical data retrieval and biobanking, as well as a response-predictive test for the new therapy, will certainly contribute to the European economic development and increased global competitiveness of the European Union.

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

Related information

Contact

Nicole Concin, (Assistant Medical Director)
Tel.: +43 51250481433
E-mail

Subjects

Life Sciences
Record Number: 195857 / Last updated on: 2017-03-14
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