CLINICAL TRIALS

Within the EU project GANNET53 two different clinical trials are conducted which are accompanied by companion diagnostics activities and the establishment of an extensive biobank.

  • The first clinical trial is the GANNET53 CLINICAL TRIAL consisting of a Phase I and a Phase II trial. The GANNET53 trial is a Europe-wide multi-centre clinical trial, involving national trial groups to safeguard sufficient enrolment of patients. Recruitment in the GANNET53 Phase II clinical trial has already been closed in September 2016.
  • The EUDARIO CLINICAL TRIAL is a European, multi-center, randomised three-arm open-label Phase II trial in mutp53, platinum-sensitive ovarian cancer patients. It evaluates the safety and efficacy of Ganetespib in combination with Carboplatin on one hand and the Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor Niraparib on the other hand in comparison to standard treatment options. THE EUDARIO CLINICAL TRIAL IS CURRENTLY OPEN FOR RECRUITMENT.

EUDARIO Clinical Trial

The objectives of the EUDARIO trial are

  • Definition of safety of Ganetespib in combination with Carboplatin in platinum-sensitive ovarian cancer patients in the EUDARIO trial;
  • Definition of safety of Ganetespib in a new combination with the PARPi Niraparib in the EUDARIO trial;
  • Determine EFFICACY in the EUDARIO trial
  • collect biomaterials for molecular efficacy testing of Ganetespib and for p53 status analysis

The EUDARIO trial is an open label three-arm randomised Phase II study where the efficacy of Ganetespib 150mg/m2 in combination with Carboplatin AUC5 followed by maintenance treatment with the PARPi Niraparib (+/- Ganetespib in arms B and C, respectively) is compared versus standard Carboplatin combination treatment (investigator`s choice: Carboplatin puls Gemcitabine or Carboplatin plus Paclitaxel, respectively) followed by maintenance treatment with Niraparib in platinum-sensitive ovarian cancer patients.

EUDARIO Patient Recruitment Strategy

The EUDARIO trial is also a Europe-wide multi-centre clinical trial, involving national trial groups to safeguard sufficient and fast enrolment of patients. The EUDARIO trial will be open in Belgium, Austria, Germany, France and Italy via the respective national trial groups.

The national trial groups are:

  1. A-AGO (Austrian Gynaecological Oncology Trial Group) with its trial centre at Innsbruck Medical University (P1)
  2. NOGGO (North-Eastern German Society of Gynaecological Oncology; P9)
  3. GINECO (Groupe d’Investigateurs Nationaux pour l’Étude des Cancers Ovariens et du Sein; P10)
  4. BGOG (Belgium and Luxembourg Gynaecological Oncology Group) with its trial center at KU Leuven (P2)
  5. MITO (Multicenter Italian Trials in Ovarian cancer and gynaecologic malignancies; P20)

BGOG trial centre is the legal sponsor and the lead-trial group of the EUDARIO trial.

All core competences related to the performance of clinical trials are available in the BGOG trial centre and the national trial groups. With this concept we avoid the inclusion of for-profit service providers.


GANNET53 Clinical Trial

The GANNET53 Clinical Trial (EUDRACT Number: 2013-003868-31) addresses women with platinum-resistant, high-grade serous, high-grade endometrioid, or undifferentiated epithelial ovarian, fallopian tube or primary peritoneal cancer.

The GANNET53 trial combats metastatic platinum-resistant ovarian cancer with a novel drug strategy that targets the central driver of aggressiveness and metastatic ability of epithelial ovarian cancers, namely stabilised mutant p53 protein, for degradation via an innovative Hsp90 (heat shock protein 90) inhibition mechanism in order to substantially improve SURVIVAL.

The GANNET53 drug strategy is targeting a central driver of tumour aggressiveness and metastatic ability, namely mutant p53, via an innovative new Hsp90 (heat shock protein 90) inhibition mechanism. The most advanced, second-generation Hsp90 inhibitor is used, Ganetespib.

The first part (Phase I) of the GANNET53 trial will test the safety of Ganetespib in a new combination with standard chemotherapy (Paclitaxel weekly) in high-grade serous, high-grade endometrioid or undifferenciated, platinum-resistant ovarian cancer patients. The second part (randomised Phase II) will examine the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone in this group of ovarian cancer patients.

The GANNET53 Phase I

GANNET53 Phase II

Description of work

Translational Research

Biobank

Objectives

  • Develop a database for biosample collection (virtual tumour bank) and biosample tracking
  • Organise prospective and retrospective collection, deposition and delivery of biomaterials
  • Provide Central Histopathological Review (CHR) to ensure the inclusion of solely Type II tumours into Phase II and to ensure tissue sample quality for experimental work

Description of Work

Results

An outstanding biobank was established by the clinical partners from patients included in the randomised Phase II trial. Collected biomaterials include archival formalin-fixed, paraffin-embedded (FFPE) tumour tissues, biopsies of the actual relapse (fresh-frozen or FFPE), blood fractions (plasma, serum, cell pallets) collected taken at different time-points prior and during study treatment, circulating tumour cells (CTCs) in the blood, as well as ascites and pleural effusion samples.

Archival FFPE tumour tissues

Plasma, serum, cell pellets

Circulating tumour cells (CTCs)

Biopsies of the actual relapse

Ascites and pleura effusions

Companion Diagnostics

Objectives

  • Determine the exact p53 status in Phase II patients
  • Perform molecular efficacy testing: (1) a functional molecular test (proximity ligation assay) will be developed and evaluated for its value to predict responsiveness to Ganetespib. (2) CTC analysis before and during experimental therapy will be performed and evaluated for its value to monitor responsiveness to Ganetespib.

Results

Functional molecular test (proximity ligation assay) developed

The proximity ligation assay (PLA) is an in situ technology, which allows a sensitive detection of protein, protein interactions. The signal can be localized with single molecule resolution. Specific antibodies recognize the two targets and are subsequently bound by PLA probes. They have a short DNA strand attached, and when in close proximity, they interact, are ligated and amplified via rolling circle amplification. Fluorochrome-labelled probes are then added to visualize the product, which is than seen as bright spot in the fluorescence microscope.

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p53 mutational status in all Phase II patients determined

The GANNET53 project is based on the hypothesis that mutant p53 is stabilized through the chaperon HSP90 and can therefore neither fulfil its function, nor be degraded. This stabilization is a prerequisite for gain-of-function capabilities promoting tumour growth. Furthermore, tumours carrying a missense TP53 mutation develop a dependency on the high protein levels and withdrawal should results in cytotoxicity. The HSP90 inhibitor Ganetespib is used to release stabilized p53 and target it for degradation. The GANNET53 trial includes patients with Type II ovarian cancer. This type of cancer is characterized by an almost ubiquitous presence of TP53 mutations. As part of the companion diagnostics, the TP53 mutation status of all patients is determined. For this purpose, it was mandatory that archival tissue of each patient included in the study was available. This analysis allows linking effects of the treatment to the presence of a TP53 mutation in general, and to certain mutations in specific. Furthermore, those results are the basis for additional projects which are conducted as part of the companion diagnostics, as for example the analysis of circulating DNA.

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Mouse Models and Human Xenografts

Objectives

  • Provide the most stringent in vivo genetic and pharmacologic proof-of-principle for the underlying treatment concept in engineered mutp53 knock-in mice.
  • Stringently test the Ganetespib-mediated preferential killing of mutp53 cancer cells in human ovarian cancer models (cultured cells and nude mice).

Results

Publication: CELL DEATH AND DIFFERENTIATION (2016), 1–17: Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitoticDNA fragmentation in ovarian cancer cells. Kramer D, Stark N, Schulz-Heddergott R, Erytch N, Edmunds S, Roßmann L, Bastians H, Concin N, Moll UM, Dobbelstein M. doi: 10.1038/cdd.2016.124. [Epub ahead of print] PMID: 27834954; Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299713/;