GANNET53: Ganetespib in Metastatic, p53-mutant, Platinum-resistant Ovarian Cancer

A Two-part, Multicentre, International Phase I and II Trial Assessing the Safety and Efficacy of the Hsp90 Inhibitor Ganetespib in Combination With Paclitaxel Weekly in Women With High-grade Serous, High-grade Endometrioid, or Undifferentiated, Platinum-resistant Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy causing 41900 deaths annually in Europe. The predominance of aggressive Type II tumours, which are characterised by a high frequency of p53 mutations, and primary or acquired resistance to platinum-based chemotherapy profoundly contribute to the high mortality rate. With current standard therapy the median overall survival of metastatic platinum-resistant (Pt-R) ovarian cancer patients is only 14 month. There is a pressing need for more effective, innovative treatment strategies to particularly improve survival in this subgroup of EOC patients. This is a drug strategy 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 will be 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 Pt-R EOC patients. The second part (randomised Phase II) will examine the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone in EOC patients with Pt-R tumours.

Study Overview

• Status: Terminated
• Conditions: Fallopian Tube Cancer; Epithelial Ovarian Cancer; Primary Peritoneal Cancer
• Intervention / Treatment: Drug: Paclitaxel; Drug: Ganetespib

• Study Type: Interventional
• Enrollment (Actual): 133
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Medical University Innsbruck, Department for Gynaecology and Obstetrics
• Belgium
  • Leuven, Belgium, 3000
    • Katholieke Universiteit Leuven, Dept. of Gynaecologic Oncology
• France
  • Caen, France, 14076
    • Centre de Lutte Contre le Cancer François Baclesse
  • Lyon, France, 69373
    • Centre anticancereux Leon Berard
  • Paris, France, 45004
    • Assistance Publique - Hôpitaux de Paris Medical Oncology Department
• Germany
  • Berlin, Germany, 10117
    • Universitätsmedizin Berlin Charité, Dept. for Gynecology
  • Dresden, Germany, 01069
    • University Hospital Carl Gustav Carus Dresden, Department of Gynaecology and Obstetrics
  • Essen, Germany, 45136
    • Kliniken Essen Mitte, Evang. Huyssens-Stiftung / Knappschaft GmbH Department of Gynaecologic Oncology
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf Dept. of Gynecology and Gynecologic Oncology
  • Magdeburg, Germany, 39106
    • Otto-von-Guericke-Universität Magdeburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Ability to understand and willingness to sign and date a written informed consent document
• Female patients ≥18 years of age
• High-grade serous, high-grade endometrioid, or undifferentiated epithelial ovarian, fallopian tube or primary peritoneal cancer

• Patients in part II: High-grade serous, high-grade endometrioid, or undifferentiated epithelial ovarian, fallopian tube or primary peritoneal cancer confirmed by central histopathology through archival formalin-fixed paraffin embedded (FFPE) or fresh-frozen tumour samples.

  • Platinum-resistant disease:

• primary platinum-resistant disease: progression > 1 month and ≤ 6 months after completion of primary platinum-based therapy
• secondary platinum-resistant disease (including secondary platinum-refractory disease): progression ≤ 6 months after (or during) reiterative platinum-based therapy
• Patients must have disease that is measurable according to RECIST 1.1 or assessable according to the GCIG (Eastern Cooperative Oncology Group) CA-125 criteria
• ECOG performance status of 0-1
• Life expectancy of at least 3 months as assessed by the investigator

Adequate function of the bone marrow:

• Platelets ≥100 x 109/L
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Haemoglobin ≥ 8.5 g/dl. Patients may receive blood transfusion(s) to maintain haemoglobin values > 8.5 g/dl.

Adequate organ functions:

• Creatinine < 2 mg/dl (<177 µmol/L)
• Total bilirubin ≤ 1.5 x upper limit of normal
• SGOT ( serum glutamate oxaloacetate transaminase)/SGPT (serum glutamate pyruvate transaminase) (AST/ALT) ≤ 3 x upper limit of normal
• Urinanalysis or urine dipstick for proteinuria less than 2+. Patients with ≥ 2+ on dipstick should undergo 24-hour urine collection and must demonstrate < 1 g of protein/24 hours. Alternatively, proteinuria testing can be performed according to local standards
• Negative urine/serum pregnancy test in women of childbearing potential (WOCBP, see section 5). WOCBP who are sexually active, agree to use highly effective means of contraception during the study and for at least 6 months post-study treatment. Allowed are accepted and effective non-hormonal methods of contraception and sexual abstinence or vasectomised partners (>3 months previously). Vasectomy has to be confirmed by two negative semen analyses.
• Availability of archival ovarian cancer tissue for central histopathological review and p53 mutational analysis

Exclusion Criteria:

• Ovarian tumours with low malignant potential (i.e. borderline tumours)
• Primary platinum-refractory disease (progression during primary platinum-based chemotherapy)

PRIOR, CURRENT OR PLANNED TREATMENT:

• Previous treatment with > 2 chemotherapy regimens in the platinum-resistant setting (excluding targeted and endocrine therapies).
• More than 4 previous lines of chemotherapy.
• Major surgery within 2 weeks prior to first dose of ganetespib

PRIOR OR CONCOMITANT CONDITIONS OR PROCEDURES:

• Patients with a history of prior malignancies, except, disease-free time-frame of ≥ 3 years prior to randomisation.
• Patients with prior in-situ carcinomas, except:

complete removal of the tumour is given

• Known history of severe (grade 3 or 4) allergic or hypersensitivity reactions to excipients (e.g., polyethylene glycol [PEG] 300 and Polysorbate 80)
• History of intolerance or hypersensitivity to paclitaxel and/or adverse events related to paclitaxel that resulted in paclitaxel being permanently discontinued
• Peripheral neuropathy of grade > 2 per NCI CTCAE (Common Toxicity Criteria for Adverse Effects), version 4.03, within 4 weeks prior to randomisation
• Clinical symptomatic bowel obstruction at time of screening
• Left ventricular ejection fraction defined by MUGA (multigated acquisition)/ECHO below the institutional lower limit of normal
• Patients with symptomatic brain metastases
• Significant cardiac disease: New York Heart Association (NYHA) Class 3 or 4; myocardial infarction within the past 6 months; unstable angina; coronary angioplasty or coronary artery bypass graft (CABG) within the past 6 month; or uncontrolled atrial or ventricular cardiac arrhythmias.
• History of prolonged QT syndrome, or family member with prolonged QT syndrome
• QTc (corrected QT interval) interval > 470 msec when 3 consecutive EKG values are averaged
• Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a Class Ia antiarrhythmic drug (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of other antiarrhythmic drugs is permitted
• Second- or third-degree atrioventricular (AV) block, except:

treated with a permanent pacemaker

• Complete left bundle branch block (LBBB)
• Any other condition that, in the opinion of the investigator, may compromise the safety, compliance of the patient, or would preclude the patient from successful completion of the study.
• Participation in another clinical study with experimental therapy within 28 days before start of treatment.
• Women who are pregnant or are lactating

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ganetespib + Paclitaxel; Drug: ganetespib, dose will depend on phase I results, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle); Drug: paclitaxel, 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression.	Drug: Paclitaxel; Drug: Ganetespib
ACTIVE_COMPARATOR: Paclitaxel; Drug: paclitaxel: 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression	Drug: Paclitaxel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	evaluate the efficacy of ganetespib in combination with weekly paclitaxel compared to weekly paclitaxel alone as measured by Progression-free survival (PFS). Response or progression will be evaluated in this study according to Response Evaluation Criteria In Solid Tumors Criteria version 1.1., CA-125 according to published GCIG criteria, and by the investigator on the basis of physical and/or gynaecological examinations.	Time until progression (median w/o new drug 4 months)

Collaborators and Investigators

• Sponsor: Medical University Innsbruck
• Collaborators: European Commission
• Investigators: Principal Investigator: Nicole Concin, MD, Medical University Innsbruck

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 4, 2014
• Primary Completion (ACTUAL): November 30, 2017
• Study Completion (ACTUAL): December 4, 2017

Study Registration Dates

• First Submitted: December 2, 2013
• First Submitted That Met QC Criteria: December 10, 2013
• First Posted (ESTIMATE): December 16, 2013

Study Record Updates

• Last Update Posted (ACTUAL): August 13, 2019
• Last Update Submitted That Met QC Criteria: June 25, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: undifferentiated; High-grade serous; high-grade endometrioid
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Ovarian Neoplasms; Fallopian Tube Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel
• Other Study ID Numbers: GANNET53; 2013-003868-31 (EUDRACT_NUMBER)