Brief Title
GANNET53: Ganetespib in Metastatic, p53-mutant, Platinum-resistant Ovarian Cancer
Official Title
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
Brief Summary
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 Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Progression Free Survival (PFS)
Condition
Epithelial Ovarian Cancer
Intervention
Ganetespib
Study Arms / Comparison Groups
Ganetespib + Paclitaxel
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
133
Start Date
July 4, 2014
Completion Date
December 4, 2017
Primary Completion Date
November 30, 2017
Eligibility Criteria
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
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Nicole Concin, MD, ,
Location Countries
Austria
Location Countries
Austria
Administrative Informations
NCT ID
NCT02012192
Organization ID
GANNET53
Secondary IDs
2013-003868-31
Responsible Party
Principal Investigator
Study Sponsor
Medical University Innsbruck
Collaborators
European Commission
Study Sponsor
Nicole Concin, MD, Principal Investigator, Medical University Innsbruck
Verification Date
June 2019