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
- Conditions
- high-grade serous, high-grade endometrioid, of undifferentiated platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancerTherapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2013-003868-31-DE
- Lead Sponsor
- Medical University of Innsbruck, Austrian AGO Trial Centre
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- Female
- Target Recruitment
- 222
• 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.
o Patients in part II: High-grade serous, high-grade endometrioid, or undifferentiated epithelial ovarian, fallopian tube or primary peritoneal cancer confirmed by central histophathology through archival FFPE or fresh-frozen tumour samples.
• Platinum-resistant disease:
o primary platinum-resistant disease: progression > 1 month and = 6 months after completion of primary platinum-based therapy
o 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 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:
o Platelets =100 x 10^9/L
o Absolute neutrophil count (ANC) = 1.5 x 10^9/L
• Haemoglobin = 8.5 g/dl. Patients may receive blood transfusion(s) to maintain haemoglobin values > 8.5 g/dl.
• Adequate organ functions:
o Creatinine < 2 mg/dl (< 177 µmol/L)
o Total bilirubin = 1.5 x upper limit of normal
o SGOT/SGPT (AST/ALT) = 3 x upper limit of normal
o 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, except the proteinuria is clearly related to a cathether in the urinary system.
• Adequate coagulation parameters:
aPTT = 1.5 x ULN (patients on heparin treatment must have an aPTT between 1.5-2.5 x ULN), or INR = 1.5. (In patients receiving anticoagulants (such as warfarin) INR must be between 2.0 and 3.0 in two consecutive measurements 1-4 days apart).
• 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.
Only in part II of the trial:
• Availability of archival ovarian cancer tissue for central histopathological review and p53 mutational analysis
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 100
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 122
CANCER-RELATED:
• Ovarian tumours with low malignant potential (ie. borderline tumours)
- carcinosarcoma of the ovary
• Primary platinum-refractory disease (progression during primary platinum-based chemotherapy)
• History of evidence of hemorrhagic disorders; patients with active bleeding or pathologic conditions that carry high risk of bleeding disorders, coagulopathy, or tumour involving major vessels
PRIOR, CURRENT OR PLANNED TREATMENT:
• Previous treatment with > 2 chemotherapy regimens in the platinum-resistant setting (excluding targeted and endocrine therapies)
- Previous weekly Paclitaxel in relapse treatment
• More than 4 previous lines of chemotherapy
• Any prior radiotherapy to the pelvis or abdomen
• Surgery (including open biopsy and traumatic injury) within 4 weeks prior to first dose of ganetespib, or anticipation of the need for major surgery during study treatment.
• Minor surgical procedures, within 24 hours prior to the first study treatment
• Current or recent (within 10 days prior to the first study drug dose) chronic daily treatment with aspirin (>325 mg/day).
• Chronic daily treatment with corticosteroids (dose >10 mg/day methylprednisolone equivalent), excluding inhaled steroids
PRIOR OR CONCOMITANT CONDITIONS OR PROCEDURES:
• Patients with a history of prior malignancies, except,
o disease-free time-frame of = 3 years prior to randomisation
• Patients with prior in-situ carcinomas, except:
o 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, version 4.03, within 4 weeks prior to randomisation
• Clinically significant gastro-intestinal (GI) tract abnormalities that may increase the risk for GI bleeding and/or perforation including but not limited to: active peptic ulcer disease, known intraluminal metastatic lesion/s with risk of bleeding, inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), history of bowel obstruction within 1 year prior to first study treatment (excluding postoperative, i.e. within 4 weeks post surgery), other GI condition with increased risk of perforation such as a recurrence deeply infiltrating into the muscularis or mucosa of the rectosigmoid or the mucosa of the bladder, or history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
• Non-healing wound or non-healing bone fracture
• Left ventricular ejection fraction defined by MUGA/ECHO below the institutional lower limit of normal
• Patients with symptomatic brain metastases
• Cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or sub-arachnoid haemorrhage within =6 months prior to first study treatment
• 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 months; or uncontrolled atrial or ventricular cardiac arrhythmias
• History of prolonged QT syndrome, or family member with prolonged QT syndrome
• QTc interval > 470 msec when 3 consecutive EKG values are averaged
• Ventricular tachycardia or a supraventricular tach
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: Part I: to determine the safety of ganetespib + paclitaxel weekly <br><br>Part II: to determine efficacy of ganetespib + paclitaxel weekly vs. paclitaxel weekly alone;Secondary Objective: Part I: to determine the ganetespib combination dose to be used in part II<br><br>Part II: Patient related outcome, Pharmacokinetic<br><br>;Primary end point(s): Part I<br>• Safety: Adverse events (AEs) (measure according to NCI CTCAE, version 4.03), laboratory parameters, Eastern Cooperative Oncology Group (ECOG) performance status (PS), vital signs<br><br>Part II<br>• Progression-free survival (PFS) and PFS rates at 6 months;Timepoint(s) of evaluation of this end point: Part I<br>• Safety: days 1, 8, 15 of each cycle<br><br>Part II<br>• Progression-free survival (PFS) at 6 months and after end of trial
- Secondary Outcome Measures
Name Time Method