BNC105P Combination Study in Partially Platinum Sensitive Ovarian Cancer Patients

Study Overview
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Brief Summary
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This phase I/II trial will determine the recommended dose and activity of BNC105P for patients with partially platinum sensitive ovarian cancer in first or second relapse.

Detailed Description
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OUTLINE: This is a multi-center study. BNC105P is a novel vascular disrupting agent (VDA) with promising preclinical activity combined with platinum or gemcitabine. The results of standard chemotherapy with carboplatin and gemcitabine for ovarian cancer relapsing within 12 months of an initial platinum-based regimen require improvement. This trial will determine the recommended dose and activity of BNC105P administered with carboplatin and gemcitabine. PHASE I: This trial uses a standard 3+3 design for allocating participants to a starting dose level in Phase I. If dose level 1 is deemed to have acceptable toxicity then dose levels 2a and 2b can be opened at the same time. Dose level 3 will only open if both dose levels 2a and 2b are deemed to have acceptable toxicity. The underlying assumptions for determining the recommended doses for the triple combination of carboplatin, gemcitabine and BNC105P are that the likely minimum doses required of each agent are carboplatin AUC 4, gemcitabine 800 mg/m2 and BNC105P 12 mg/m2. This corresponds to dose level 1. PHASE II 1:1 RANDOMIZATION: Carboplatin AUC 4 on day 1, gemcitabine 800 or 1000 mg/m2 on days 1 and 8 of a 21 day cycle for a maximum of 6 cycles. OR Carboplatin AUC 4 on day 1, gemcitabine 800 or 1000 mg/m2 on days 1 and day 8 with dose of BNC105P as determined in phase I, on days 2 and 9 of a 21 day cycle for a maximum of 6 cycles, followed by single agent maintenance BNC105P 16 mg/m2 for a maximum of 6 additional cycles Minimum follow up for 12 months ECOG Performance Status for Phase I: 0-1; ECOG Performance Status for Phase II: 0-2 Life Expectancy: Less than 12 weeks Hematopoietic (both phases): Platelet count ≥ 100 x 109/L ANC ≥ 1.5 x 109/L Haemoglobin > 9g/dl (can be post transfusion) INR ≤ 1.5 x ULN Hepatic (both phases): Total Bilirubin ≤ 1.5 x the upper limit of normal (ULN) ALT ≤ 2.5 x ULN Renal (both phases): Creatinine clearance ≥ 55 mL/min according to Cockcroft Gault formula If Calculated GFR is 50 - 54 mL/min an isotopic GFR may be performed. If the isotopic GFR is > 55ml/min, the patient will be eligible for the study but the calculated GFR will be used for dose calculation. Cardiovascular (both phases): Normal left ventricular ejection fraction (LVEF), i.e. ≥ 50% on Gated Heart Pool Scan, or fractional shortening on echocardiogram ≥ institutional LLN performed within 2 months prior to randomisation Corrected QTc < 470 msec on ECG performed within 4 weeks prior to randomisation.

Official Title
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Phase I/II BNC105P Combination Study in Partially Platinum Sensitive Ovarian Cancer Patients in First or Second Relapse

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Gemcitabine
* Drug: Carboplatin
* Drug: Gemcitabine
* Drug: BNC105P


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Phase I Only: Histologically or cytologically proven diagnosis of epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, including all histological subtypes and carcinosarcoma. Inclusion Criteria for Phase II Only: Histologically proven diagnosis of epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer. Progression-free interval between 4 to 9 months after first line chemotherapy or 4 to 12 months after second-line chemotherapy with a platinum (cisplatin or carboplatin) based regimen. Subjects must have progressed (based on GCIG CA125 and/or RECIST criteria) after last platinum based regimen. Subjects must be assessable for response based on GCIG CA125 and/or RECIST criteria. Subjects with clinically evident ascites and/or pleural effusions must be assessable by RECIST. Study treatment both planned and able to start within 7 days of randomisation Exclusion Criteria for Phases I and II: Non-epithelial ovarian cancer and ovarian tumours of low malignant potential (borderline tumours) More than two prior chemotherapy regimens for ovarian cancer (excluding hormonal therapy or biologic agents). Any prior chemotherapy for other cancers, but >10 years permitted for phase II only, except for high dose chemotherapy/autologous or allogeneic transplantation Chemotherapy within 20 days prior to registration. Hormonal therapy or biologic therapy within 28 days prior to registration Concurrent treatment with any experimental drugs or other anti-cancer therapy. Concurrent treatment with clopidogrel, ticlopidine, persantin and other antiplatelet agents Radiotherapy within 21 days prior to registration, or to greater than 15% of the bone marrow. Persistent toxic effects of previous chemotherapy of greater than Grade 1 severity (CTCAE v 4, appendix 8) Known brain or leptomeningeal disease (baseline CT brain or MRI is only required if there is clinical suspicion of central nervous system involvement). Subjects with other invasive malignancies who had (or have) any evidence of another cancer present within the last 3 years, with the exception of early stage non-melanoma skin cancer, carcinoma in situ of cervix, and synchronous endometrial cancer (stage 1 G1,2) Untreated and/or uncontrolled cardiovascular conditions and/or symptomatic cardiac dysfunction (unstable angina, congestive cardiac failure, myocardial infarction) within the previous year, or cardiac ventricular arrhythmias requiring medication, or history of 2nd or 3rd degree atrioventricular conduction defects. Cerebrovascular accident or transient ischemic attack within 6 months prior to registration. Poorly controlled hypertension: systolic BP >150 or diastolic BP >100 mmHg. Antihypertensive medications are permitted but BP must be ≤150 systolic and ≤100 diastolic on 2 readings separated by at least 24 hours. Deep vein thrombosis, pulmonary embolism, within 6 months of registration or arterial thrombosis, or arterial embolism within 12 months prior to registration. Receiving full dose, therapeutic anti-coagulation with warfarin, related oral anti-coagulants or unfractionated or low molecular weight heparin. Low dose heparin given for prophylaxis, and aspirin at a dose ≤ 325 mg/day is acceptable. Significant infection including active hepatitis B, hepatitis C with abnormal liver function tests, or HIV. Testing for these is not mandatory. Screening for Hepatitis B should be as per institutional policy. Patients known to be Hep B surface antigen positive will be not be eligible even if on antiviral treatment. Serious medical or psychiatric conditions which might prevent management according to the protocol. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomisation Pregnancy, lactation, or inadequate contraception. Women must be post menopausal or sterile, or use two reliable means of contraception. Women of childbearing potential must have a pregnancy test taken and proven negative within 7 days prior to registration. Life expectancy of less than 12 weeks. Exclusion Criteria for Phase II only: Carcinosarcoma and mucinous carcinoma

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase II Arm A<br>Phase II Arm A will randomize patients to treatment regimen of carboplatin and gemcitabine without BNC105P | Drug: Carboplatin<br>* Carboplatin AUC4 on day 1 of 21-day cycle, for a maximum of 6 cycles.<br>Drug: Gemcitabine<br>* Gemcitabine escalations 800 and 1000 mg/m2 (as determined in phase I) on days 1 and 8 of a 21 day cycle, for a maximum of 6 cycles.<br>|
| Experimental: Phase II Arm B<br>Phase II Arm B will randomize patients to treatment regimen of carboplatin and gemcitabine and will include BNC105P | Drug: Carboplatin<br>* Carboplatin AUC 4 on day 1 of a 21 day cycle, for a maximum of 6 cycles.<br>Drug: Gemcitabine<br>* Gemcitabine 800 or 1000 mg/m2 (as determined in phase I) on days 1 and day 8 of 21-day cycle, for a maximum of 6 cycles.<br>Drug: BNC105P<br>* BNC105P as determined in phase I, on days 2 and 9 of a 21 day cycle for a maximum of 6 cycles, followed by single agent maintenance BNC105P 16 mg/m2 for a maximum of 6 additional cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Determine Maximum Tolerated Dose for Patients | To determine the recommended dose of BNC105P given with gemcitabine and carboplatin (maximum dose of BNC105P with no more than 1 DLT in 6 phase I participants) | 12 months | 
| Phase II: Determine Objective Response Rate in Patients | To determine the objective response rate (ORR) in those with evaluable disease (ORR = CR, PR according to RECIST 1.1 and/or GCIG CA125 criteria) (percentage of those with measurable disease achieving CR or PR according to RECIST 1.1 and/or GCIG CA125 criteria) | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free and Overall Survival Distribution | To determine the progression free and overall survival distribution rates in this patient population | 12 months | 
| Patient Side Effects and Tolerability | To determine the adverse event rates (Numbers (%) with G2-5 AE (NCI CTCAE v4.0) | 12 months | 
| Patient Quality of Life Benefits | To determine the effects on aspects of health related quality of life (HRQL measured with FOSI and MOST), including symptom benefit (Numbers (%) with significant symptom benefit) | 12 months | 
| Assessment of BNC105P Pharmacokinetics to Determine Interaction with Carboplatin and Gemcitabine | Plasma will be collected to assess BNC105P pharmacokinetics on days 2 and 9 of cycle 1 only. Results will be compared with data from previous trials of BNC105P to determine their consistency and to establish if there is any major interaction with carboplatin and gemcitabine. | 12 months | 
| Association of Biomarkers, Predictions and Outcomes | To determine the associations between baseline biomarkers, ORR, PFS, OS and AE | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vascular Disrupting Agents, BNC105P, Partially platinum sensitive