Efficacy of Platinum-based Chemotherapy in Platinum-resistant Ovarian Cancer) (EPITOC)

Study Overview
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Brief Summary
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This is a phase II/III randomized controlled trial to evaluate efficacy of platinum-based chemotherapy vs conventionally prescribed non-platinum monochemotherapy in patients with platinum-resistant ovarian cancer

Detailed Description
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Recurrent ovarian cancer (ROC) is usually subdivided to platinum-sensitive (platinum-free interval [PFI] ≥6 mo.) and platinum-resistant ovarian cancer [PROC] (PFI <6 mo.) subtypes. Prognosis for the latter group is dismal and current guidelines recommend treating these patients with non-platinum based chemotherapy. However, the evidence behind this is quite unconvincing and according to recent data patients with non-platinum refractory platinum-resistant ovarian cancer could derive benefit from platinum rechallenge. This trial is designed for head-to-head comparison of platinum and non-platinum therapy efficacy in treatment of platinum-resistant ovarian cancer.

Official Title
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Randomized Phase II/III Trial to Assess the Efficacy of Platinum-based Chemotherapy vs Standard Non-platinum Therapy in Patients With Platinum-resistant Recurrent Ovarian Cancer (ROC)

Conditions
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Ovarian Cancer, Ovarian Neoplasms, Serous Adenocarcinoma, BRCA1 Mutation, BRCA2 Mutation, Chemotherapy

Intervention / Treatment
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* Drug: Platinum-Based Drug
* Drug: Conventional chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70 years; Histologically confirmed epithelial ovarian cancer (excluding mucinous, clear-cell and low-grade subtypes); Ovarian cancer recurrence within 3-6 months after completion of platinum-based chemotherapy (given to possible variability in follow-up practices and tumor growth kinetics patients with platinum-free interval ≥3 and <7 months will be considered platinum-resistant); Platinum-free interval ≤12 months; Eastern Cooperative Oncology Group (ECOG) performance status ≤2; Response to penultimate platinum-based chemotherapy defined as partial or complete response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or ≥50% reduction in CA-125 concentration for patients without measurable lesions; Not refractory to penultimate platinum-based chemotherapy regimen (ie, the disease did not progress during platinum-based chemotherapy and within ≤3 months after its completion); Patients received ≤3 lines of prior chemotherapy; No central nervous system (CNS) metastatic involvement; No severe and uncontrolled concomitant diseases; Adequate organ function: Bone marrow - hemoglobin ≥ 90 g/l; Neutrophils ≥1,5x109/l; Platelets ≥75x109/l); Renal - estimated creatinine clearance ≥50 ml/min (determined by Cockcroft-Gault equation); Hepatic - alanine aminotransferase (ALaT) & aspartate transaminase (ASaT) ≤3 upper limit of normal (ULN), total bilirubin ≤ 25 umol/l; Known BRCA1/2 mutation status as it will be used for stratification; Life expectancy >3 months; Patient is willingly consent to participate in the trial and signed informed consent form Exclusion Criteria: Platinum-refractory ovarian cancer defined as disease progression during penultimate platinum-based chemotherapy or ≤3 month after its completion; No response to penultimate platinum-based chemotherapy; Mucinous, clear-cell or low-grade serous/endometrioid histology; >3 lines of prior therapy lines for advanced ovarian cancer (prior maintenance endocrine therapy or poly ADP ribose polymerase (PARP) inhibitors is allowed); Prior therapy with PARP-inhibitors and endocrine therapy as a treatment for progressive ovarian cancer; Platinum-free interval >12 months; Symptoms of bowel obstruction of any etiology; Contraindications to platinum-based chemotherapy; Planned administration of PARP inhibitors during or after this line of chemotherapy; Life expectancy <3 months; Uncontrolled and/or severe concomitant diseases (eg, uncontrolled diabetes mellitus, renal failure, hepatic failure, uncontrolled arterial hypertension, arrhythmia, heart failure); Metastatic CNS involvement; Neuropathy grade >2.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Parallel Assignment
Interventional Model Description: Randomized phase II/III trial to assess the efficacy of platinum-based chemotherapy vs standard non-platinum therapy in patients with platinum-resistant recurrent ovarian cancer (ROC)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Platinum-based chemotherapy<br>This is an experimental arm of this study. Allowed therapeutic options: Paclitaxel 60-80 mg/m2 + carboplatin area under curve (AUC) 2-2.7 d 1, 8, 15 every 3 or 4 weeks (Q3W or Q4W); Gemcitabine 1000 mg/m2 d 1, 8 + cisplatin 75 mg/m2 1 every 3 weeks; Doxorubicin 40-50 mg/m2 d 1 + carboplatin AUC5 or cisplatin 60-75 mg/m2 d 1 every 3 weeks; Topotecan 0.75 mg/m2 d 1-3 + cisplatin 60-75 mg/m2 or carboplatin AUC 4-5 d 1 every 3 weeks; Etoposide 100 mg once daily orally d 1-7 + cisplatin 60-75 mg/m2 d1 every 3 weeks. Up to 6 cycles of chemotherapy will be administered to study participants allocated to this arm. | Drug: Platinum-Based Drug<br>* Reintroduction of platinum-based chemotherapy<br>|
| Active Comparator: Non-platinum monochemotherapy<br>This is a control arm of this study. Allowed therapeutic options: Paclitaxel 60-80 mg/m2 weekly (or day 1, 8, 15 every 4 weeks schedule); Gemcitabine 1000 mg/m2 d 1, 8, 15 every 4 weeks; Doxorubicin 50-60 mg/m2 d 1 every 3 weeks; Topotecan 1,2-1,5 mg/m2 d 1-5 every 3 weeks; Etoposide 100 mg once daily orally d 1-10 every 3 weeks. Up to 6 cycles of chemotherapy will be administered to study participants allocated to this arm. | Drug: Conventional chemotherapy<br>* Conventional chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (RR) according to RECIST 1.1 criteria | Primary outcome for Phase II part: response rate to treatment according to RECIST1.1 criteria. For patients without measurable disease Rustin criteria is allowed. | 0-18 weeks | 
| Overall survival defined as time from randomization to death from any reason; | Primary outcome for Phase III part: 2. Overall survival defined as time from randomization to death from any reason | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Progression-free survival (PFS) defined as time from randomization to disease progression according to RECIST 1.1 criteria or death from any reason; | 12 months | 
| Overall survival | Overall survival defined as time from randomization to death from any reason (for Phase II part only); | 12 months | 
| Progression-free survival 2 (PFS2) | PFS2 defined as time from randomization to second disease progression event according to RECIST 1.1 criteria or death from any reason; | 24 months | 
| Objective response rate (RR) according to RECIST 1.1 criteria | Response rate to treatment according to RECIST1.1 criteria. For patients without measurable disease Rustin criteria is allowed (only for Phase II part). | 12 months |