Phase 3 Study of Rucaparib as Switch Maintenance After Platinum in Relapsed High Grade Serous or Endometrioid Ovarian Cancer (ARIEL3)

Study Overview
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Brief Summary
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Patients enrolled into this study will be stratified into 3 groups based on gene mutations identified in their tumor tissue. The purpose of this study is to evaluate patient response to maintenance treatment with rucaparib versus placebo. Response to treatment will be analyzed based on homologous recombination (HR) status of tumor samples.

Detailed Description
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Rucaparib is an orally available, small molecule inhibitor of poly-adenosine diphosphate [ADP] ribose polymerase (PARP) being developed for treatment of ovarian cancer associated with homologous recombination (HR) DNA repair deficiency (HRD). Clinical data have shown that ovarian cancer patients with and without evidence of a gBRCA mutation benefit from treatment with a PARP and that maintenance treatment with a PARP inhibitor following a response to platinum-based treatment increases PFS in patients with ovarian cancer. While patients with a BRCA mutation derived the most benefit, patients without evidence of a BRCA mutation also derived significant benefit. Patients enrolled into this study will be stratified into 3 groups based on tumor HRD status. The purpose of this study is to identify which of these groups of patients will most likely benefit from treatment with rucaparib. It is anticipated that rucaparib will provide therapeutic benefit and increase PFS in patients with HRD associated with a BRCA gene mutation or other HR gene alteration.

Official Title
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A Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer ( ARIEL3 )

Conditions
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Ovarian Cancer, Fallopian Tube Cancer, Peritoneal Cancer

Intervention / Treatment
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* Drug: Rucaparib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer. Received ≥2 prior platinum-based treatment regimens including platinum based regimen that must have been administered immediately prior to maintenance therapy in this trial. Received no more than 1 non-platinum chemotherapy regimen. Prior hormonal therapy will not be counted as a non-platinum regimen. Must have had at least a 6-month disease-free period following prior treatment with the penultimate platinum-based chemotherapy and achieved a response. For the last chemotherapy course prior to study entry, patients must have received a platinum-based doublet chemotherapy regimen and have achieved a CR or PR (as defined by RECIST) and/or a GCIG CA-125 response. Have sufficient archival tumor tissue for analysis. Exclusion Criteria: History of prior cancer except for non-melanoma skin cancer, breast cancer curatively > 3 years ago, curatively treated solid tumor (>5 years ago without evidence of recurrence), and synchronous endometrial cancer (Stage 1A) with ovarian cancer. Prior treatment with any PARP inhibitor, including rucaparib. Patients who received prior iniparib are eligible. Untreated or symptomatic central nervous system metastases. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of study drug. Required drainage of ascites during the final 2 cycles of their last platinum-based regimen and/or during the period between the last dose of chemotherapy of that regimen and randomization to maintenance treatment in this study.

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rucaparib<br>Oral tablets administered twice daily with 8 oz (240 mL) of water on an empty stomach or with food; 28-day cycles of treatment. Doses should be taken as close to 12 hours apart as possible, preferably at the same times every day. Tablets should be swallowed whole. | Drug: Rucaparib<br>* Oral tablets administered twice daily with 8 oz (240 mL) of water on an empty stomach or with food; 28-day cycles of treatment. Doses should be taken as close to 12 hours apart as possible, preferably at the same times every day. Tablets should be swallowed whole.<br>* Other names: AG 14699;|
| Placebo Comparator: Placebo<br>Oral tablets administered twice daily with 8 oz (240 mL) of water on an empty stomach or with food; 28-day cycles of treatment. Doses should be taken as close to 12 hours apart as possible, preferably at the same times every day. Tablets should be swallowed whole. | Drug: Placebo<br>* Oral tablets administered twice daily with 8 oz (240 mL) of water on an empty stomach or with food; 28-day cycles of treatment. Doses should be taken as close to 12 hours apart as possible, preferably at the same times every day. Tablets should be swallowed whole.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Progression According to RECIST Version 1.1, as Assessed by the Investigator, or Death From Any Cause (Investigator Progression Free Survival as Per invPFS) | Progression-free survival by Investigator (invPFS) is defined as the time from randomization to disease progression, according to RECIST v1.1 criteria as assessed by the investigator, or death due to any cause, whichever occurs first. Progressive disease is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of measurable lesions, an unequivocal increase in existing non-measurable lesion(s), or the appearance of unequivocal new lesion(s). | Every 12 calendar weeks (within 7 days prior is permitted) after start of treatment until treatment discontinuation due to disease progression. Total follow-up was up to approximately 3 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Progression According to RECIST v1.1, as Assessed by Independent Radiology Review (IRR), or Death From Any Cause (irrPFS) | To evaluate PFS by RECIST v1.1, as assessed by independent radiology review (IRR). | Every 12 calendar weeks (within 7 days prior is permitted) after start of treatment until treatment discontinuation due to disease progression. Total follow-up was up to approximately 8.2 years. | 
| Overall Survival (OS) | Overall survival (OS) is defined as the number of days from the date of randomization to the date of death (due to any cause). Patients who are still alive were censored on the date of their last available visit or last date known to be alive. | All patients were followed for survival up to approximately 8.2 years. | 
| Time to a 4-point Decrease in the Disease-related Symptoms - Physical (DRS-P) Subscale of the FOSI-18 | The National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index (FOSI-18) is a questionnaire, for completion by patients, designed to assess the impact of cancer therapy on ovarian cancer-related symptoms and is based on numerical point scoring of symptoms. The DRS-P subscale of the questionnaire is specifically designed to assess physical symptoms of ovarian cancer and evaluate changes in the subscale point score in individual assessments over time. This study looked at the time to a 4-point reduction in subscale score as an indicator of improvement in disease-related physical symptoms on cancer therapy. | Screening, Day 1 of each treatment cycle, Treatment Discontinuation visit, and 28-day Follow-up visit. Total follow-up was up to approximately 6.4 years. | 
| Time to an 8-point Decrease in the Total Score of the FOSI-18 | The National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index (FOSI-18) is a questionnaire, for completion by patients, designed to assess the impact of cancer therapy on ovarian cancer-related physical, emotional and treatment-related symptoms, and is based on numerical point scoring of symptoms. The questionnaire is designed to evaluate changes in the total score in individual assessments over time. This study looked at the time to an 8-point reduction in the total score as an indicator of improvement in disease-related symptoms on cancer therapy. | Screening, Day 1 of each treatment cycle, Treatment Discontinuation visit, and 28-day Follow-up visit. Total follow-up was up to approximately 6.4 years. | 
| Individual Model Parameter Estimates of Rucaparib and Covariates Identification | Concentration summary statistics | Study data collection occurred over approximately 7 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARIEL3, ARIEL 3, platinum sensitive, PARP Inhibitor, rucaparib, homologous recombination, homologous recombination deficiency, CO-338, PF 01367338, AG 14699, platinum sensitive ovarian cancer, platinum sensitive fallopian tube cancer, platinum sensitive primary peritoneal cancer, platinum sensitive peritoneal cancer, gynecological cancer, Clovis, Clovis Oncology