ARIEL4: A Study of Rucaparib Versus Chemotherapy BRCA Mutant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients

Phase 3

Completed

• Conditions: Ovarian Cancer; Epithelial Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cancer
• Interventions: Drug: Chemotherapy; Drug: Rucaparib

• Registration Number: NCT02855944
• Lead Sponsor: pharmaand GmbH

Brief Summary

The purpose of this study is to determine how patients with ovarian, fallopian tube, and primary peritoneal cancer will best respond to treatment with rucaparib versus chemotherapy.

Detailed Description

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). The safety and efficacy of rucaparib has been evaluated in several Phase 1 and Phase 2 studies. An oral formulation is the focus of current development efforts. Rucaparib is currently being investigated as monotherapy in patients with cancer associated with breast cancer susceptibility gene 1 (BRCA1) or BRCA2 mutations.

While PARP inhibitors have demonstrated consistent robust clinical activity in patients with relapsed ovarian cancer associated with HRD, prospective studies evaluating efficacy and safety of PARPi versus standard of care chemotherapy have been limited. The primary purpose of this Phase 3 study is to compare the efficacy and safety of rucaparib versus chemotherapy as treatment for relapsed ovarian cancer in patients with a deleterious BRCA1/2 mutation in their tumor.

Study Timeline

• Study First Submitted: 2016-07-22
• Study First Submitted QC: 2016-08-01
• Study First Posted: 2016-08-04
• Study Start: 2017-03-01
• Primary Completion: 2020-12-03
• Results First Submitted: 2021-11-29
• Results First Submitted QC: 2022-01-19
• Results First Posted: 2022-02-11
• Study Completion: 2022-09-16
• Status Verified: 2023-06
• Last Update Submitted: 2023-06-07
• Last Update Posted: 2023-06-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 349

Inclusion Criteria

• Be 18 years of age at the time the informed consent form is signed
• Have a histologically confirmed diagnosis of high-grade serous or Grade 2 or Grade 3 endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer
• Received ≥ 2 prior chemotherapy regimens and have relapsed or progressive disease as confirmed by radiologic assessment
• Have biopsiable and evaluable disease. Note: biopsy is optional for patients known to harbor a BRCA1/2 mutation
• Have sufficient archival formalin-fixed paraffin-embedded (FFPE) tumor tissue available for planned analyses

Exclusion Criteria

• History of prior cancers except for those that have been curatively treated, with no evidence of cancer currently (provided all chemotherapy was completed >6 months prior and/or bone marrow transplant >2 years prior to first dose of rucaparib).
• Prior treatment with any PARP inhibitor
• Symptomatic and/or untreated central nervous system metastases
• Pre-existing duodenal stent and/or any other gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of rucaparib
• Women who are pregnant or breast feeding
• Hospitalization for bowel obstruction within 3 months prior to enrollment

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Chemotherapy	Chemotherapy	Monotherapy platinum (cisplatin or carboplatin) or platinum-based doublet chemotherapy (carboplatin/paclitaxel, carboplatin/gemcitabine, or cisplatin/gemcitabine administered per local standard of care and regulations. Specific comparator will depend on platinum status and investigator decision. Single agent paclitaxel will be administered per local standard of care and regulations. Specific comparator will depend on platinum status and investigator decision.
Rucaparib	Rucaparib	Drug: Oral rucaparib 600 mg BID (twice a day) Other Names: * CO-338 * PF 01367338 * AG 14699 * Rubraca

Primary Outcome Measures

Name	Time	Method
Investigator Assessed Progression-Free Survival (invPFS) by RECIST Version 1.1 for Rucaparib Versus Chemotherapy (Efficacy Population)	Assessments every 8 weeks from Cycle 1 Day 1 (C1D1) until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.	The primary efficacy endpoint is invPFS for the Treatment Part of the study. The time to invPFS is calculated in months as the time from randomization to disease progression +1 day, as determined by RECIST v1.1 (Response Evaluation Criteria in Solid Tumors) criteria or death due to any cause, whichever occurs first. Progression is defined using RECIST v1.1, as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Investigator Assessed Progression-Free Survival (invPFS) by RECIST Version 1.1 for Rucaparib Versus Chemotherapy (ITT Population)	Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.	The primary efficacy endpoint is invPFS for the Treatment Part of the study. The time to invPFS is calculated in months as the time from randomization to disease progression +1 day, as determined by RECIST v1.1 (Response Evaluation Criteria in Solid Tumors) criteria or death due to any cause, whichever occurs first. Progression is defined using RECIST v1.1, as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

Name	Time	Method
Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 (ITT Population)	Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.	A secondary endpoint is the ORR for the Treatment Part of the study. ORR is defined as the percentage of patients with a confirmed CR (complete response) or PR (partial response) by RECIST v1.1. The confirmed response is defined as a CR or PR on subsequent tumor assessment at least 28 days after first response documentation. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.
Investigator Assessed Duration of Response (DOR) by RECIST v1.1 (ITT Population)	Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.	A secondary endpoint is the DOR for the Treatment Part of the study. The DOR as assessed by investigator is analyzed in the subgroup of patients who had a confirmed response by RECIST v1.1. DOR for any confirmed RECIST CR or PR will be measured from the date of the first response until the first date that progressive disease (PD) is documented. DOR is calculated in months as the time from the first date of the scan showing a response to the first scan with disease progression +1 day. Any patients with an ongoing response are censored at the date of the last post-baseline scan. Only tumor scans up to and within 6 weeks of start of any subsequent anti-cancer treatment are included. Progressive disease (PD) is defined using RECIST v1.1, as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 and/or CA-125 Response (Efficacy Population)	Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.	A secondary endpoint is ORR for the Treatment Part of the study defined as the percentage of patients with best response of CR or PR using RECIST v1.1 or response per Gynecologic Cancer InterGroup Cancer Antigen 125 (GCIG CA-125) criteria. Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Response to CA-125 has occurred if there is at least a 50% decrease from baseline: 1. in a sample collected after initiation of study treatment AND 2. that is confirmed in a subsequent sample collected ≥21 days after the prior sample. The absolute value of this confirmatory sample must be ≤110% of the prior sample. The date when the first sample with a 50% decrease from baseline is observed is the date of the CA-125 response.
Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 (Efficacy Population)	Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.	A secondary endpoint is the ORR for the Treatment Part of the study. ORR is defined as the percentage of patients with a confirmed CR (complete response) or PR (partial response) by RECIST v1.1. The confirmed response is defined as a CR or PR on subsequent tumor assessment at least 28 days after first response documentation. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.
Least Squares Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status Score for the First 6 Cycles (Efficacy Population)	Baseline to the end of Cycle 6, or up to approximately 6 months	EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer patients. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. Mean changes from baseline global score over the first 6 cycles in the Treatment Part of the study were analyzed.
Least Squares Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status Score for the First 6 Cycles (ITT Population)	Baseline to the end of Cycle 6, or up to approximately 6 months	EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer patients. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. Mean changes from baseline global score over the first 6 cycles in the Treatment Part of the study were analyzed.
Overall Survival (Efficacy Population)	All patients were followed for survival up to approximately 3.5 years.	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.
Overall Survival (ITT Population)	All patients were followed for survival up to approximately 3.5 years.	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.
Investigator Assessed Duration of Response (DOR) by RECIST v1.1 (Efficacy Population)	Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.	A secondary endpoint is the DOR for the Treatment Part of the study. The DOR as assessed by investigator is analyzed in the subgroup of patients who had a confirmed response by RECIST v1.1. DOR for any confirmed RECIST CR or PR will be measured from the date of the first response until the first date that progressive disease (PD) is documented. DOR is calculated in months as the time from the first date of the scan showing a response to the first scan with disease progression +1 day. Any patients with an ongoing response are censored at the date of the last post-baseline scan. Only tumor scans up to and within 6 weeks of start of any subsequent anti-cancer treatment are included. Progressive disease (PD) is defined using RECIST v1.1, as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 and/or CA-125 Response (ITT Population)	Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.	A secondary endpoint is ORR for the Treatment Part of the study defined as the percentage of patients with best response of CR or PR using RECIST v1.1 or response per Gynecologic Cancer InterGroup Cancer Antigen 125 (GCIG CA-125) criteria. Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Response to CA-125 has occurred if there is at least a 50% decrease from baseline: 1. in a sample collected after initiation of study treatment AND 2. that is confirmed in a subsequent sample collected ≥21 days after the prior sample. The absolute value of this confirmatory sample must be ≤110% of the prior sample. The date when the first sample with a 50% decrease from baseline is observed is the date of the CA-125 response.

Trial Locations

Locations (76)

Bialostockie Centrum Onkologii im. Marii Sklodowskiej-Curie; 🇵🇱 Bialystok, Poland

Volyn Regional Oncology Dispensary; 🇺🇦 Lutsk, Ukraine

Sumy Regional Oncology Center; 🇺🇦 Sumy, Ukraine

Fakultní Nemocnice Ostrava; 🇨🇿 Ostrava, Czechia

Augusta University; 🇺🇸 Augusta, Georgia, United States

Hospital do Cancer de Barretos; 🇧🇷 Barretos, SAO Paulo, Brazil

Hospital Haroldo Juacaba Instituto do Cancer do Ceara; 🇧🇷 Fortaleza, Ceara, Brazil

Instituto de Oncologia do Parana (IOP); 🇧🇷 Curitiba, Parana, Brazil

Instituto Nacional de Câncer Hospital do Câncer II; 🇧🇷 Rio de Janeiro, Brazil

Rabin Medical Center; 🇮🇱 Petach-Tikva, Israel

Chaim Sheba Medical Center; 🇮🇱 Ramat Gan, Israel

Országos Onkológiai Intézet; 🇭🇺 Budapest, Hungary

Hadassah Medical Organization; 🇮🇱 Jerusalem, Israel

Carmel Medical Center; 🇮🇱 Haifa, Israel

Arkhangelsk Clinical Oncological Dispensary; 🇷🇺 Arkhangelsk, Russian Federation

Istituto per la Ricerca e la Cura del Cancro Istituto di Candiolo; 🇮🇹 Candiolo, Italy

Moscow Clinical Scientific and Practical Center of Moscow Healthcare Department; 🇷🇺 Moscow, Russian Federation

Saint Petersburg City Oncological Dispensary; 🇷🇺 Saint-Petersburg, Russian Federation

Republic Clinical Oncology Dispensary of the Ministry of Healthcare of Republic of Bashkortostan; 🇷🇺 Ufa, Russian Federation

Omsk Region Clinical Oncologic Dispensary; 🇷🇺 Omsk, Russian Federation

Azienda Ospedaliero-Universitaria Policlinico di Modena; 🇮🇹 Modena, Italy

Hospital Universitari de Girona Doctor Josep Trueta; 🇪🇸 Girona, Spain

State Healthcare Institution Oncologic Dispensary No. 2 - Health Department of Krasnodar Region; 🇷🇺 Sochi, Russian Federation

União Brasileira de Educação e Assistência / Hospital São Lucas da PUCRS; 🇧🇷 Porto Alegre, RIO Grande DO SUL, Brazil

CEPON-Centro de pesquisas Oncologicas; 🇧🇷 Florianópolis, Santa Catarina, Brazil

Rocky Mountain Cancer Center; 🇺🇸 Denver, Colorado, United States

Princess Margaret Hospital; 🇨🇦 Toronto, Ontario, Canada

The Ottawa Hospital - General Campus; 🇨🇦 Ottawa, Ontario, Canada

Hospital Pérola Byington - Centro de Referência da Saúde da Mulher; 🇧🇷 Sao Paulo, Brazil

Hospital São Camilo; 🇧🇷 Sao Paulo, Brazil

Tom Baker Cancer Center; 🇨🇦 Calgary, Alberta, Canada

CIUSSS de l'Estrie CHUS; 🇨🇦 Sherbrooke, Quebec, Canada

Centre Hospitalier de L'Universite de Montreal (CHUM); 🇨🇦 Montreal, Quebec, Canada

Masarykuv Onkologicky Ustav, Oddeleni komplexni klinicke onkologie; 🇨🇿 Brno, Jihormoravsky KRAJ, Czechia

Fakultni Nemocnice v Motole; 🇨🇿 Praha 5, Praha, Czechia

Debreceni Egyetem Klinikai Központ; 🇭🇺 Debrecen, Hajdu-bihar, Hungary

Všeobecná Fakultní Nemocnice v Praze; 🇨🇿 Praha, Czechia

Edith Wolfson Medical Center; 🇮🇱 Holon, Israel

Tel Aviv Sourasky Medical Center, Oncology Dept.; 🇮🇱 Tel Aviv, Israel

Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi; 🇮🇹 Bologna, Italy

AO per l'emergenza Cannizzaro; 🇮🇹 Catania, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori; 🇮🇹 Milano, Italy

Istituto Europeo di Oncologia; 🇮🇹 Milano, Italy

Istituto Nazionale per lo studio e la cura dei tumori "Fondazione Pascale" Oncologia Medica; 🇮🇹 Napoli, Italy

Fondazione Policlinico Universitario Agostino Gemelli; 🇮🇹 Roma, Italy

Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie; 🇵🇱 Lublin, Poland

Wojewodzki Szpital Specjalistyczny w Olsztynie; 🇵🇱 Olsztyn, Poland

Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Pozna; 🇵🇱 Poznan, Poland

Pomorska Akademia Medyczna w Szczecinie, Samodzielny Publiczny Szpital Kliniczny Nr 2; 🇵🇱 Szczecin, Poland

Kursk Regional Oncologic Dispensary; 🇷🇺 Kursk, Russian Federation

Pyatigorsk Oncological Dispensary; 🇷🇺 Pyatigorsk, Russian Federation

Ryazan Regional Clinical Oncology Dispensary; 🇷🇺 Ryazan, Russian Federation

Pavlov First Saint-Petersburg State Medical University; 🇷🇺 Saint Petersburg, Russian Federation

Hospital Duran i Reynals; 🇪🇸 Barcelona, Spain

Hospital Universitari Vall DHebron; 🇪🇸 Barcelona, Spain

Centro Oncologico Regional de Galicia; 🇪🇸 La Coruna, Spain

Hospital Clinico San Carlos; 🇪🇸 Madrid, Spain

MD Anderson Cancer Center; 🇪🇸 Madrid, Spain

Hospital Universitario Ramón y Cajal; 🇪🇸 Madrid, Spain

Dnipropetrovsk City Multifield Clinical Hospital Number 4; 🇺🇦 Dnipropetrovsk, Ukraine

National Cancer Institute of the Ministry of Health of Ukraine; 🇺🇦 Kyiv, Ukraine

Universidad Autonoma de Madrid (UAM) - Hospital Universitario La Paz; 🇪🇸 Madrid, Spain

Lviv Regional Oncology Dispensary; 🇺🇦 Lviv, Ukraine

Zakarpattya Regional Clinical Oncological Dispensary; 🇺🇦 Uzhgorod, Ukraine

The Royal Marsden NHS Foundation Trust; 🇬🇧 Sutton, Surrey, United Kingdom

The Christie NHS Foundation Trust - Clinical Trial Pharmacy; 🇬🇧 Manchester, England, United Kingdom

University Hospital of Coventry and Warwickshire NHS Trust; 🇬🇧 Coventry, United Kingdom

Velindre NHS Trust; 🇬🇧 Cardiff, United Kingdom

Derby Teaching Hospital NHS Foundation Trust; 🇬🇧 Derby, United Kingdom

University College London Hospitals; 🇬🇧 London, United Kingdom

NHS Greater Glasgow and Clyde; 🇬🇧 Glasgow, United Kingdom

East and North Hertfordshire NHS Trust; 🇬🇧 Middlesex, United Kingdom

Republican oncological dispensary of Republic of Mordovia; 🇷🇺 Saransk, Russian Federation

Cambridge University Hospitals NHS Foundation Trust; 🇬🇧 Cambridge, United Kingdom

Newcastle Hospitals NHS Foundation Trust; 🇬🇧 Newcastle upon Tyne, United Kingdom

Niepubliczny Zaklad Opieki Zdrowotnej Innowacyjna Medycyna Sp z o.o.; 🇵🇱 Grzybnica, West Pomeranian Voivodeship, Poland