Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

All Conditions

Immune System Diseases

Symptoms and General Pathology

Digestive System Diseases

Rare Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Hypersensitivity

Cicatrix

Carcinoma

Fallopian Tube Neoplasms

Peritoneal Neoplasms

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Fallopian Tube Diseases

Abdominal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Peritoneal Diseases

Ovarian Cancer

Ovarian Epithelial Cancer

Fallopian Tube Cancer

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Paclitaxel

Carboplatin

Albumin-Bound Paclitaxel

Cisplatin

Poly(ADP-ribose) Polymerase Inhibitors

Rucaparib

Tubulin Modulators

Antimitotic Agents

Antimetabolites

Enzyme Inhibitors

Drug: Oral rucaparib

600 mg BID (twice a day)

Other Names:

* CO-338
* PF 01367338
* AG 14699
* Rubraca

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.

Chemotherapy will be administered per local standard of care and regulations. Specific comparator will depend on platinum status and investigator decision.

Chemotherapy

Tablets of rucaparib, at a dose of 600 mg, will be taken orally twice a day

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.

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.

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

ARIEL4 (Assessment of Rucaparib In Ovarian CancEr TriaL): A Phase 3 Multicenter, Randomized Study of Rucaparib Versus Chemotherapy in Patients With Relapsed, BRCA Mutant, High Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

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.

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.

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.

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.

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 (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.

Foundation Medicine

pharmaand GmbH

Adverse events are reported for the Safety Population, defined as patients who received at least one dose of protocol-specified treatment.

Patients randomized to the rucaparib arm in the Treatment Part of the study.

Rucaparib (Treatment Part)

Patients randomized to the chemotherapy arm in the Treatment Part of the study.

Chemotherapy (Treatment Part)

Patients randomized to chemotherapy who then crossed over upon disease progression and were treated with rucaparib.

Rucaparib (Crossover Part)

Patients randomized to the rucaparib arm.

Patients randomized to the chemotherapy arm.

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Eastern Cooperative Oncology Group (ECOG) Performance Status Scale. ECOG 0 = Fully active, able to carry on all pre-disease performance without restriction. ECOG 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work or office work).

ECOG at Baseline

Number of Prior Chemotherapy Regimens

Number of Prior Platinum Regimens

* Platinum resistant: patients who progressed ≥ 1 to \< 6 months after the last dose of platinum-based chemotherapy;
* Partially platinum-sensitive: patients who progressed ≥ 6 to \< 12 months after last dose of platinum-based chemotherapy; and
* Platinum sensitive: patients who progressed ≥ 12 months after last dose of platinum-based chemotherapy

Randomization Stratification: Platinum Status

* BRCA1: patients with a deleterious breast cancer susceptibility gene 1 (BRCA1) mutation in their tumor
* BRCA2: patients with a deleterious breast cancer susceptibility gene 2 (BRCA2) mutation in their tumor
* Non-BRCA: patients without a BRCA mutation in their tumor

Combined Local and Central Lab BRCA Mutation Results

Mutation Type

Patients with a BRCA Reversion Mutation

Medical Information Department

Efficacy Population - All randomized patients in the treatment part of study with a deleterious BRCA mutation, excluding those identified to have a BRCA reversion mutation. As noted in the Baseline Characteristics Module, 1 patient in the Chemotherapy Arm did not have a BRCA mutation (Non-BRCA) and is therefore excluded from the overall number of patients analyzed.

Investigator Assessed Progression-Free Survival (invPFS) by RECIST Version 1.1 for Rucaparib Versus Chemotherapy (Efficacy Population)

Intent-to-treat (ITT) Population - All randomized patients in the treatment part of study.

Investigator Assessed Progression-Free Survival (invPFS) by RECIST Version 1.1 for Rucaparib Versus Chemotherapy (ITT Population)

Efficacy population with measurable disease at baseline. Efficacy population defined as all randomized patients with a deleterious BRCA mutation, excluding those identified to have a BRCA reversion mutation.

Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 (Efficacy Population)

Intent-to-treat (ITT) population with measurable disease at baseline. ITT population defined as all randomized patients.

Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 (ITT Population)

Efficacy population with measurable disease at baseline and a confirmed response. Efficacy population defined as all randomized patients with a deleterious BRCA mutation, excluding those identified to have a BRCA reversion mutation. As noted in the Baseline Characteristics Module, 1 patient in the Chemotherapy Arm did not have a BRCA mutation (Non-BRCA) and is therefore excluded from the overall number of patients analyzed.

Investigator Assessed Duration of Response (DOR) by RECIST v1.1 (Efficacy Population)

Intent-to-treat (ITT) population with measurable disease at baseline and a confirmed response. ITT population defined as all randomized patients.

Investigator Assessed Duration of Response (DOR) by RECIST v1.1 (ITT Population)

Efficacy population with measurable disease at baseline and/or CA-125 response evaluable. Efficacy population defined as all randomized patients with a deleterious BRCA mutation, excluding those identified to have a BRCA reversion mutation.

Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 and/or CA-125 Response (Efficacy Population)

Intent-to-treat (ITT) population with measurable disease at baseline and/or CA-125 response evaluable. ITT population defined as all randomized patients.

Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 and/or CA-125 Response (ITT Population)

Efficacy population - All randomized patients with a deleterious BRCA mutation, excluding those identified to have a BRCA reversion mutation, and with a baseline value and at least one post-baseline value for the EORTC QLQ-C30 Global Health Status score during the first 6 cycles.

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)

Intent-to-treat (ITT) population - All randomized patients with a baseline value and at least one post-baseline value for the EORTC QLQ-C30 Global Health Status score during the first 6 cycles.

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)

Overall Survival (Efficacy Population)

Intent-to-Treat (ITT) Population - All randomized patients in the treatment part of the study.

Overall Survival (ITT Population)

Patients randomized to the rucaparib arm received oral rucaparib 600 mg twice a day (BID) in continuous 28-day cycles.

Patients randomized to the chemotherapy arm received either weekly intravenous (IV) paclitaxel or IV platinum-based chemotherapy per investigator choice and per standard of care. The starting dose of weekly paclitaxel was 60 to 80 mg/m2 administered via IV infusion (ie, on Days 1, 8, and 15) in each 28-day cycle (with a week break from dosing on Day 22 in each cycle). The dosage and administration of single-agent cisplatin or carboplatin or doublet carboplatin/paclitaxel, carboplatin/gemcitabine, or cisplatin/gemcitabine IV infusion followed institutional guidelines for each agent. Upon progression of disease, patients had the option to cross over to rucaparib and receive oral rucaparib 600 mg BID in continuous 28-day cycles.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
ARIEL4: A Study of Rucaparib Versus Chemotherapy BRCA Mutant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients	NCT02855944	Ovarian Cancer Epithelial Ovar... Fallopian Tube ... Peritoneal Canc...	Chemotherapy Rucaparib	18 Years -	pharmaand GmbH
ARIEL4: A Study of Rucaparib Versus Chemotherapy BRCA Mutant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients	NCT02855944	Ovarian Cancer Epithelial Ovar... Fallopian Tube ... Peritoneal Canc...	Chemotherapy Rucaparib	18 Years -	pharmaand GmbH

Spots Global Cancer Trial Database for platinum resistant primary ovarian cancer