Ariel 4
Research type
Research Study
Full title
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.
IRAS ID
206855
Contact name
Rebecca Kristeleit
Contact email
Sponsor organisation
Clovis Oncology, Inc.
Eudract number
2016-000816-14
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
106289, IND Number
Duration of Study in the UK
4 years, 0 months, 1 days
Research summary
Summary of Research
Globally, ovarian cancer is the eighth most common cancer and the seventh leading cause of cancer death among women. Cancer is caused by changes to genes that control the way our cells function. Chemical substances and other formulations are used in treatment. Chemotherapy is a treatment where chemical substances are used to damage and kill cancer cells. An enzyme inhibitor is a molecule that binds to an enzyme, to help slow down a reaction or to prevent unwanted change. Inhibitors are used in cancer treatments for that purpose. Rucaparib is a molecule inhibitor of enzymes. The main purpose of this study is to evaluate safety, disease status and progression-free survival of Rucaparib versus standard chemotherapy for treatment of certain ovarian, fallopian tube and primary peritoneal cancers with specific changes in certain gene cells. Patients aged 18 years and older with these cancers may be eligible to take part and will be enrolled onto the study to receive randomly either Rucaparib or chemotherapy. Participants receiving chemotherapy will receive either paclitaxel or the investigators choice of chemotherapy. Rucaparib will be given orally on a daily basis in 28 day cycles and chemotherapy will be given intravenously (into a vein). Some chemotherapy treatment will be given up to a maximum of 8 cycles. Participants who are randomly assigned to receive chemotherapy may crossover to receive rucaparib if their disease worsens. All other participants and those who crossover, continue with treatment cycles until the disease progresses. This study will take place at oncology clinics, within hospital settings.
Summary of Results
This study, “ARIEL4: 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” was sponsored and funded by Clovis Oncology, Inc. Rucaparib belongs to a class of anti-cancer agents known as PARP (or poly ADP-ribose polymerase) inhibitors. PARP is a protein inside cells that helps repair damage to DNA. DNA is the genetic material that carries the instructions for the body’s growth and development and allows cells to continue living and it is constantly being damaged and repairing itself within our bodies. Cancer can result when there are changes in a person’s genetic material (sometimes called DNA mutations) that can cause cancer cells to grow out of control. Cancers that have a mutation in the BRCA1 or BRCA2 gene also have a poor DNA repair system. Blocking PARP with a PARP inhibitor in tumors with a BRCA1 or BRCA mutation can cause cancer cells to stop growing and means that treatment with a PARP inhibitor is more likely to be effective in these tumors.
This study evaluated the efficacy and safety of rucaparib versus active, standard of care chemotherapy comparator as treatment for patients who’d received > 2 prior lines of chemotherapy (with at least 1 platinum-based) and had evidence of a BRCA mutation. The purpose of ARIEL4 was to see how long rucaparib might stop recurrent ovarian cancer from growing or spreading (also referred to as progression-free survival or PFS) as compared to chemotherapy in patients who had received at least 2 prior chemotherapy regimens. It was the first study to compare a PARP inhibitor with standard-of-care platinum and nonplatinum-based chemotherapy in patients with germline (inherited) or somatic (acquired) BRCA mutations and relapsed ovarian carcinoma. It also had a crossover component, which allowed chemotherapy subjects to receive rucaparib upon progression, with the approval of the PI and Medical Monitor. Its primary purpose was to confirm clinical benefit seen with rucaparib in the Phase 2 studies CO-338-017 (ARIEL2) and CO-338-010 (Study 10), and to fulfill post-marketing commitments and obligations for the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the indication of third line and later treatment in BRCA-mutant ovarian cancer patients.
The study enrolled 349 subjects across 64 sites in Brazil, Canada, Czech Republic, Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, United Kingdom, and United States between March 2017 and September 2020. All study subjects were female with an average age of 58 years (range, 38-85 years). The majority of subjects were white (94.0% rucaparib; 97.4% chemotherapy). Most subjects were recruited from central or eastern Europe. All subjects initially received 600 mg rucaparib orally twice a day.
In the Treatment Part of the study, the Intent-to-treat Population (all patients randomized) consisted of 349 patients (rucaparib=233 and chemotherapy=116). The Safety Population consisted of 345 patients who received at least 1 dose of rucaparib (n=232) or chemotherapy (n=113). The Efficacy Population consisted of all 325 randomized patients with a deleterious BRCA mutation, excluding those identified to have a BRCA reversion mutation (220 received rucaparib, while 105 received chemotherapy). The hypothesis around excluding these patients from the Efficacy Population is that the patients who have a BRCA reversion mutation may not benefit from treatment with rucaparib.
In the Crossover Part of the study, 80 of the 116 patients (64%) randomized to chemotherapy, later crossed over to rucaparib.
The primary endpoint of investigator-assessed progression-free survival (invPFS) by RECIST v1.1 was achieved in December 2020 and demonstrated a treatment benefit of rucaparib in patients with a BRCA mutation compared to active, standard-of-care chemotherapy comparators.
The secondary endpoint of overall survival was achieved in April 2022 and demonstrated a median OS of 19.4 months in the rucaparib group versus 25.4 months in the chemotherapy group. The difference in overall survival was driven by the platinum-resistant subgroup and was heavily confounded by the crossover patients.
Rucaparib side effects could typically be managed by decreasing the dose and/or receiving supportive care. The most common side effects were nausea, fatigue, constipation, vomiting, abdominal pain, abnormal taste, decreased appetite, decreased amount of red blood cells, decreased platelet count, and decreased amount of white blood cells as well as changes in kidney and liver function blood tests.
The last patient on treatment was transitioned off study on 16 September 2022 (last patient last visit (LPLV), and the study was officially closed as of that date.REC name
West Midlands - Edgbaston Research Ethics Committee
REC reference
16/WM/0437
Date of REC Opinion
24 Nov 2016
REC opinion
Further Information Favourable Opinion