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)

• ClinicalTrials.gov Identifier: NCT01968213
• Recruitment Status: Active, not recruiting
• First Posted: October 23, 2013
• Results First Posted: August 3, 2018
• Last Update Posted: June 10, 2022
• Sponsor: Clovis Oncology, Inc.
• Collaborators: Foundation Medicine; Myriad Genetics, Inc.
• Information provided by (Responsible Party): Clovis Oncology, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cancer	Drug: Rucaparib; Drug: Placebo	Phase 3

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). 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 564 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase 3 Study of Rucaparib as Switch Maintenance After Platinum in Relapsed High Grade Serous and Endometrioid Ovarian Cancer (ARIEL3)
• Actual Study Start Date: April 7, 2014
• Actual Primary Completion Date: April 1, 2017
• Estimated Study Completion Date: December 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Rucaparib; 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; 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.; Other Name: CO-338; PF 01367338, AG 14699
Placebo Comparator: Placebo; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. 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) [ Time Frame: Every 12 calendar weeks (within 7 days prior is permitted) after start of treatment until treatment discontinuation due to disease progression. Study data collection expected to last for ~3 years. ]
   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).

Secondary Outcome Measures :

1. Disease Progression According to RECIST v1.1, as Assessed by Independent Radiology Review (IRR), or Death From Any Cause (irrPFS) [ Time Frame: Every 12 calendar weeks (within 7 days prior is permitted) after start of treatment until treatment discontinuation due to disease progression. Study data collection expected to last for ~3 years. ]
   To evaluate PFS by RECIST, as assessed by independent radiology review (IRR)
2. Time to a 4-point Decrease in the Disease-related Symptoms - Physical (DRS-P) Subscale of the FOSI-18 [ Time Frame: Screening, Day 1 of each treatment cycle, Treatment Discontinuation visit, and 28-day Follow-up visit. Study data collection expected to last for ~3 years. ]
   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.
3. Time to an 8-point Decrease in the Total Score of the FOSI-18 [ Time Frame: Screening, Day 1 of each treatment cycle, Treatment Discontinuation visit, and 28-day Follow-up visit. Study data collection expected to last for ~3 years. ]
   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
4. Overall Survival (OS) [ Time Frame: Continuously for ~5 years after patient enrolls into study. ]
   The final OS analysis has not been performed yet and will be performed when 70% of the events have been collected.
5. Individual Model Parameter Estimates of Rucaparib and Covariates Identification [ Time Frame: Study data collection expected to last for ~7 months. ]
   Concentration summary statistics

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Arizona

University of Arizona Cancer Center

Tucson, Arizona, United States, 85704

United States, California

Saint Jude Heritage Medical Center

Fullerton, California, United States, 92835

UC Davis Comprehensive Cancer Center

Sacramento, California, United States, 95817

University of California San Francisco (UCSF)

San Francisco, California, United States, 94158

Coastal Integrative Cancer Care

San Luis Obispo, California, United States, 93422

Central Coast Medical Oncology

Santa Maria, California, United States, 93454

University of California Los Angeles (UCLA)

Santa Monica, California, United States, 90404

United States, Colorado

Rocky Mountain Cancer Centers

Lakewood, Colorado, United States, 80228

United States, Florida

Memorial Healthcare System

Hollywood, Florida, United States, 33021

Sylvester Comprehensive Cancer Center

Miami, Florida, United States, 33136

Florida Hospital

Orlando, Florida, United States, 32804

United States, Maryland

Johns Hopkins Universty

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, Michigan

Karmanos Cancer Institute - Wayne State University

Detroit, Michigan, United States, 48201

United States, Missouri

Washington University School of Medicine - Division of Gynaecological Oncology

Saint Louis, Missouri, United States, 63110

United States, New York

Memorial Sloan-Kettering Cancer Center

New York, New York, United States, 10065

United States, North Carolina

Hope Women's Cancer Centers

Asheville, North Carolina, United States, 28806

United States, Ohio

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States, 43210

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Washington

University of Washington at Seattle

Seattle, Washington, United States, 98109

Australia, New South Wales

Prince of Wales Hospital

Sydney, New South Wales, Australia, 2031

Westmead Hospital

Westmead, New South Wales, Australia, 2145

Australia, Queensland

Royal Brisbane & Women's Hospital

Herston, Queensland, Australia, 4029

Australia, South Australia

Flinders Medical Centre

Bedford Park, South Australia, Australia, 5042

Australia, Victoria

Royal Melbourne Hospital

Parkville, Victoria, Australia, 3052

Australia, Western Australia

Sir Charles Gairdner Hospital

Nedlands, Western Australia, Australia, 6009

St John of God Hospital Subiaco

Subiaco, Western Australia, Australia, 608

Belgium

AZ St Augustinus

Antwerpen, Belgium, 2610

UZ Gent

Gent, Belgium, B-9000

UZ Leuven

Leuven, Belgium, 3000

Clinique Sainte-Elisabeth

Namur, Belgium, 5000

Canada, Alberta

Tom Baker Cancer Centre

Calgary, Alberta, Canada, T2N4N2

Cross Cancer Institute

Edmonton, Alberta, Canada, T6G1Z2

Canada, Ontario

Juravinski Cancer Centre

Hamilton, Ontario, Canada, L8V5C2

London Regional Cancer Centre

London, Ontario, Canada, N6A4L6

Ottawa Hospital Cancer Centre

Ottawa, Ontario, Canada, K1H8L6

Princess Margaret Cancer Centre

Toronto, Ontario, Canada, M5G2M9

Canada, Quebec

CHUM Centre Hospitalier de l'Université de Montréal

Montreal, Quebec, Canada, H2L4M1

Canada

Centre Hospitalier Universitaire de Québec

Quebec, Canada, G1R2J6

France

Centre Francois Baclesse

Caen Cedex 05, Basse-Normandie, France, 14076

Institut Gustave Roussy

Villejuif, Ile De France, France, 94805

Hôpital Européen Georges-Pompidou

Paris, Ile-de-France, France, 75908

Institut Claudius Regaud

Toulouse, Midi-Pyrenees, France, 31052

Centre Catherine de Sienne

Nantes Cedex, Pays De La Loire, France, 44202

Centre Leon Berard

Lyon, Rhone-Alpes, France, 69373

Centre Hospitalier Lyon Sud

Pierre Benite, Rhone-Alpes, France, 69495

Institute Bergonie

Bordeaux, France, 33076

Hospital Tenon

Paris, France, 75020

Germany

Klinikum Stuttgart

Stuttgart, Baden-Wuerttemberg, Germany, 70174

Klinikum Ludwigsburg-Bietigheim gGmbH

Ludwigsburg, Baden-Wuerttembert, Germany, 71640

Rotkreuzklinikum Muenchen gGmbH

Munich, Bavaria, Germany, 80637

Universitätsklinikum Frankfurt

Frankfurt am Main, Hessen, Germany, 60596

Dr. Horst Schmidt Klinik, Klinik fuer Gynaekologie und Gyn. Onkologie

Wiesbaden, Hessen, Germany, 65199

Klinikum Chemnitz gGmbH

Chemnitz, Sachsen, Germany, 09116

Technische Universität Dresden

Dresden, Sachsen, Germany, 01307

Israel

Rambam Health Care Campus

Haifa, Israel, 31096

Lady Davis Carmel Medical Center

Haifa, Israel

Rabin Medical Center

Petach-Tikva, Israel, 49100

Oncology Institute, Sheba Medical Center

Ramat Gan, Israel, 52621

Sourasky Medical Center

Tel-Aviv, Israel, 64239

Assaf Harofeh M.C.

Zerifin, Israel, 70300

Italy

Oncology Unit City Hospital degli Infermi

Faenza, Ravenna, Italy, 48018

Arcispedale Santa Maria Nuova IRCCS

Reggio Emilia, Reggio Nella Emilia, Italy, 42100

Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi

Bologna, Italy, 40138

Fondazione IRCCS National Cancer Institute

Milan, Italy, 20133

Instituto Europeo di Oncologia

Milan, Italy, 20141

Azienda Ospedaliero Universitaria Policlinico di Modena

Modena, Italy, 41124

Istituto Nazionale Tumori IRCCS Fondazione Pascale

Napoli, Italy, 80131

Policlinico Universitario Agostino Gemelli

Roma, Italy, 00158

New Zealand

Auckland City Hospital

Auckland, Grafton, New Zealand, 1023

Palmsteron North Hospital

Palmerston North, Manawatu, New Zealand, 4442

Wellington Hospital

Newtown, Wellington, New Zealand, 6021

Spain

Hospital Central de Asturias

Oviedo, Asturias, Spain, 33011

Centro Oncologico de Galica

A Coruna, Spain, 15009

Hospital Vall D'Hebron

Barcelona, Spain, 8035

Hospital Ramón y Cajal

Madrid, Spain, 28034

Hospital Universitario San Carlos

Madrid, Spain, 28040

Centro Integral Oncológico Clara Campal, Hospital de Madrid Norte-San Chinarro

Madrid, Spain, 28050

Hospital Regional Universitario Carlos Haya de Malaga

Malaga, Spain, 29011

Hospital Universitario Virgen del Rocío

Sevilla, Spain, 41013

Instituto Valencia de Oncologia-Fundacion

Valencia, Spain, 46009

Hospital Clinico Universitario de Valencia

Valencia, Spain, 46010

United Kingdom

Royal Marsden Hospital

London, England, United Kingdom, SW3 6JJ

Belfast City Hospital

Belfast, Northern Ireland, United Kingdom, BT9 7AB

Beatson West of Scotland Cancer Centre

Glasgow, Scotland, United Kingdom, G120YN

The Royal Marsden NHS Foundation Trust

Sutton, Surrey, United Kingdom, SM2 5PT

St. James University Hospital

Leeds, West Yorkshire, United Kingdom, LS97TF

Addenbrookes Hospital

Cambridge, United Kingdom, CB20QQ

Barts Health NHS Trust

London, United Kingdom, EC1M6BQ

Imperial College Healthcare NHS Trust

London, United Kingdom, W120HS

Sarah Cannon Reserach Institute UK

London, United Kingdom, W1G6AD

University College London

London, United Kingdom, W1T4TJ

The Christie NHS Foundation Trust

Manchester, United Kingdom, M204BX

Sir Bobby Robson Cancer trials research Centre, Northern Centre For Cancer Care

Newcastle Upon Tyne, United Kingdom, NE77DN

Sponsors and Collaborators

Clovis Oncology, Inc.

Foundation Medicine

Myriad Genetics, Inc.

Investigators

• Study Director: Heidi Giordano; Clovis Oncology, Inc.

  Study Documents (Full-Text)

Documents provided by Clovis Oncology, Inc.:

Study Protocol  [PDF] July 7, 2016

Statistical Analysis Plan  [PDF] April 21, 2017

More Information

Additional Information:

ARIEL program website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Green ML, Ma SC, Goble S, Giordano H, Maloney L, Simmons AD, Beltman J, Harding TC, Xiao JJ. Population pharmacokinetics of rucaparib in patients with advanced ovarian cancer or other solid tumors. Cancer Chemother Pharmacol. 2022 May;89(5):671-682. doi: 10.1007/s00280-022-04413-7. Epub 2022 Apr 10.

Tattersall A, Ryan N, Wiggans AJ, Rogozinska E, Morrison J. Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Cochrane Database Syst Rev. 2022 Feb 16;2(2):CD007929. doi: 10.1002/14651858.CD007929.pub4.

Colombo N, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, Weberpals JI, Clamp AR, Scambia G, Leary A, Holloway RW, Gancedo MA, Fong PC, Goh JC, O'Malley DM, Armstrong DK, Banerjee S, Garcia-Donas J, Swisher EM, Meunier J, Cameron T, Maloney L, Goble S, Bedel J, Ledermann JA, Coleman RL. The effect of age on efficacy, safety and patient-centered outcomes with rucaparib: A post hoc exploratory analysis of ARIEL3, a phase 3, randomized, maintenance study in patients with recurrent ovarian carcinoma. Gynecol Oncol. 2020 Oct;159(1):101-111. doi: 10.1016/j.ygyno.2020.05.045. Epub 2020 Aug 26.

Ledermann JA, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, Colombo N, Weberpals JI, Clamp AR, Scambia G, Leary A, Holloway RW, Gancedo MA, Fong PC, Goh JC, O'Malley DM, Armstrong DK, Banerjee S, Garcia-Donas J, Swisher EM, Cameron T, Maloney L, Goble S, Coleman RL. Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 May;21(5):710-722. doi: 10.1016/S1470-2045(20)30061-9.

Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, Colombo N, Weberpals JI, Clamp A, Scambia G, Leary A, Holloway RW, Gancedo MA, Fong PC, Goh JC, O'Malley DM, Armstrong DK, Garcia-Donas J, Swisher EM, Floquet A, Konecny GE, McNeish IA, Scott CL, Cameron T, Maloney L, Isaacson J, Goble S, Grace C, Harding TC, Raponi M, Sun J, Lin KK, Giordano H, Ledermann JA; ARIEL3 investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Oct 28;390(10106):1949-1961. doi: 10.1016/S0140-6736(17)32440-6. Epub 2017 Sep 12. Erratum In: Lancet. 2017 Oct 28;390(10106):1948.

• Responsible Party: Clovis Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT01968213
• Other Study ID Numbers: CO-338-014
• First Posted: October 23, 2013
• Results First Posted: August 3, 2018
• Last Update Posted: June 10, 2022
• Last Verified: June 2022

Keywords provided by Clovis Oncology, Inc.:

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

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Fallopian Tube Diseases; Rucaparib; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents