A Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (ARIEL2)

Ovarian Cancer Clinical Trial

— ARIEL2  

Official title:

A Phase 2, Open-Label Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (ARIEL2)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01891344
• Other study ID #: CO-338-017
• Secondary ID: 2013-000517-20
• Status: Completed
• Phase: Phase 2
• Start date: October 30, 2013
• Est. completion date: September 28, 2021

Study information

• Verified date: June 2023
• Source: zr Pharma & GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Clinical data with PARP inhibitors indicate there is an ovarian cancer patient population beyond just those with germline BRCA (gBRCA) mutations that may benefit from treatment with a PARP inhibitor. This study will define a molecular signature of HRD in ovarian cancer that correlates with response to rucaparib and enables selection of appropriate ovarian cancer patients for treatment with rucaparib. The HRD signature will be based on an association between the extent of genomic scarring (a downstream consequence of HRD) in a patient's tumor and observed clinical benefit from rucaparib treatment. Genomic scarring can be assessed by quantifying the extent of loss of heterozygosity across the tumor genome (tumor genomic LOH). One of the main advantages of detecting tumor genomic LOH is that it can identify HRD tumors regardless of the underlying mechanisms, which include both known (i.e., BRCA mutations) and unknown genetic and other mechanisms.

Once determined, this signature will be prospectively applied to ARIEL2 PART 2 and ARIEL3. This Phase 2 study (ARIEL2) will also compare archival versus recently collected tumor tissue in order to validate the use of archival tumor tissue for assessment of HRD status in ARIEL3.

This study will include 2 parts:

PART 1 (completed enrollment): Evaluation of HRD status and rucaparib efficacy in patients who received ≥1 prior platinum-based regimen and had platinum-sensitive disease

PART 2 (completed enrollment): Evaluation of HRD status and rucaparib efficacy in patients who received at least 3 prior chemotherapy regimens

Recruitment information / eligibility

• Status: Completed
• Enrollment: 491
• Est. completion date: September 28, 2021
• Est. primary completion date: November 5, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

The following eligibility criteria pertain to patients enrolling into PART 2 of the study:

Inclusion:

• 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 at least 3 prior chemotherapy regimens. Non-chemotherapy regimens and maintenance therapies administered as single agent treatment will not count as a chemotherapy regimen

• Relapsed/progressive disease as confirmed by CT scan

• Have biopsiable and measurable disease. Note: biopsy is optional for patients known to harbor a deleterious gBRCA mutation

• Have sufficient archival formalin-fixed paraffin-embedded (FFPE) tumor tissue available for planned analyses

Exclusion:

• 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

• Hospitalization for bowel obstruction within 3 months prior to enrollment

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Epithelial Ovarian Cancer
• Fallopian Tube Cancer
• Fallopian Tube Neoplasms
• Hypersensitivity
• Ovarian Cancer
• Ovarian Neoplasms
• Peritoneal Cancer
• Peritoneal Neoplasms

Intervention

Drug:
• Oral rucaparib
600 mg BID

Locations

Country	Name	City	State
Australia	Flinders Cancer Clinic - Flinders Medical Centre (FMC)	Bedford Park	South Australia
Australia	Mercy Hospital for Women	Heidelberg	Victoria
Australia	Royal Brisbane & Women's Hospital	Herston	Queensland
Australia	Charles Gairdner Hospital	Nedlands	Western Australia
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal North Shore Hospital	Saint Leonards	New South Wales
Australia	Prince of Wales Hospital	Sydney	New South Wales
Australia	Crown Princess Mary Cancer Centre (Westmead Hospital)	Westmead	Wentworthville
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Centre	Edmonton	Alberta
Canada	British Columbia Cancer Agency	Kelowna	British Columbia
Canada	London Regional Cancer Centre	London	Ontario
Canada	Centre Hospitalier de L'Universite de Montreal	Montreal	Quebec
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Ottawa Hospital Cancer Centre	Ottawa	Ontario
Canada	CHU de Québec - Université Laval	Québec
Canada	BC Cancer Agency - Fraser Valley Centre	Surrey	British Columbia
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	Vancouver Cancer Centre, British Columbia Cancer Agency (BCCA)	Vancouver	British Columbia
France	Institut Bergonie	Bordeaux	Aquitaine
France	Centre Leon Berard	Lyon	Rhone-Alpes
France	Centre Catherine de Sienne	Nantes	Pays De La Loire
France	Hôpital Européen Georges-Pompidou	Paris	Ile-de-France
France	Hopital Tenon	Paris	Ile-de-France
France	Centre Hospitalier Lyon Sud	Pierre-Benite	Rhone-Alpes
France	Institut Claudius Regaud	Toulouse	Midi-Pyrenees
France	Institut de cancerologie Gustave Roussy	Villejuif	Ile-de-France
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Instituto Valencia de Oncologia	Valencia
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow	Scotland
United Kingdom	St James University Hospital	Leeds	West Yorkshire
United Kingdom	Imperial College Healthcare NHS Trust - Hammersmith Hospital	London
United Kingdom	Royal Marsden NHS Foundation Trust	London
United Kingdom	University College London	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care	Newcastle upon Tyne
United Kingdom	Royal Marsden Sutton Hospital	Sutton	Surrey
United States	Women's Cancer Care Associates	Albany	New York
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	Hope - A Woman's Cancer Institute	Asheville	North Carolina
United States	Johns Hopkins Kimmel Cancer Center	Baltimore	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Cincinnati Physicians Company	Cincinnati	Ohio
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Saint Jude Heritage Medical Center	Fullerton	California
United States	Comprehensive Cancer Centers of Nevada	Henderson	Nevada
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	Horizon BioAdvance	Lafayette	Indiana
United States	Altus Research	Lake Worth	Florida
United States	Rocky Mountain Cancer Centers	Lakewood	Colorado
United States	University of California Los Angeles	Los Angeles	California
United States	Norton Cancer Institute	Louisville	Kentucky
United States	University of Miami Hospital & Clinics Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	New York University Langone Medical Center	New York	New York
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	Florida Hospital Cancer Institute	Orlando	Florida
United States	UF Health Cancer Center	Orlando	Florida
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	UPMC Cancer Center	Pittsburgh	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	UC San Diego	San Diego	California
United States	California Pacific Medical Center	San Francisco	California
United States	University of California, San Francisco	San Francisco	California
United States	Coastal Integrative Cancer Care	San Luis Obispo	California
United States	Central Coast Medical Oncology	Santa Maria	California
United States	University of Washington - Seattle Cancer Care Alliance	Seattle	Washington
United States	Stanford University	Stanford	California
United States	University of Arizona Cancer Center	Tucson	Arizona

Sponsors (3)

Lead Sponsor	Collaborator
zr Pharma & GmbH	Foundation Medicine, Myriad Genetics, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) According to RECIST v1.1 in Molecularly-defined HRD (Homologous Recombination Deficiency) Subgroups (Part 1 of Study)	The primary efficacy endpoint of PFS is calculated as 1+ the number of days from the first dose of study drug to disease progression by RECIST (Response Evaluation Criteria in Solid Tumors), as determined by the investigator 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 measureable increase in a non-target lesion, or the appearance of new lesions.	Assessments every 8 weeks from C1D1 until disease progression, death or withdrawal of consent. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3 years.
Primary	Objective Response Rate (ORR) by RECIST v1.1 in Molecularly-defined HRD Subgroups (Part 2 of Study)	The confirmed response rate by RECIST v1.1 is defined as the percentage of patients with a confirmed complete response (CR) or partial response (PR) on subsequent tumor assessment at least 28 days after first response documentation. 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.	Assessments every 8 weeks from C1D1 until disease progression, death or withdrawal of consent. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3 years.
Secondary	Objective Response Rate (ORR) by RECIST v1.1 (Part 1 of Study)	The confirmed response rate by RECIST v1.1 is defined as the percentage of patients with a confirmed CR or PR on subsequent tumor assessment at least 28 days after first response documentation. 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.	Assessments every 8 weeks from C1D1 until disease progression, death or withdrawal of consent. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3 years.
Secondary	Objective Response Rate (ORR) by RECIST v1.1 and GCIG CA-125 Criteria	The endpoint of ORR defined as the percentage of patients with a best response of CR or PR using RECIST v 1.1 or a 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. A 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.	Assessments every 8 weeks from C1D1 until disease progression, death or withdrawal of consent. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3 years.
Secondary	Duration of Response Per RECIST v1.1	Duration of response (DOR) for any confirmed RECIST CR or PR measured from the date of the first occurrence of a response until the first occurrence of progressive disease (PD) per RECIST. For patients who continued treatment post-progression, the first date of progression was used for the analysis. Any patients with an ongoing response were censored at the date of the last post-baseline scan. 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.	Assessments every 8 weeks from C1D1 until disease progression, death or withdrawal of consent. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3 years.
Secondary	Progression-free Survival (PFS) According to RECIST v1.1 in Molecularly-defined HRD Subgroups (Part 2 of Study)	Progression-Free Survival (PFS) is calculated as 1+ the number of days from the first dose of study drug to disease progression by RECIST, as determined by the investigator 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 measureable increase in a non-target lesion, or the appearance of new lesions.	Assessments every 8 weeks from C1D1 until disease progression, death or withdrawal of consent. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3 years.
Secondary	Overall Survival (Part 2 of Study)	Overall survival (OS) is defined as the number of days from the date of first dose of study drug to the date of death (due to any cause). Patients without a known date of death will be censored on the date the patient was last known to be alive.	All patients in Part 2 were followed for survival, subsequent therapy, and secondary malignancy every 12 weeks until death, loss to follow-up, withdrawal of consent from study or study closure, whichever happened first, up to 7 years.
Secondary	Steady State Trough (Cmin) Level Rucaparib Concentrations	Per protocol, the secondary PK endpoint, trough (Cmin) concentrations of rucaparib were summarized with descriptive statistics overall and by cycle in all patients with at least one PK sample collected. Blood samples for trough level PK analysis of rucaparib were drawn at the following timepoints only: on Day 15 of Cycle 1 and on Day 1 of Cycles 2, 3, and 4. Data for other timepoints is not available.	Cycle 1 Day 15 to Cycle 4 Day 1, or approximately 10 weeks

External Links

•   ARIEL trials website