Clinical trial NCT01891344: A Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ovarian Cancer
Epithelial Ovarian Cancer
Fallopian Tube Cancer
Peritoneal Cancer
Keywords: ovarian cancer
fallopian tube cancer
primary peritoneal cancer
peritoneal cancer
platinum sensitive
relapsed disease
PARP Inhibitor
rucaparib
homologous recombination
homologous recombination deficiency
genomic scarring
loss of heterozygosity
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
ARIEL2
ARIEL 2
ARIEL3
ARIEL 3
Lead sponsor: pharmaand GmbH
Sponsor class: INDUSTRY
Collaborators: name: Foundation Medicine
name: Myriad Genetics, Inc.
First posted: 2013-07-03
Enrollment: 491
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Progression-free Survival (PFS) According to RECIST v1.1 in Molecularly-defined HRD (Homologous Recombination Deficiency) Subgroups (Part 1 of Study)
timeFrame: 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.
measure: Objective Response Rate (ORR) by RECIST v1.1 in Molecularly-defined HRD Subgroups (Part 2 of Study)
timeFrame: 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 outcomes:
measure: Objective Response Rate (ORR) by RECIST v1.1 (Part 1 of Study)
timeFrame: 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.
measure: Objective Response Rate (ORR) by RECIST v1.1 and GCIG CA-125 Criteria
timeFrame: 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.
measure: Duration of Response Per RECIST v1.1
timeFrame: 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.
measure: Progression-free Survival (PFS) According to RECIST v1.1 in Molecularly-defined HRD Subgroups (Part 2 of Study)
timeFrame: 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.
measure: Overall Survival (Part 2 of Study)
timeFrame: 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.
measure: Steady State Trough (Cmin) Level Rucaparib Concentrations
timeFrame: Cycle 1 Day 15 to Cycle 4 Day 1, or approximately 10 weeks
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: Providence Alaska Medical Center
state: Alaska
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Fullerton
country: United States
facility: Saint Jude Heritage Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: San Diego
country: United States
facility: UC San Diego
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: San Luis Obispo
country: United States
facility: Coastal Integrative Cancer Care
state: California
city: Santa Maria
country: United States
facility: Central Coast Medical Oncology
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Lakewood
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Lake Worth
country: United States
facility: Altus Research
state: Florida
city: Miami
country: United States
facility: University of Miami Hospital & Clinics Sylvester Comprehensive Cancer Center
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Cancer Institute
state: Florida
city: Orlando
country: United States
facility: UF Health Cancer Center
state: Florida
city: Lafayette
country: United States
facility: Horizon BioAdvance
state: Indiana
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Henderson
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Albany
country: United States
facility: Women's Cancer Care Associates
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Asheville
country: United States
facility: Hope - A Woman's Cancer Institute
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Physicians Company
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: University of Washington - Seattle Cancer Care Alliance
state: Washington
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: Bedford Park
country: Australia
facility: Flinders Cancer Clinic - Flinders Medical Centre (FMC)
state: South Australia
city: Heidelberg
country: Australia
facility: Mercy Hospital for Women
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Westmead
country: Australia
facility: Crown Princess Mary Cancer Centre (Westmead Hospital)
state: Wentworthville
city: Nedlands
country: Australia
facility: Charles Gairdner Hospital
state: Western Australia
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Centre
state: Alberta
city: Kelowna
country: Canada
facility: British Columbia Cancer Agency
state: British Columbia
city: Surrey
country: Canada
facility: BC Cancer Agency - Fraser Valley Centre
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver Cancer Centre, British Columbia Cancer Agency (BCCA)
state: British Columbia
city: London
country: Canada
facility: London Regional Cancer Centre
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier de L'Universite de Montreal
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Québec
country: Canada
facility: CHU de Québec - Université Laval
city: Bordeaux
country: France
facility: Institut Bergonie
state: Aquitaine
city: Paris
country: France
facility: Hopital Tenon
state: Ile-de-France
city: Paris
country: France
facility: Hôpital Européen Georges-Pompidou
state: Ile-de-France
city: Villejuif
country: France
facility: Institut de cancerologie Gustave Roussy
state: Ile-de-France
city: Toulouse
country: France
facility: Institut Claudius Regaud
state: Midi-Pyrenees
city: Nantes
country: France
facility: Centre Catherine de Sienne
state: Pays De La Loire
city: Lyon
country: France
facility: Centre Leon Berard
state: Rhone-Alpes
city: Pierre-Benite
country: France
facility: Centre Hospitalier Lyon Sud
state: Rhone-Alpes
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Valencia
country: Spain
facility: Instituto Valencia de Oncologia
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
state: Scotland
city: Sutton
country: United Kingdom
facility: Royal Marsden Sutton Hospital
state: Surrey
city: Leeds
country: United Kingdom
facility: St James University Hospital
state: West Yorkshire
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: London
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust - Hammersmith Hospital
city: London
country: United Kingdom
facility: University College London
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Newcastle upon Tyne
country: United Kingdom
facility: Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care
Study officials:
References:
citation: 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.
citation: 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.
citation: Swisher EM, Kwan TT, Oza AM, Tinker AV, Ray-Coquard I, Oaknin A, Coleman RL, Aghajanian C, Konecny GE, O'Malley DM, Leary A, Provencher D, Welch S, Chen LM, Wahner Hendrickson AE, Ma L, Ghatage P, Kristeleit RS, Dorigo O, Musafer A, Kaufmann SH, Elvin JA, Lin DI, Chambers SK, Dominy E, Vo LT, Goble S, Maloney L, Giordano H, Harding T, Dobrovic A, Scott CL, Lin KK, McNeish IA. Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2). Nat Commun. 2021 May 3;12(1):2487. doi: 10.1038/s41467-021-22582-6.
citation: Kristeleit RS, Oaknin A, Ray-Coquard I, Leary A, Balmana J, Drew Y, Oza AM, Shapira-Frommer R, Domchek SM, Cameron T, Maloney L, Goble S, Lorusso D, Ledermann JA, McNeish IA. Antitumor activity of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy in patients with platinum-sensitive, relapsed, BRCA-mutated, high-grade ovarian cancer, and an update on safety. Int J Gynecol Cancer. 2019 Nov;29(9):1396-1404. doi: 10.1136/ijgc-2019-000623.
citation: Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, Konecny GE, Coleman RL, Tinker AV, O'Malley DM, Kristeleit RS, Ma L, Bell-McGuinn KM, Brenton JD, Cragun JM, Oaknin A, Ray-Coquard I, Harrell MI, Mann E, Kaufmann SH, Floquet A, Leary A, Harding TC, Goble S, Maloney L, Isaacson J, Allen AR, Rolfe L, Yelensky R, Raponi M, McNeish IA. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017 Jan;18(1):75-87. doi: 10.1016/S1470-2045(16)30559-9. Epub 2016 Nov 29.