Phase 3 Study of Rucaparib as Switch Maintenance After Platinum in Relapsed High Grade Serous or Endometrioid Ovarian Cancer (ARIEL3) (ARIEL3)

• ClinicalTrials.gov Identifier: NCT01968213
• Recruitment Status: Completed
• First Posted: October 23, 2013
• Results First Posted: August 3, 2018
• Last Update Posted: June 9, 2023
• Sponsor: pharmaand GmbH
• Collaborators: Foundation Medicine; Myriad Genetics, Inc.
• Information provided by (Responsible Party): pharmaand GmbH

Tracking Information

• First Submitted Date: October 17, 2013
• First Posted Date: October 23, 2013
• Results First Submitted Date: May 8, 2018
• Results First Posted Date: August 3, 2018
• Last Update Posted Date: June 9, 2023
• Actual Study Start Date: April 7, 2014
• Actual Primary Completion Date: April 1, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 8, 2023)

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. Total follow-up was up to approximately 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).

• Original Primary Outcome Measures (submitted: October 18, 2013): Disease progression according to RECIST Version 1.1 (v1.1), as assessed by the investigator, or death from any cause (investigator Progression Free Survival or invPFS), in molecularly defined subgroups [ Time Frame: Screening, within 7 days prior to the end of every 3rd cycle of treament, and Treatment Discontinuation visit. Study data collection expected to last for ~3 years. ]

Current Secondary Outcome Measures (submitted: February 8, 2023)

• 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. Total follow-up was up to approximately 8.2 years. ]
  To evaluate PFS by RECIST v1.1, as assessed by independent radiology review (IRR).
• Overall Survival (OS) [ Time Frame: All patients were followed for survival up to approximately 8.2 years. ]
  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.
• 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. Total follow-up was up to approximately 6.4 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.
• 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. Total follow-up was up to approximately 6.4 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.
• Individual Model Parameter Estimates of Rucaparib and Covariates Identification [ Time Frame: Study data collection occurred over approximately 7 months. ]
  Concentration summary statistics

Original Secondary Outcome Measures (submitted: October 18, 2013)

• Disease progression according to RECIST v1.1, as assessed by Independent Radiology Review (IRR), or death from any cause (irrPFS), in molecularly defined subgroups [ Time Frame: Screening, within 7 days prior to the end of every 3rd cycle of treament, and Treatment Discontinuation visit. Study data collection expected to last for ~3 years. ]
• Time to a specified decrease in the DSR P subscale of the FOSI-18 patient reported outcome questionnaire [ 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. ]
• Time to a specified decrease in the total score of the FOSI-18 patient reported outcome questionnaire [ 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. ]
• Overall Survival (OS) [ Time Frame: Continuously for ~5 years after patient enrolls into study. ]
• Incidence of Adverse Events (AEs), clinical laboratory abnormalities, and dose modifications [ Time Frame: Continuously for ~3 years after patient enrolls into study. ]
• Individual model parameter estimates of rucaparib and covariates identification (PK) [ Time Frame: Cycle 1 Day 15, and Cycle 2 Day 1, Cycle 2 Day 15, Cycle 4 Day 1, and Cycle 7 Day 1. Study data collection expected to last for ~7 months. ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase 3 Study of Rucaparib as Switch Maintenance After Platinum in Relapsed High Grade Serous or Endometrioid Ovarian Cancer (ARIEL3)
• Official Title: 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 )
• 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.

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Ovarian Cancer
• Fallopian Tube Cancer
• Peritoneal Cancer

Intervention

• 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 Names:

  • CO-338
  • PF 01367338
  • AG 14699
• 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.

Study Arms

• 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.
  Intervention: Drug: Rucaparib
• 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.
  Intervention: Drug: Placebo

Publications *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 1, 2018): 564
• Original Estimated Enrollment (submitted: October 18, 2013): 540
• Actual Study Completion Date: July 7, 2022
• Actual Primary Completion Date: April 1, 2017 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, France, Germany, Israel, Italy, New Zealand, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT01968213
• Other Study ID Numbers: CO-338-014; 2013-000518-39 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: pharmaand GmbH
• Original Responsible Party: Clovis Oncology, Inc.
• Current Study Sponsor: pharmaand GmbH
• Original Study Sponsor: Clovis Oncology, Inc.

Collaborators

• Foundation Medicine
• Myriad Genetics, Inc.

Investigators

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

• PRS Account: pharmaand GmbH
• Verification Date: June 2023