A Study of Oral Rucaparib in Patients With a Solid Tumor (Phase I) or With gBRCA Mutation Ovarian Cancer (Phase II)

• ClinicalTrials.gov Identifier: NCT01482715
• Recruitment Status: Completed
• First Posted: November 30, 2011
• Results First Posted: December 8, 2020
• Last Update Posted: January 22, 2021
• Sponsor: Clovis Oncology, Inc.
• Collaborator: Foundation Medicine
• Information provided by (Responsible Party): Clovis Oncology, Inc.

Study Description

Brief Summary:

Part 1 (Completed Enrollment) - The purpose of the first part of the study was to evaluate the safety of different doses and dosing regimens of oral rucaparib administered daily to patients with solid tumors.

Part 2A (Completed Enrollment) and Part 2B (Completed Enrollment) - The purpose of the second part of the study is to determine the safety and clinical activity of the RP2D of oral rucaparib administered daily to patients with a known deleterious BRCA mutation (germline or somatic).

Part 3 (Completed Enrollment) - The purpose of the third part of the study is to further evaluate PK of higher dose strength tablets at the RP2D in patients with any advanced solid tumor, inclusive of lymphoma, with evidence of a BRCA mutation (germline or somatic).

Condition or disease	Intervention/treatment	Phase
Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cancer; Advanced Solid Tumor With Evidence of Germline or Somatic BRCA	Drug: Rucaparib	Phase 1; Phase 2

Detailed Description:

Rucaparib (CO-338; formerly known as PF 01367338 and AG 14699) 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 BRCA1 or BRCA2 mutations. For this study, it is anticipated that rucaparib will promote cell death in the BRCA-deficient tumor cells of ovarian cancer patients with evidence of a germline mutation, thereby limiting tumor progression and providing therapeutic benefit.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 136 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II, Open-Label, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Oral Rucaparib in Patients With gBRCA Mutation Ovarian Cancer or Other Solid Tumor
• Actual Study Start Date: November 2011
• Actual Primary Completion Date: March 2019
• Actual Study Completion Date: May 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1 (Phase 1); Rucaparib 40, 80, 160, 300, 500 mg QD and 240, 360, 480, 600, 840 mg BID, for continuous 21-day cycles. Patients in Part 1 were initially treated in a Dose-escalation Evaluation Period (Cycle 1) and could then continue to receive treatment in an optional Treatment-extension Period (Cycle 2 and beyond).	Drug: Rucaparib; Oral tablets administered daily with 8 oz (240 mL) of water on an empty stomach or with food; 21-day cycles of treatment. In Part 1, the initial dose level is 40 mg/day (once a day); doses and dosing frequency(e.g. twice a day or three times a day) will be adjusted until Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) are established. Patients enrolled in Part 2 and Part 3 will receive the RP2D for continuous 21-day treatment cycles until disease progression.; Other Name: CO-338; PF 01367338, AG 14699
Experimental: Part 2A (Phase 2); Rucaparib 600 mg BID for 21-day cycles.	Drug: Rucaparib; Oral tablets administered daily with 8 oz (240 mL) of water on an empty stomach or with food; 21-day cycles of treatment. In Part 1, the initial dose level is 40 mg/day (once a day); doses and dosing frequency(e.g. twice a day or three times a day) will be adjusted until Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) are established. Patients enrolled in Part 2 and Part 3 will receive the RP2D for continuous 21-day treatment cycles until disease progression.; Other Name: CO-338; PF 01367338, AG 14699
Experimental: Part 2B (Phase 2); Rucaparib 600 mg BID for 21-day cycles.	Drug: Rucaparib; Oral tablets administered daily with 8 oz (240 mL) of water on an empty stomach or with food; 21-day cycles of treatment. In Part 1, the initial dose level is 40 mg/day (once a day); doses and dosing frequency(e.g. twice a day or three times a day) will be adjusted until Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) are established. Patients enrolled in Part 2 and Part 3 will receive the RP2D for continuous 21-day treatment cycles until disease progression.; Other Name: CO-338; PF 01367338, AG 14699
Experimental: Part 3 (Phase 2); Rucaparib 600 mg BID for 21-day cycles. Patients also received a single administration of 600 mg rucaparib on both Day -7 and Day 1 for assessing the effect of food on PK.	Drug: Rucaparib; Oral tablets administered daily with 8 oz (240 mL) of water on an empty stomach or with food; 21-day cycles of treatment. In Part 1, the initial dose level is 40 mg/day (once a day); doses and dosing frequency(e.g. twice a day or three times a day) will be adjusted until Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) are established. Patients enrolled in Part 2 and Part 3 will receive the RP2D for continuous 21-day treatment cycles until disease progression.; Other Name: CO-338; PF 01367338, AG 14699

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate Per RECIST Version 1.1 (Part 2) [ Time Frame: Time from first dose to date of progression, up to approximately 8 months ]
   The confirmed response rate by RECIST v1.1 is defined as the proportion of patients with a confirmed Complete Response (CR) or Partial Response (PR) on subsequent tumor assessment at least 28 days after first response documentation.
2. Number of Participants With a Dose Limiting Toxicity (DLT) [ Time Frame: Cycle 1 Day 1 to Cycle 1 Day 21 ]
   The number of Part 1 (Phase 1) patients who experienced dose limiting toxicities after one cycle (21 days) of study drug.
3. PK Profile of Rucaparib - Cmax (Part 1) [ Time Frame: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days ]
   Cmax = maximum concentration following administration of rucaparib
4. PK Profile of Rucaparib - Tmax (Part 1) [ Time Frame: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days ]
   Tmax = time to maximum concentration following administration of rucaparib
5. PK Profile of Rucaparib - AUC Last (Part 1) [ Time Frame: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days ]
   AUC last = Area under the plasma concentration-time curve from time 0 to the last recorded observation

Secondary Outcome Measures :

1. Progression-free Survival (PFS) According to RECIST v1.1, as Assessed by the Investigator (Part 2) [ Time Frame: Cycle 1 Day 1 to End of Treatment, up to approximately 51 months ]
   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.
2. Duration of Response Per RECIST Version 1.1 (Part 2) [ Time Frame: Cycle 1 Day 1 to End of Treatment, up to approximately 48 months ]
   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 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.
3. Overall Survival (Part 2B) [ Time Frame: Cycle 1 Day 1 to date of death, assessed up to 38 months ]
   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 documented event of death will be censored on the date of their last visit.
4. Food Effect on PK of Rucaparib - Cmax (Part 1 and Part 3) [ Time Frame: Day -7 to Cycle 1 Day 1, or approximately 7 days ]
   Cmax = maximum concentration following administration of rucaparib. The effect of food on rucaparib PK parameters was assessed over a 24-hour period in blood samples from a subset of patients. Patients were given a single dose of 40 mg or 300 mg rucaparib (Part 1), or 600 mg rucaparib (Part 3) and were randomized to one of two sequences where they were either Fed (with a high-fat meal) or Fasted (without a high-fat meal) on Day -7 or Cycle 1 Day 1. On each day, patients underwent blood sampling for PK at the specified time points. The median Fed and Fasted Cmax values were calculated for each arm.
5. Food Effect on PK of Rucaparib - Tmax (Part 1 and Part 3) [ Time Frame: Day -7 to Cycle 1 Day 1, or approximately 7 days ]
   Tmax = time to maximum concentration following administration of rucaparib. The effect of food on rucaparib PK parameters was assessed over a 24-hour period in blood samples from a subset of patients. Patients were given a single dose of 40 mg or 300 mg rucaparib (Part 1), or 600 mg rucaparib (Part 3) and were randomized to one of two sequences where they were either Fed (with a high-fat meal) or Fasted (without a high-fat meal) on Day -7 or Cycle 1 Day 1. On each day, patients underwent blood sampling for PK at the specified time points. The median Fed and Fasted Tmax values were calculated for each arm.
6. Food Effect on PK of Rucaparib - AUC Last (Part 1 and Part 3) [ Time Frame: Day -7 to Cycle 1 Day 1, or approximately 7 days ]
   AUC last = Area under the plasma concentration-time curve from time 0 to the last recorded observation. The effect of food on rucaparib PK parameters was assessed over a 24-hour period in blood samples from a subset of patients. Patients were given a single dose of 40 mg or 300 mg rucaparib (Part 1), or 600 mg rucaparib (Part 3) and were randomized to one of two sequences where they were either Fed (with a high-fat meal) or Fasted (without a high-fat meal) on Day -7 or Cycle 1 Day 1. On each day, patients underwent blood sampling for PK at the specified time points. The median Fed and Fasted AUC last values were calculated for each arm.
7. QTcF Value Change From Baseline (Part 1) [ Time Frame: Screening to End of Treatment, up to approximately 15 months ]
   QTcF value change from baseline by daily dose corrected using Fridericia's method (QTcF). To evaluate the effects of rucaparib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Screening, on Cycle 1 Day -1, Cycle 1 Day 1, Cycle 1 Day 15, Cycle 1 Day 22, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient.

Eligibility Criteria

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

Criteria

The following eligibility criteria below pertain to patients enrolling into Part 2B of the study.

Inclusion Criteria:

• Have a known deleterious BRCA mutation (gBRCA or sBRCA) (as determined by a local laboratory that has received an international or country-specific, quality standards certification)
• Have evidence of measurable disease as defined by RECIST Version 1.1
• Have sufficient archival FFPE tumor tissue available for planned analyses. Archival tissue from the most recently collected biopsy or debulking surgery should be provided, if available.
• Have a histologically confirmed diagnosis of high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer
• Have received at least three prior chemotherapy regimens and have relapsed disease confirmed by radiologic assessment

Exclusion Criteria:

• Active second malignancy, i.e., patient known to have potentially fatal cancer present for which she may be (but not necessarily) currently receiving treatment

  a. Patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enroll in the trial provided all chemotherapy was completed >6 months prior and/or bone marrow transplant (BMT) >2 years prior to first dose of rucaparib

• Prior treatment with any PARP inhibitor.
• Untreated or symptomatic central nervous system (CNS) metastases. Patients with asymptomatic CNS metastases are eligible provided they have been clinically stable for at least 4 weeks.
• Received treatment with chemotherapy, radiation, antibody therapy or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental drugs 14 days prior to first dose of rucaparib and/or ongoing adverse effects from such treatment > NCI CTCAE Grade 1 (Grade 2 non-hematologic toxicity to most recent treatment may be permitted with prior advanced approval from Sponsor).
• Hospitalization for bowel obstruction within 3 months prior to enrollment.

Contacts and Locations

Locations

United States, California

UCSF

San Francisco, California, United States, 94155

United States, Florida

Sarah Cannon Research Institute

Sarasota, Florida, United States, 34232

United States, Massachusetts

Dana-Farber Cancer Institute (Part 3 only)

Boston, Massachusetts, United States, 02215

United States, Michigan

Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Tennessee

Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37203

Canada, Ontario

Princess Margaret Cancer Centre

Toronto, Ontario, Canada, MSG 2M9

Israel

Sheba Medical Center

Ramat Gan, Israel, 52621

Tel Aviv Sourasky Medical Center

Tel Aviv, Israel, 632394

Spain

Hospital Vall d'Hebron

Barcelona, Spain, 8035

United Kingdom

Guy's and St Thomas NHS Foundation Trust

London, England, United Kingdom, SE1 9RT

Royal Marsden NHS Foundation Trust

London, England, United Kingdom, SW3 6JJ

Imperial College Healthcare

London, England, United Kingdom, W12 0HS

Newcastle University

Newcastle Upon Tyne, England, United Kingdom, UK NE7

Institution of Cancer Science, University of Glasgow Wolfson Wohl Cancer Research

Glasgow, Scotland, United Kingdom, G61 1QH

University College London Cancer Institute

London, United Kingdom, WC1E 6BT

Sponsors and Collaborators

Clovis Oncology, Inc.

Foundation Medicine

  Study Documents (Full-Text)

Documents provided by Clovis Oncology, Inc.:

Study Protocol  [PDF] June 29, 2016

Statistical Analysis Plan  [PDF] May 10, 2019

More Information

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.

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.

Shapiro GI, Kristeleit RS, Burris HA, LoRusso P, Patel MR, Drew Y, Giordano H, Maloney L, Watkins S, Goble S, Jaw-Tsai S, Xiao JJ. Pharmacokinetic Study of Rucaparib in Patients With Advanced Solid Tumors. Clin Pharmacol Drug Dev. 2019 Jan;8(1):107-118. doi: 10.1002/cpdd.575. Epub 2018 May 25.

• Responsible Party: Clovis Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT01482715
• Other Study ID Numbers: CO-338-010
• First Posted: November 30, 2011
• Results First Posted: December 8, 2020
• Last Update Posted: January 22, 2021
• Last Verified: November 2020

Keywords provided by Clovis Oncology, Inc.:

gBRCA ovarian cancer; platinum sensitive; PARP Inhibitor; Rucaparib; CO-338; PF 01367338; AG 14699; BRCA1; BRCA2; platinum sensitive ovarian cancer; platinum sensitive gBRCA ovarian cancer; gynecological cancer; relapsed disease; homologous recombination deficiency; HRD

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; 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