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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Collaborator:
Foundation Medicine
Information provided by (Responsible Party):
Clovis Oncology, Inc.

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.

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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


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




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.



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01482715


Locations
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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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Clovis Oncology, Inc.
ClinicalTrials.gov Identifier: NCT01482715    
Other Study ID Numbers: CO-338-010
First Posted: November 30, 2011    Key Record Dates
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:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Fallopian Tube Neoplasms
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
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