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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)

Primary Purpose

Ovarian Cancer, Fallopian Tube Cancer, Peritoneal Cancer

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Rucaparib
Sponsored by
pharmaand GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ovarian Cancer focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

  • UCSF
  • Sarah Cannon Research Institute
  • Dana-Farber Cancer Institute (Part 3 only)
  • Karmanos Cancer Institute
  • University of Pennsylvania
  • Sarah Cannon Research Institute
  • Princess Margaret Cancer Centre
  • Sheba Medical Center
  • Tel Aviv Sourasky Medical Center
  • Hospital Vall d'Hebron
  • Guy's and St Thomas NHS Foundation Trust
  • Royal Marsden NHS Foundation Trust
  • Imperial College Healthcare
  • Newcastle University
  • Institution of Cancer Science, University of Glasgow Wolfson Wohl Cancer Research
  • University College London Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Part 1 (Phase 1)

Part 2A (Phase 2)

Part 2B (Phase 2)

Part 3 (Phase 2)

Arm Description

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).

Rucaparib 600 mg BID for 21-day cycles.

Rucaparib 600 mg BID for 21-day cycles.

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.

Outcomes

Primary Outcome Measures

Overall Response Rate Per RECIST Version 1.1 (Part 2)
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.
Number of Participants With a Dose Limiting Toxicity (DLT)
The number of Part 1 (Phase 1) patients who experienced dose limiting toxicities after one cycle (21 days) of study drug.
PK Profile of Rucaparib - Cmax (Part 1)
Cmax = maximum concentration following administration of rucaparib
PK Profile of Rucaparib - Tmax (Part 1)
Tmax = time to maximum concentration following administration of rucaparib
PK Profile of Rucaparib - AUC Last (Part 1)
AUC last = Area under the plasma concentration-time curve from time 0 to the last recorded observation

Secondary Outcome Measures

Progression-free Survival (PFS) According to RECIST v1.1, as Assessed by the Investigator (Part 2)
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.
Duration of Response Per RECIST Version 1.1 (Part 2)
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.
Overall Survival (Part 2B)
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.
Food Effect on PK of Rucaparib - Cmax (Part 1 and Part 3)
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.
Food Effect on PK of Rucaparib - Tmax (Part 1 and Part 3)
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.
Food Effect on PK of Rucaparib - AUC Last (Part 1 and Part 3)
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.
QTcF Value Change From Baseline (Part 1)
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.

Full Information

First Posted
November 22, 2011
Last Updated
June 7, 2023
Sponsor
pharmaand GmbH
Collaborators
Foundation Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT01482715
Brief Title
A Study of Oral Rucaparib in Patients With a Solid Tumor (Phase I) or With gBRCA Mutation Ovarian Cancer (Phase II)
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
November 2011 (Actual)
Primary Completion Date
March 2019 (Actual)
Study Completion Date
May 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
pharmaand GmbH
Collaborators
Foundation Medicine

4. Oversight

Data Monitoring Committee
No

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ovarian Cancer, Fallopian Tube Cancer, Peritoneal Cancer, Advanced Solid Tumor With Evidence of Germline or Somatic BRCA
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
136 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part 1 (Phase 1)
Arm Type
Experimental
Arm Description
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).
Arm Title
Part 2A (Phase 2)
Arm Type
Experimental
Arm Description
Rucaparib 600 mg BID for 21-day cycles.
Arm Title
Part 2B (Phase 2)
Arm Type
Experimental
Arm Description
Rucaparib 600 mg BID for 21-day cycles.
Arm Title
Part 3 (Phase 2)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Rucaparib
Other Intervention Name(s)
CO-338; PF 01367338, AG 14699
Intervention Description
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.
Primary Outcome Measure Information:
Title
Overall Response Rate Per RECIST Version 1.1 (Part 2)
Description
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.
Time Frame
Time from first dose to date of progression, up to approximately 8 months
Title
Number of Participants With a Dose Limiting Toxicity (DLT)
Description
The number of Part 1 (Phase 1) patients who experienced dose limiting toxicities after one cycle (21 days) of study drug.
Time Frame
Cycle 1 Day 1 to Cycle 1 Day 21
Title
PK Profile of Rucaparib - Cmax (Part 1)
Description
Cmax = maximum concentration following administration of rucaparib
Time Frame
Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
Title
PK Profile of Rucaparib - Tmax (Part 1)
Description
Tmax = time to maximum concentration following administration of rucaparib
Time Frame
Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
Title
PK Profile of Rucaparib - AUC Last (Part 1)
Description
AUC last = Area under the plasma concentration-time curve from time 0 to the last recorded observation
Time Frame
Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
Secondary Outcome Measure Information:
Title
Progression-free Survival (PFS) According to RECIST v1.1, as Assessed by the Investigator (Part 2)
Description
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.
Time Frame
Cycle 1 Day 1 to End of Treatment, up to approximately 51 months
Title
Duration of Response Per RECIST Version 1.1 (Part 2)
Description
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.
Time Frame
Cycle 1 Day 1 to End of Treatment, up to approximately 48 months
Title
Overall Survival (Part 2B)
Description
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.
Time Frame
Cycle 1 Day 1 to date of death, assessed up to 38 months
Title
Food Effect on PK of Rucaparib - Cmax (Part 1 and Part 3)
Description
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.
Time Frame
Day -7 to Cycle 1 Day 1, or approximately 7 days
Title
Food Effect on PK of Rucaparib - Tmax (Part 1 and Part 3)
Description
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.
Time Frame
Day -7 to Cycle 1 Day 1, or approximately 7 days
Title
Food Effect on PK of Rucaparib - AUC Last (Part 1 and Part 3)
Description
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.
Time Frame
Day -7 to Cycle 1 Day 1, or approximately 7 days
Title
QTcF Value Change From Baseline (Part 1)
Description
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.
Time Frame
Screening to End of Treatment, up to approximately 15 months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Facility Information:
Facility Name
UCSF
City
San Francisco
State/Province
California
ZIP/Postal Code
94155
Country
United States
Facility Name
Sarah Cannon Research Institute
City
Sarasota
State/Province
Florida
ZIP/Postal Code
34232
Country
United States
Facility Name
Dana-Farber Cancer Institute (Part 3 only)
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Sarah Cannon Research Institute
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Princess Margaret Cancer Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
MSG 2M9
Country
Canada
Facility Name
Sheba Medical Center
City
Ramat Gan
ZIP/Postal Code
52621
Country
Israel
Facility Name
Tel Aviv Sourasky Medical Center
City
Tel Aviv
ZIP/Postal Code
632394
Country
Israel
Facility Name
Hospital Vall d'Hebron
City
Barcelona
ZIP/Postal Code
8035
Country
Spain
Facility Name
Guy's and St Thomas NHS Foundation Trust
City
London
State/Province
England
ZIP/Postal Code
SE1 9RT
Country
United Kingdom
Facility Name
Royal Marsden NHS Foundation Trust
City
London
State/Province
England
ZIP/Postal Code
SW3 6JJ
Country
United Kingdom
Facility Name
Imperial College Healthcare
City
London
State/Province
England
ZIP/Postal Code
W12 0HS
Country
United Kingdom
Facility Name
Newcastle University
City
Newcastle Upon Tyne
State/Province
England
ZIP/Postal Code
UK NE7
Country
United Kingdom
Facility Name
Institution of Cancer Science, University of Glasgow Wolfson Wohl Cancer Research
City
Glasgow
State/Province
Scotland
ZIP/Postal Code
G61 1QH
Country
United Kingdom
Facility Name
University College London Cancer Institute
City
London
ZIP/Postal Code
WC1E 6BT
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
35397664
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.
Results Reference
derived
PubMed Identifier
31685558
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.
Results Reference
derived
PubMed Identifier
29799676
Citation
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.
Results Reference
derived

Learn more about this trial

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

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