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

pharmaand GmbH136 enrolled

Overview

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).

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

136

Conditions

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (16)

UCSF

San Francisco, California, United States

Sarah Cannon Research Institute

Sarasota, Florida, United States

Dana-Farber Cancer Institute (Part 3 only)

Boston, Massachusetts, United States

Karmanos Cancer Institute

Detroit, Michigan, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

Princess Margaret Cancer Centre

Toronto, Ontario, Canada

Sheba Medical Center

Ramat Gan, Israel

Tel Aviv Sourasky Medical Center

Tel Aviv, Israel

Hospital Vall d'Hebron

Barcelona, Spain

...and 6 more locations

Outcomes

Primary Outcomes

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.

Time frame: Time from first dose to date of progression, up to approximately 8 months

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.

Time frame: Cycle 1 Day 1 to Cycle 1 Day 21

PK Profile of Rucaparib - Cmax (Part 1)

Cmax = maximum concentration following administration of rucaparib

Time frame: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

PK Profile of Rucaparib - Tmax (Part 1)

Tmax = time to maximum concentration following administration of rucaparib

Time frame: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

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

Time frame: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

Secondary Outcomes

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.

Time frame: Cycle 1 Day 1 to End of Treatment, up to approximately 51 months

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.

Time frame: Cycle 1 Day 1 to End of Treatment, up to approximately 48 months

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.

Time frame: Cycle 1 Day 1 to date of death, assessed up to 38 months

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.

Time frame: Day -7 to Cycle 1 Day 1, or approximately 7 days

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.

Time frame: Day -7 to Cycle 1 Day 1, or approximately 7 days

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.

Time frame: Day -7 to Cycle 1 Day 1, or approximately 7 days

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.

Time frame: Screening to End of Treatment, up to approximately 15 months

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

Overview

Conditions

Interventions

Eligibility

Locations (16)

Outcomes

Primary Outcomes

Secondary Outcomes