Gynecologic Neoplasms
Conditions
Brief summary
This is a Phase Ib, open-label, non-randomized study in patients with previously treated advanced ovarian or endometrial cancer (Part 1) and platinum-sensitive ovarian cancer or triple-negative breast cancer (TNBC) (Part 2) to investigate the dose, safety, pharmacokinetics, and preliminary efficacy of rucaparib in combination with atezolizumab. The study is conducted in 2 parts: a Dose-Finding Phase (Part 1) and a Dose-Expansion Phase (Part 2)
Interventions
DRUGAtezolizumab
Atezolizumab 1200 mg (equivalent to an average body weight-based dose of 15 milligrams per kilogram \[mg/kg\]) will be administered by IV infusion once every 3 weeks, corresponding to a 21-day treatment cycle. Participants will receive atezolizumab starting on Cycle 1, Day 1. Participants deriving clinical benefit will be allowed to continue on study treatment until the absence of unacceptable toxicity or compelling evidence of disease progression.
DRUGRucaparib
The starting dosage level of rucaparib for Part 1 is 400 mg PO BID during a 21-day treatment cycle. During Part 1, the rucaparib doses were increased up to a maximum of 600 mg PO BID using a standard 3 + 3 dose escalation. RP2D was identified as 600 mg BID. During Part 2 of the study, rucaparib will be dosed at the RP2D determined in Part 1. Participants in Part 1 of the study will receive rucaparib starting on Cycle 1, Day 1. During Part 2, participants will receive rucaparib monotherapy during a 21-day run-in period. After completion of the rucaparib run-in period and the first on-treatment biopsy between Days 15 and 21 of the run-in period, participants will begin Cycle 1, Day 1 of the rucaparib. Participants deriving clinical benefit will be allowed to continue on study treatment until the absence of unacceptable toxicity or compelling evidence of disease progression.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * A life expectancy of at least 3 months * Have disease that is measurable as according to RECIST v1.1 * Have sufficient archival formalin-fixed paraffin-embedded (FFPE) tumor tissue available for planned analyses * For Part 1, have a histologically confirmed diagnosis of ovarian or endometrial cancer, and have received at least one line of prior therapy for metastatic disease * For Part 2 ONLY, have disease that can be safely biopsied * For Part 2 ONLY, have a deleterious germline or somatic breast cancer susceptibility gene 1 (BRCA1) or BRCA2 mutation or tumors that are wild-type BRCA but show high levels of loss of heterozygosity (LOH) (tBRCAwt/LOHhigh) signature * For Part 2 Cohort 1 (ovarian cancer), high-grade serous or Grade 3 endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer (PPC) * For Part 2 Cohort 1, have received at least one and no more than two lines of prior platinum-containing therapy and progressed after the most recent platinum therapy in a platinum-sensitive timeframe * For Part 2 ONLY, Cohort 1, have a CA125 measurement that is greater than 2 times the upper limit of normal (ULN) * For Part 2 Cohort 2 (TNBC), metastatic, histologically confirmed estrogen receptor (ER)-negative, progesterone receptor-negative, and HER2-negative adenocarcinoma of the breast per local laboratory assessment * For Part 2 Cohort 2, radiologic/objective evidence of recurrence or disease progression after one line of chemotherapy for TNBC in the metastatic setting * Have adequate organ function
Exclusion criteria
* History of prior malignancy except a) curatively treated non-melanoma skin cancer, b) solid tumor treated curatively more than 3 years ago without evidence of recurrence, c) For Cohort 1 (ovarian cancer): breast cancer with no evidence of disease or inactive for at least 3 years, and d) synchronous endometrial cancer (Stage 1A) with ovarian cancer * Treatment with chemotherapy, radiation, hormones (except corticosteroids and megestrol acetate), or other anticancer therapies less than or equal to (\<=) 14 days prior to first dose of study treatment * Preexisting duodenal stent and/or any gastrointestinal disorder or defect that would, in the opinion of the investigator, interfere with absorption of rucaparib * Symptomatic and/or untreated central nervous system metastases * Prior treatment with any poly adenosine diphosphate-ribose polymerase (PARP) inhibitor
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Adverse Events | Baseline up to approximately 45 months |
| Percentage of Participants With Dose-Limiting Toxicities (DLTs) [Part 1] | Cycle 1 (Day 1 up to Day 21) |
| Recommended Phase II Dose (RP2D) of Rucaparib for the Combination [Part 1] | Cycle 1 (Day 1 up to Day 21) |
| Number of Dose Modifications due to Adverse Events [Part 2] | Baseline up to approximately 45 months |
Secondary
| Measure | Time frame |
|---|---|
| Progression-Free Survival (PFS) as Determined by Investigator Assessment Using RECIST v1.1 | Baseline until disease progression or death from any cause, whichever occurs first (assessed every 12 weeks up to approximately 45 months) |
| PFS as Determined by Investigator Assessment Using Immune-Modified RECIST Incorporating Immune-Response (CA125 Response) Considerations | Baseline until disease progression or death from any cause, whichever occurs first (assessed every 12 weeks up to approximately 45 months) |
| Overall Survival | Baseline until Death (up to 45 months) |
| Steady State Maximum Plasma Concentration Observed (Cmax) for Rucaparib [Part 1] | Predose (0 hours [hrs]) on Day 1 of Cycles 1-4; 0, 0.5, 1, 1.5, 2.5, 4, 6, 8 hrs postdose on Day 15 of Cycle 1; at 30 days after the last dose of study treatment (up to 45 months; cycle length=21 days) |
| Time to Maximum Plasma Concentration (tmax) for Rucaparib [Part 1] | Predose (0 hrs) on Day 1 of Cycles 1-4; 0, 0.5, 1, 1.5, 2.5, 4, 6, 8 hrs postdose on Day 15 of Cycle 1; at 30 days after the last dose of study treatment (up to 45 months; cycle length=21 days) |
| Percentage of Participants With Objective Response of Complete Response (CR) or Partial Response (PR) as Determined by Investigator Assessment Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Baseline until disease progression or death from any cause, whichever occurs first (assessed every 12 weeks up to approximately 45 months) |
| Apparent Clearance (CL/F) for Rucaparib [Part 1] | Predose (0 hrs) on Day 1 of Cycles 1-4; 0, 0.5, 1, 1.5, 2.5, 4, 6, 8 hrs postdose on Day 15 of Cycle 1; at 30 days after the last dose of study treatment (up to 45 months; cycle length=21 days) |
| Minimum Plasma Concentration During the Dosing Interval (Cmin) for Rucaparib [Part 2] | Predose (0 hrs) on Day 1 of Cycles 1-4; at 30 days after the last dose of study treatment (up to 45 months; cycle length=21 days) |
| Serum Concentration of Atezolizumab [Parts 1 and 2] | Predose (0 hrs) on Day 1 of Cycles 1-4, 8 and every 8 cycles (up to 45 months); 0.5 hrs postdose (infusion duration=30-60 minutes) on Day 1 of Cycles 1 and 3; at 30 and 120 days after last dose of study treatment (up to 45 months; cycle length=21 days) |
| Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Baseline up to approximately 45 months |
| Area Under the Plasma Concentration-Time Curve (AUC) for Rucaparib [Part 1] | Predose (0 hrs) on Day 1 of Cycles 1-4; 0, 0.5, 1, 1.5, 2.5, 4, 6, 8 hrs postdose on Day 15 of Cycle 1; at 30 days after the last dose of study treatment (up to 45 months; cycle length=21 days) |
| Percentage of Participants With Objective Response of CR or PR as Determined by Investigator Assessment Using Immune-Modified RECIST Incorporating Immune-Response (Cancer Antigen 125 [CA125] Response) Considerations | Baseline until disease progression or death from any cause, whichever occurs first (assessed every 12 weeks up to approximately 45 months) |
| Duration of Response (DOR) as Determined by Investigator Assessment Using RECIST v1.1 | Baseline until disease progression or death from any cause, whichever occurs first (assessed every 12 weeks up to approximately 45 months) |
| DOR as Determined by Investigator Assessment Using Immune-Modified RECIST Incorporating Immune-Response (CA125 Response) Considerations | Baseline until disease progression or death from any cause, whichever occurs first (assessed every 12 weeks up to approximately 45 months) |
Countries
Australia, France, Spain, United Kingdom
Outcome results
None listed