A Phase Ib, Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Ipatasertib in Combination With Rucaparib in Patients With Advanced Breast, Ovarian, or Prostate Cancer
Overview
- Phase
- Phase 1
- Intervention
- Ipatasertib
- Conditions
- Breast Cancer
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 51
- Locations
- 17
- Primary Endpoint
- Percentage of Participants With Prostate-Specific Antigen Response (PSAR)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a study in participants with advanced breast, ovarian, or prostate cancer to investigate the dose, safety, pharmacokinetics, and preliminary efficacy of ipatasertib in combination with rucaparib. The study consists of two parts: a Dose-Escalation Phase (Part 1) in participants with previously treated advanced breast cancer, ovarian cancer, or prostate cancer and a Dose-Expansion Phase (Part 2) in participants with advanced prostate cancer who have had at least one line of prior therapy with second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, enzalutamide, apalutamide).
Detailed Description
There are two parts in the study. A Dose-Escalation Phase (Part 1) in participants with previously treated advanced breast cancer, ovarian cancer, or prostate cancer. There will be a 7-day run-in period with ipatasertib alone prior to Cycle 1, Day 1. After the completion of the ipatasertib run-in period, participants will begin Cycle 1, Day 1 of the ipatasertib and rucaparib combination treatment. Each cycle has 28 days. Participants will be split into 4 cohorts: Dose Level 1 group - 300 mg ipatasertib once daily (QD) + 400 mg rucaparib twice daily (BID), Dose Level 2a: 300 mg ipatasertib QD + 600 mg rucaparib BID, Dose Level 2b: 400 mg ipatasertib QD + 400 mg rucaparib BID, Dose Level 3: 400 mg ipatasertib QD + 600 mg rucaparib BID A Dose-Expansion Phase (Part 2) - The recommended dose identified in Part 1 (highest dose level of ipatasertib and rucaparib with an acceptable safety profile and less than one-third of participants experience a dose limiting toxicity) will be evaluated in participants with advanced prostate cancer who have had at least one line of prior therapy with second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, enzalutamide, apalutamide). Enrollment in Cohort 3 in dose escalation phase was not opened as one-third of Dose Limiting Toxicity (DLT) evaluable participants receiving the highest dose of rucaparib in Cohort 2a experienced a DLT.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •A life expectancy of at least 3 months
- •Ability to swallow oral study drug
- •Have adequate organ and marrow function as confirmed by the laboratory values listed below, obtained within 28 days prior to the first dose of study treatment:
- •Bone marrow function assessments (without transfusion within 28 days prior to receipt of study treatment):
- •ANC \>= 1500 cells/uL (1.5 x 10\^9/L) without granulocyte-colony stimulating factor support
- •Platelet count \>= 100.0 x 10\^9/L
- •Hemoglobin \>= 9 g/dL (or 5.6 mmol/L)
- •Chemistry panel assessments:
- •AST and ALT \<= 1.5 x upper limit of normal (ULN); if liver metastases, \<= 2.5 x ULN
Exclusion Criteria
- •Pregnant or breastfeeding, or intending to become pregnant during the study or within 28 days after the final dose of ipatasertib or 6 months after the final dose of rucaparib
- •Prior treatment with a PARP inhibitor, AKT inhibitor, or PI3K inhibitor
- •Treatment with investigational therapy within 14 days prior to initiation of study drug
- •Symptomatic and/or untreated CNS metastases
- •Uncontrolled tumor-related pain
- •Non-study-related minor surgical procedures \<= 5 days or major (invasive) surgical procedure \<=14 days prior to first dose of study treatment
- •Patients with active hepatitis C virus (HCV)
- •Hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test or a positive quantitative HBV DNA test
- •Known HIV infection
- •Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment
Arms & Interventions
Dose escalation-Cohort 1
Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 300 milligrams (mg), orally, once daily (QD) for 7 days in the run-in period. Participants will then receive ipatasertib, 300 mg, orally QD, and rucaparib, 400 mg, orally twice daily (BID) in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.
Intervention: Ipatasertib
Dose escalation-Cohort 1
Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 300 milligrams (mg), orally, once daily (QD) for 7 days in the run-in period. Participants will then receive ipatasertib, 300 mg, orally QD, and rucaparib, 400 mg, orally twice daily (BID) in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.
Intervention: Rucaparib
Dose escalation-Cohort 2a
Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 300 mg, orally, QD for 7 days in the run-in period. Participants will then receive ipatasertib, 300 mg, orally QD, and rucaparib, 600 mg, orally BID in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.
Intervention: Ipatasertib
Dose escalation-Cohort 2a
Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 300 mg, orally, QD for 7 days in the run-in period. Participants will then receive ipatasertib, 300 mg, orally QD, and rucaparib, 600 mg, orally BID in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.
Intervention: Rucaparib
Dose escalation-Cohort 2b
Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 400 mg, orally, QD for 7 days in the run-in period. Participants will then receive ipatasertib, 400 mg, orally QD, and rucaparib, 400 mg, orally BID in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.
Intervention: Ipatasertib
Dose escalation-Cohort 2b
Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 400 mg, orally, QD for 7 days in the run-in period. Participants will then receive ipatasertib, 400 mg, orally QD, and rucaparib, 400 mg, orally BID in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.
Intervention: Rucaparib
Dose escalation-Cohort 3
Participants with advanced breast cancer, ovarian cancer, or prostate cancer are planned to receive ipatasertib 400 mg orally QD for 7 days (run-in period prior to Cycle 1). Participants will then receive ipatasertib 400 mg orally QD and rucaparib 600 mg, orally BID in 28 days cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.
Intervention: Ipatasertib
Dose escalation-Cohort 3
Participants with advanced breast cancer, ovarian cancer, or prostate cancer are planned to receive ipatasertib 400 mg orally QD for 7 days (run-in period prior to Cycle 1). Participants will then receive ipatasertib 400 mg orally QD and rucaparib 600 mg, orally BID in 28 days cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.
Intervention: Rucaparib
Dose Expansion
The recommended dose (ipatasertib and rucaparib) identified in Part 1 will be evaluated in participants with advanced prostate cancer who have had at least one line of prior therapy with second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, enzalutamide, apalutamide).
Intervention: Ipatasertib
Dose Expansion
The recommended dose (ipatasertib and rucaparib) identified in Part 1 will be evaluated in participants with advanced prostate cancer who have had at least one line of prior therapy with second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, enzalutamide, apalutamide).
Intervention: Rucaparib
Outcomes
Primary Outcomes
Percentage of Participants With Prostate-Specific Antigen Response (PSAR)
Time Frame: From Baseline up to 1.5 years
PSA response was defined as the percentage of participants with a reduction in the PSA level of 50% or more. PSA response analysis was based on central PSA measurement. The 95% CI was estimated using the Clopper-Pearson method.
Percentage of Participants With Adverse Events
Time Frame: From Baseline up until 90 days after the last dose of study drug (up to 2 years)
An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product.
Dose Escalation: Percentage of Participants With Dose-Limiting Toxicities (DLTs) That Determine the Maximum-Tolerated Dose (MTD) of the Ipatasertib and Rucaparib Combination
Time Frame: Day -7 to Day 28 of Cycle 1 (1 cycle = 28 days) (up to 35 days)
A DLT was defined as adverse events related to study treatments occurring during the DLT reporting period, which included: any death related to study treatment; grade 4 neutropenia lasting for ≥7 days; grade ≥3 neutropenia complicated by fever ≥38°C or infection; grade 4 thrombocytopenia lasting for ≥7 days; grade ≥3 thrombocytopenia complicated by hemorrhage or that requires transfusion; study treatment-related grade ≥3 non-hematologic toxicity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5 (NCI CTCAE, v5.0).
Secondary Outcomes
- Plasma Concentration of Ipatasertib(Dose Escalation: Cycle 1: Day 1 and 15 (1, 2 ,3, 5 hours post-dose), Day 15 (Predose) and Cycle 2: Day 1 and 15 (Predose); Dose Expansion: Cycle 1: Day 15 (Predose) and Cycle 2: Day 1 and 15 (Predose) (1 cycle = 28 days))
- Plasma Concentration of Ipatasertib's Metabolite (G-037720)(Dose Escalation: Cycle 1: Day 1 and 15 (1, 2 ,3, 5 hours post-dose), Day 15 (Predose) and Cycle 2: Day 1 and 15 (Predose); Dose Expansion: Cycle 1: Day 15 (Predose) and Cycle 2: Day 1 and 15 (Predose) (1 cycle = 28 days))
- Plasma Concentration of Rucaparib(Cycle 1 Day 15 and Cycle 2 Day 1 and 15: Predose (1 cycle = 28 days))
- Percentage of Participants With Objective Response, as Assessed by Investigator Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1)(From Baseline up to 1.5 years (assessed at the end of Cycle 2,4,6, and every 3 cycles thereafter up to progression, 1 cycle= 28 days))
- Duration of Objective Response in Participants With Measurable Disease at Baseline, as Assessed by Investigator Based on RECIST v1.1(From Baseline up to 1.5 years (assessed at the end of Cycle 2,4,6, and every 3 cycles thereafter up to progression, 1 cycle= 28 days))
- Radiographic Progression Free Survival (rPFS), as Assessed by Prostate Cancer Working Group 3 Criteria (PCWG3)(From Baseline up to 1.5 years (assessed at the end of Cycle 2,4,6, and every 3 cycles thereafter up to progression, 1 cycle= 28 days))
- Overall Survival (OS) in All Participants(From Baseline to death from any cause, assessed up to 2 years)