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).
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
51
Ipatasertib will be administered orally.
Rucaparib will be administered orally.
California Cancer Associates for Research & Excellence, Inc.
San Marcos, California, United States
Regional Cancer Care Associates LLC, Central Jersey Division
East Brunswick, New Jersey, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
Mary Crowley Medical Research Center; Oncology
Dallas, Texas, United States
Kinghorn Cancer Centre; St Vincents Hospital
Darlinghurst, New South Wales, Australia
Macquarie University Hospital
Macquarie Park, New South Wales, Australia
Cabrini Hospital Malvern
Malvern, Victoria, Australia
Istituto Nazionale Tumori Regina Elena IRCCS
Rome, Lazio, Italy
Fondazione IRCCS Istituto Nazionale dei Tumori; S. C. Oncologia Medica 2
Milan, Lombardy, Italy
Azienda Ospedaliera Santa Maria di Terni
Terni, Umbria, Italy
...and 7 more locations
Percentage of Participants With Adverse Events
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.
Time frame: From Baseline up until 90 days after the last dose of study drug (up to 2 years)
Dose Escalation: Percentage of Participants With Dose-Limiting Toxicities (DLTs) That Determine the Maximum-Tolerated Dose (MTD) of the Ipatasertib and Rucaparib Combination
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).
Time frame: Day -7 to Day 28 of Cycle 1 (1 cycle = 28 days) (up to 35 days)
Percentage of Participants With Prostate-Specific Antigen Response (PSAR)
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.
Time frame: From Baseline up to 1.5 years
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)
Objective response rate (ORR), defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1). A complete response was defined as the disappearance of all lesions. Pathological lymph nodes (whether target or non-target) must have a reduction in short axis to less than 10 millimeters (mm). A partial response was defined as ≥30% decrease in the sum of the diameter of target lesions, in the absence of CR persistence of one or more non-target lesions. The analysis is based on the subset of participants with measurable lesions as per RECIST criteria at baseline. ORR was calculated, and the 95% CI was estimated using the Clopper-Pearson method.
Time frame: 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
DOR was defined as the time from the first occurrence of a documented objective response until the time of documented disease progression or death from any cause during the study, whichever occurred first. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions compared to the smallest sum of diameters on-study and an absolute increase of at least 5 mm, or the presence of new lesions. The duration of response was estimated by Kaplan-Meier. 95% CI for median was computed using the method of Brookmeyer and Crowley.
Time frame: 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)
rPFS was defined as the time from study treatment initiation to the first occurrence of documented disease progression, as assessed by the investigator with the use of the PCWG3 criteria (soft tissue: Progressive disease on computed tomography \[CT\] or MRI scans according to RECIST v1.1, and bone metastasis by bone scan according to the PCWG3 criteria) or death from any cause, whichever occurred first. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions compared to the smallest sum of diameters on-study and an absolute increase of at least 5 mm, or the presence of new lesions. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley.
Time frame: 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
OS was defined as the time from study treatment initiation to the time of death due to any cause. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley.
Time frame: From Baseline to death from any cause, assessed up to 2 years
Plasma Concentration of Ipatasertib
Time frame: 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)
Time frame: 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
Time frame: Cycle 1 Day 15 and Cycle 2 Day 1 and 15: Predose (1 cycle = 28 days)
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