Breast Cancer, Ovarian Cancer, Prostate Cancer
Conditions
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.
Interventions
DRUGIpatasertib
Ipatasertib will be administered orally.
DRUGRucaparib
Rucaparib will be administered orally.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
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 * 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): 1. ANC \>= 1500 cells/uL (1.5 x 10\^9/L) without granulocyte-colony stimulating factor support 2. Platelet count \>= 100.0 x 10\^9/L 3. Hemoglobin \>= 9 g/dL (or 5.6 mmol/L) * Chemistry panel assessments: 1. AST and ALT \<= 1.5 x upper limit of normal (ULN); if liver metastases, \<= 2.5 x ULN 2. Bilirubin \<= 1.5 x ULN (\<= 3 x ULN if hyperbilirubinemia is due to Gilbert's syndrome) 3. Serum albumin \>= 3.0 g/dL 4. Serum creatinine \<= 1.5 x ULN or creatinine clearance \>= 50 mL/min 5. Fasting glucose \<= 150 mg/dL and hemoglobin A1c \<= 7.5% * Resolved or stabilized toxicities resulting from previous therapy to Grade 1 (except for alopecia and neuropathy). Cancer-Related Inclusion Criteria * Have a histologically confirmed diagnosis of ovarian (Part 1 only), breast (Part 1 only) or prostate cancer (Part 1 and Part 2) * Disease must be either metastatic or locally advanced disease that cannot be treated with curative intent * For patients with ovarian cancer (Part 1 only): 1. High-grade (2 or 3) serous or endometrioid or clear cell epithelial ovarian, fallopian tube, or primary peritoneal cancer (PPC) 2. Must have received at least one prior platinum-based therapy and may have platinumsensitive disease (i.e., documented radiologic disease progression \>= 6 months following the last dose of the platinum treatment administered) or platinum-resistant disease 3. Have a CA-125 level that is \> 2 x ULN 4. Must have measurable disease by RECIST v1.1 * For patients with breast cancer (Part 1 only): must be human epidermal growth factor receptor 2 negative (HER2-) (estrogen receptor \[ER\]/progesterone positive or negative): 1. ER/progesterone-positive patients must have received and progressed on at least one endocrine therapy (adjuvant or metastatic) 2. ER/progesterone-negative/HER2- (triple-negative breast cancer \[TNBC\]) patients must have received at least one prior line of chemotherapy for metastatic breast cancer 3. Must not have received more than two prior lines of chemotherapy for metastatic breast cancer 4. Must have measurable disease by RECIST v1.1 For patients with prostate cancer: 1. Adenocarcinoma of the prostate without small cell or neuroendocrine features 2. Surgical or medical castration with testosterone \< 50 ng/dL (1.7 nM) 3. Patients treated with luteinizing hormone-releasing hormone analogs must have initiated therapy at least 4 weeks prior to the first dose of study treatment and continue throughout the study treatment 4. Progression of prostate cancer either via PSA progression (two rising PSA levels measured \>= 1 week apart, with second result \>= 1 ng/mL) or radiographic progression with or without PSA progression 5. Must have received at least one prior line of second-generation androgen receptor targeted therapy (e.g., abiraterone, enzalutamide, apalutamide) 6. Patients with prostate cancer must have either measurable disease by RECIST v1.1 or bone lesions by bone scan, or both. * Submission of a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or a minimum of 12 freshly cut, unstained, serial tumor slides from the most recently collected tumor tissue for central molecular analysis (retrospective NGS testing for HR and PI3K-AKT pathway status and for other protocol-mandated secondary and exploratory assessments). Cytologic or fine needle aspirate samples are not acceptable. Tumor tissue from bone metastases is not acceptable. * For men and women of child bearing potential: agreement to remain abstinent or use protocol defined contraceptive measures during the treatment period and for at least 28 days after the last dose of ipatasertib,or 6 months after the last dose of rucaparib, whichever occurs later
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 * Malabsorption syndrome or other condition that would interfere with enteral absorption * Serious infection requiring antibiotics within 14 days of first dose of study treatment * Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study * Need for chronic corticosteroid therapy of \>= 10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic disease * History of another malignancy within 5 years prior to randomization, except for either adequately treated non-melanomatous carcinoma of the skin, adequately treated melanoma in situ, adequately treated non-muscle-invasive urothelial carcinoma of the bladder (Tis, Ta, and low-grade T1 tumors), or other malignancies where the patient has undergone potentially curative therapy with no evidence of disease and are deemed by the treating physician to have a recurrence rate of \< 5% at 5 years. * History of clinically significant cardiovascular dysfunction * Presence of any other condition that may have increased the risk associated with study participation or may have interfered with the interpretation of study results, and, in the opinion of the investigator, would have made the patient inappropriate for entry into the study Ipatasertib-Specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events | 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 | 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). |
| Percentage of Participants With Prostate-Specific Antigen Response (PSAR) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) in All Participants | From Baseline to death from any cause, assessed up to 2 years | 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. |
| 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) | — |
| 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) | 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. |
| Plasma Concentration of Rucaparib | Cycle 1 Day 15 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) | — |
| 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) | 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. |
| 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) | 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. |
Countries
Australia, Italy, South Korea, Spain, United States
Participant flow
Recruitment details
Participants took part in the study at 14 investigative sites in 5 countries (Australia, Italy, the Republic of Korea, Spain, and the United States) from 12 June 2019 to 04 January 2022.
Pre-assignment details
A total of 78 participants were screened. Enrollment in Cohort 3 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.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation-Cohort 1 Participants with advanced breast cancer, ovarian cancer, or prostate cancer received ipatasertib, 300 mg, orally, QD for 7 days in the run-in period. Participants then received ipatasertib, 300 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 occurred first. | 8 |
| Dose Escalation-Cohort 2a Participants with advanced breast cancer, ovarian cancer, or prostate cancer received ipatasertib, 300 mg, orally, QD for 7 days in the run-in period. Participants then received 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 occurred first. | 6 |
| Dose Escalation-Cohort 2b Participants with advanced breast cancer, ovarian cancer, or prostate cancer received ipatasertib, 400 mg, orally, QD for 7 days in the run-in period. Participants then received 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 occurred first. | 7 |
| Dose Expansion Participants with advanced prostate cancer received 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 decision to withdraw, whichever occurred first. | 30 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 6 | 3 | 6 | 10 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 2 |
| Overall Study | Progressive Disease | 0 | 0 | 0 | 1 |
| Overall Study | Reason Not Specified | 2 | 2 | 1 | 15 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Dose Escalation-Cohort 1 | Dose Escalation-Cohort 2a | Dose Escalation-Cohort 2b | Dose Expansion | Total |
|---|---|---|---|---|---|
| Age, Continuous | 68.3 years STANDARD_DEVIATION 4.7 | 65.2 years STANDARD_DEVIATION 6 | 69.3 years STANDARD_DEVIATION 5.9 | 69.1 years STANDARD_DEVIATION 9.2 | 68.5 years STANDARD_DEVIATION 7.8 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 8 Participants | 6 Participants | 6 Participants | 28 Participants | 48 Participants |
| Race/Ethnicity, Customized Not Stated | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 6 Participants | 6 Participants | 26 Participants | 46 Participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 7 Participants | 30 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 8 | 3 / 6 | 6 / 7 | 10 / 30 |
| other Total, other adverse events | 8 / 8 | 6 / 6 | 7 / 7 | 30 / 30 |
| serious Total, serious adverse events | 2 / 8 | 1 / 6 | 1 / 7 | 8 / 30 |
Outcome results
Primary
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)
Population: Safety population included all participants who were treated with at least one dose of the study treatment. Results for dose expansion is not presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation-Cohort 1 | Dose Escalation: Percentage of Participants With Dose-Limiting Toxicities (DLTs) That Determine the Maximum-Tolerated Dose (MTD) of the Ipatasertib and Rucaparib Combination | 12.5 percentage of participants |
| Dose Escalation-Cohort 2a | Dose Escalation: Percentage of Participants With Dose-Limiting Toxicities (DLTs) That Determine the Maximum-Tolerated Dose (MTD) of the Ipatasertib and Rucaparib Combination | 33.3 percentage of participants |
| Dose Escalation-Cohort 2b | Dose Escalation: Percentage of Participants With Dose-Limiting Toxicities (DLTs) That Determine the Maximum-Tolerated Dose (MTD) of the Ipatasertib and Rucaparib Combination | 0 percentage of participants |
Primary
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)
Population: Safety population included all participants who were treated with at least one dose of the study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation-Cohort 1 | Percentage of Participants With Adverse Events | 100 percentage of participants |
| Dose Escalation-Cohort 2a | Percentage of Participants With Adverse Events | 100 percentage of participants |
| Dose Escalation-Cohort 2b | Percentage of Participants With Adverse Events | 100 percentage of participants |
| Dose Expansion | Percentage of Participants With Adverse Events | 100 percentage of participants |
Primary
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
Population: Efficacy-evaluable population included all participants who had prostate cancer, baseline lesion, and received actual dosing equivalent to the planned dose of treatment. Number of participants analyzed are participants with data available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation-Cohort 1 | Percentage of Participants With Prostate-Specific Antigen Response (PSAR) | 0 percentage of participants |
| Dose Escalation-Cohort 2a | Percentage of Participants With Prostate-Specific Antigen Response (PSAR) | 33.3 percentage of participants |
| Dose Escalation-Cohort 2b | Percentage of Participants With Prostate-Specific Antigen Response (PSAR) | 25.0 percentage of participants |
| Dose Expansion | Percentage of Participants With Prostate-Specific Antigen Response (PSAR) | 23.1 percentage of participants |
Secondary
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)
Population: Intent-to-treat population included all participants who were treated with at least one dose of the study treatment. Number of participants analyzed is the number of participants with confirmed objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation-Cohort 1 | Duration of Objective Response in Participants With Measurable Disease at Baseline, as Assessed by Investigator Based on RECIST v1.1 | NA months |
Secondary
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
Population: Efficacy-evaluable population included all participants who had prostate cancer, baseline lesion, and received actual dosing equivalent to the planned dose of treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation-Cohort 1 | Overall Survival (OS) in All Participants | 20.8 months |
| Dose Escalation-Cohort 2a | Overall Survival (OS) in All Participants | 13.8 months |
| Dose Escalation-Cohort 2b | Overall Survival (OS) in All Participants | 13.3 months |
| Dose Expansion | Overall Survival (OS) in All Participants | NA months |
Secondary
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)
Population: Efficacy-evaluable population included all participants who had prostate cancer, baseline lesion, and received actual dosing equivalent to the planned dose of treatment. Number of participants analyzed are participants with data available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation-Cohort 1 | 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) | 0 percentage of participants |
| Dose Escalation-Cohort 2a | 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) | 0 percentage of participants |
| Dose Escalation-Cohort 2b | 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) | 0 percentage of participants |
| Dose Expansion | 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) | 13.3 percentage of participants |
Secondary
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)
Population: PK-evaluable population includes all participants who had at least one evaluable PK sample. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib | Cycle 2 Day 15: Predose | 18.9 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 72.6 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:3hour post dose | 92.4 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 53.2 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib | Cycle 1 Day 15: Predose | 21.6 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 57.1 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib | Cycle 2 Day 1: Predose | 19.2 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 108.1 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:2 hour post dose | 98.7 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 98 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:1 hour post dose | 160 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 262.1 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:1 hour post dose | 130 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 126.3 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:3 hour post dose | 116 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 85.7 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:2 hour post dose | 159 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 59 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:5 hour post dose | 85.1 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 28.7 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:5 hour post dose | 93.4 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 52.9 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:1 hour post dose | 242 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 100.8 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:1 hour post dose | 172 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 89.2 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:3hour post dose | 141 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 108.7 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:2 hour post dose | 133 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 77.7 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:3 hour post dose | 131 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 49 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:5 hour post dose | 127 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 58.4 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib | Cycle 1 Day 15: Predose | 39.4 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 178.4 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:2 hour post dose | 177 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 119.3 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:5 hour post dose | 105 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 126.1 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib | Cycle 2 Day 1: Predose | 20.9 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 51.3 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib | Cycle 2 Day 15: Predose | 31.1 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 78 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:1 hour post dose | 192 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 106 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:5 hour post dose | 171 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 23.9 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:3hour post dose | 181 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 43.1 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:3 hour post dose | 249 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 24.5 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:1 hour post dose | 158 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 94.8 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib | Cycle 1 Day 15: Predose | 33.5 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 29.5 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:2 hour post dose | 177 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 51.3 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib | Cycle 1 Day 15:5 hour post dose | 172 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 33.1 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib | Cycle 1 Day 1:2 hour post dose | 230 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 44.7 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib | Cycle 2 Day 15: Predose | 49.4 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 43.5 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib | Cycle 2 Day 1: Predose | 40.1 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 33.2 |
| Dose Expansion | Plasma Concentration of Ipatasertib | Cycle 2 Day 15: Predose | 48.6 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 77.2 |
| Dose Expansion | Plasma Concentration of Ipatasertib | Cycle 2 Day 1: Predose | 31.2 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 226.3 |
| Dose Expansion | Plasma Concentration of Ipatasertib | Cycle 1 Day 15: Predose | 48.4 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 96.6 |
Secondary
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)
Population: PK-evaluable population includes all participants who had at least one evaluable PK sample. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15:2 hour post dose | 43.2 ng/mL | Geometric Coefficient of Variation 85.9 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:5 hour post dose | 44.0 ng/mL | Geometric Coefficient of Variation 53.3 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 2 Day 15: Predose | 11.3 ng/mL | Geometric Coefficient of Variation 29.9 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15:1 hour post dose | 38.0 ng/mL | Geometric Coefficient of Variation 111.9 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15: Predose | 11.8 ng/mL | Geometric Coefficient of Variation 25 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 2 Day 1: Predose | 10.3 ng/mL | Geometric Coefficient of Variation 58 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:2 hour post dose | 71.2 ng/mL | Geometric Coefficient of Variation 51.7 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15: 5 hour post dose | 33.0 ng/mL | Geometric Coefficient of Variation 42.8 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15:3 hour post dose | 38.5 ng/mL | Geometric Coefficient of Variation 62.8 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:3 hour post dose | 57.8 ng/mL | Geometric Coefficient of Variation 62.2 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:1 hour post dose | 65.0 ng/mL | Geometric Coefficient of Variation 187.1 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15: Predose | 23.7 ng/mL | Geometric Coefficient of Variation 128.8 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:1 hour post dose | 81.1 ng/mL | Geometric Coefficient of Variation 81.1 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:2 hour post dose | 92.7 ng/mL | Geometric Coefficient of Variation 70.6 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:3 hour post dose | 85.0 ng/mL | Geometric Coefficient of Variation 46.2 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:5 hour post dose | 85.3 ng/mL | Geometric Coefficient of Variation 54.3 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 2 Day 15: Predose | 19.7 ng/mL | Geometric Coefficient of Variation 99.6 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15: 5 hour post dose | 53.3 ng/mL | Geometric Coefficient of Variation 81.9 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15:1 hour post dose | 67.4 ng/mL | Geometric Coefficient of Variation 35.8 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15:2 hour post dose | 76.3 ng/mL | Geometric Coefficient of Variation 55.4 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15:3 hour post dose | 65.8 ng/mL | Geometric Coefficient of Variation 61.9 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 2 Day 1: Predose | 13.9 ng/mL | Geometric Coefficient of Variation 62.9 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:3 hour post dose | 141 ng/mL | Geometric Coefficient of Variation 42.8 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 2 Day 1: Predose | 22.4 ng/mL | Geometric Coefficient of Variation 35.1 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15:2 hour post dose | 65.0 ng/mL | Geometric Coefficient of Variation 69 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:2 hour post dose | 115 ng/mL | Geometric Coefficient of Variation 53 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:1 hour post dose | 82.0 ng/mL | Geometric Coefficient of Variation 119.3 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15:3 hour post dose | 75.9 ng/mL | Geometric Coefficient of Variation 56.8 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15: Predose | 20.2 ng/mL | Geometric Coefficient of Variation 21.4 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15: 5 hour post dose | 73.4 ng/mL | Geometric Coefficient of Variation 34.3 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 1:5 hour post dose | 112 ng/mL | Geometric Coefficient of Variation 32.2 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 2 Day 15: Predose | 26.4 ng/mL | Geometric Coefficient of Variation 38.8 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15:1 hour post dose | 56.1 ng/mL | Geometric Coefficient of Variation 104.8 |
| Dose Expansion | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 2 Day 15: Predose | 23.6 ng/mL | Geometric Coefficient of Variation 75.4 |
| Dose Expansion | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 1 Day 15: Predose | 25.7 ng/mL | Geometric Coefficient of Variation 103.2 |
| Dose Expansion | Plasma Concentration of Ipatasertib's Metabolite (G-037720) | Cycle 2 Day 1: Predose | 16.3 ng/mL | Geometric Coefficient of Variation 131.2 |
Secondary
Plasma Concentration of Rucaparib
Time frame: Cycle 1 Day 15 and Cycle 2 Day 1 and 15: Predose (1 cycle = 28 days)
Population: PK-evaluable population included all participants who had at least one evaluable PK sample. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation-Cohort 1 | Plasma Concentration of Rucaparib | Cycle 1 Day 15: Predose | 775 ng/mL | Geometric Coefficient of Variation 102.3 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Rucaparib | Cycle 2 Day 15: Predose | 1090 ng/mL | Geometric Coefficient of Variation 51.4 |
| Dose Escalation-Cohort 1 | Plasma Concentration of Rucaparib | Cycle 2 Day 1: Predose | 631 ng/mL | Geometric Coefficient of Variation 178.9 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Rucaparib | Cycle 1 Day 15: Predose | 3130 ng/mL | Geometric Coefficient of Variation 142.5 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Rucaparib | Cycle 2 Day 15: Predose | 263 ng/mL | Geometric Coefficient of Variation 6165.7 |
| Dose Escalation-Cohort 2a | Plasma Concentration of Rucaparib | Cycle 2 Day 1: Predose | 1660 ng/mL | Geometric Coefficient of Variation 79.1 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Rucaparib | Cycle 2 Day 1: Predose | 1050 ng/mL | Geometric Coefficient of Variation 57.7 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Rucaparib | Cycle 1 Day 15: Predose | 994 ng/mL | Geometric Coefficient of Variation 57.2 |
| Dose Escalation-Cohort 2b | Plasma Concentration of Rucaparib | Cycle 2 Day 15: Predose | 1250 ng/mL | Geometric Coefficient of Variation 48.3 |
| Dose Expansion | Plasma Concentration of Rucaparib | Cycle 1 Day 15: Predose | 1660 ng/mL | Geometric Coefficient of Variation 64.8 |
| Dose Expansion | Plasma Concentration of Rucaparib | Cycle 2 Day 15: Predose | 975 ng/mL | Geometric Coefficient of Variation 217.5 |
| Dose Expansion | Plasma Concentration of Rucaparib | Cycle 2 Day 1: Predose | 1210 ng/mL | Geometric Coefficient of Variation 200.1 |
Secondary
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)
Population: Efficacy-evaluable population included all participants who had prostate cancer, baseline lesion, and received actual dosing equivalent to the planned dose of treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation-Cohort 1 | Radiographic Progression Free Survival (rPFS), as Assessed by Prostate Cancer Working Group 3 Criteria (PCWG3) | 11.0 months |
| Dose Escalation-Cohort 2a | Radiographic Progression Free Survival (rPFS), as Assessed by Prostate Cancer Working Group 3 Criteria (PCWG3) | 3.0 months |
| Dose Escalation-Cohort 2b | Radiographic Progression Free Survival (rPFS), as Assessed by Prostate Cancer Working Group 3 Criteria (PCWG3) | 5.1 months |
| Dose Expansion | Radiographic Progression Free Survival (rPFS), as Assessed by Prostate Cancer Working Group 3 Criteria (PCWG3) | 7.2 months |