Genes, BRCA 1, Locally Advanced or Metastatic Solid Tumors
Conditions
Keywords
BRCA, ATM
Brief summary
Avelumab in combination with talazoparib will be investigated in patients with locally advanced or metastatic solid tumors with a BRCA or ATM defect.
Detailed description
Avelumab is a human immunoglobulin (Ig)G1 monoclonal antibody (mAb) directed against programmed death ligand 1 (PD-L1). Avelumab selectively binds to PD-L1 and competitively blocks its interaction with programmed death receptor 1 (PD-1), thereby interfering with this key immune checkpoint inhibition pathway. Avelumab is currently being investigated as single agent and in combination with other anti cancer therapies in patients with locally advanced or metastatic solid tumors and various hematological malignancies. Talazoparib is a potent, orally bioavailable poly (adenosine diphosphate \[ADP\] ribose) polymerase (PARP) inhibitor, which is cytotoxic to human cancer cell lines harboring gene mutations that compromise deoxyribonucleic acid (DNA) repair, an effect referred to as synthetic lethality, and by trapping PARP protein on DNA thereby preventing DNA repair, replication, and transcription. Avelumab in combination with talazoparib will be investigated in patients with locally advanced (primary or recurrent) or metastatic solid tumors with a BReast CAncer susceptibility gene (BRCA)1, or BRCA2, or ataxia telangiectasia mutated (ATM) gene defect.
Interventions
DRUGAvelumab
IV treatment
DRUGTalazoparib
Oral treatment
Sponsors
Pfizer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open label
Intervention model description
Single arm study with two cohorts enrolled in parallel. * Cohort 1 will enroll patients with locally advanced or metastatic solid tumors with one or more defects in the BRCA1 or BRCA2 genes * Cohort 2 will enroll patients with locally advanced or metastatic solid tumors with one or more defects in the ATM gene
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* BRCA1, BRCA2 and/or ATM gene defect. * Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent * Availability a tumor tissue sample from a diagnostic biopsy/surgery or a metastatic tumor biopsy. * Progressive disease at study enrollment. * Minimum age 18 years (in Japan, minimum age 20 years). * ECOG performance status 0 or 1. * Adequate bone marrow, renal and liver function. * For childbearing female patients, negative serum or urine pregnancy test at screening * Signed and dated informed consent document.
Exclusion criteria
* Prior anti-cancer therapy or radiation therapy within 2 weeks prior to enrolment. Palliative radiotherapy to metastatic lesion(s) permitted providing that it has been completed at least 2 days prior to enrolment and no significant toxicity are expected. * Major surgery within 4 weeks prior to study enrollment. * Current use of immunosuppressive medication at the time of study enrollment. * Known prior severe hypersensitivity to investigational products or any component in their formulations * Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis. * Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. * Prior organ transplantation including allogenic stem-cell transplantation. * Administration of live attenuated vaccines within 4 weeks of study enrollment. * Diagnosis of myelodysplastic syndrome. * Known symptomatic brain metastases requiring steroids. * Persisting toxicity related to prior therapy Grade \>1. * Known history of HIV or AIDS. * Positive HBV or HCV test indicating acute or chronic infection. * Active infection requiring systemic therapy. * Clinically significant (active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months prior to study enrollment; unstable angina, congestive heart failure or a serious cardiac arrhythmia requiring medication. * Diagnosis of any other malignancy within 2 years prior to study enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast, bladder, or cervix, or low-grade prostate cancer or other early-stage low-risk cancers. * Pregnant or breastfeeding female patients; female or male patients who are able to have children who are unable or unwilling to use contraception as outlined in the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR) | From the first dose of study treatment until the date of first documented disease progression or date of death from any cause, whichever came first, assessed up to approximately 24 months | For participants with solid tumors, except metastatic Castration Resistant Prostate Cancer (mCRPC), OR was defined as a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), both confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. For participants with mCRPC, OR was defined as the percentage of participants with a best overall soft tissue response of CR or PR per RECIST v1.1 with no evidence of confirmed bone disease progression per Prostate Cancer Working Group 3 (PCWG3) criteria. Per RECIST v1.1, CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. Non-target PR lesions must be non-Progressive Disease (PD), where PD was unequivocal progression of pre-existing lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately | The laboratory results were graded according to the CTCAE v4.03 severity grade whenever applicable. Laboratory test abnormalities were summarized according to worst toxicity grade observed for each laboratory test. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. On-treatment period was defined as the time from the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy - 1 day). |
| Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately | The laboratory results were graded according to the CTCAE v4.03 severity grade whenever applicable. Laboratory test abnormalities were summarized according to worst toxicity grade observed for each laboratory test. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. On-treatment period was defined as the time from the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy - 1 day). |
| Serum Lowest (Trough) Concentration (Ctrough) of Avelumab | Predose on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1 | Ctrough was defined as predose concentration during multiple dosing. The determination method of Ctrough was observing directly from data. The lower limit of quantification (LLQ) was 0.2 mcg/mL. For Cycle 1 Day 1, as the number of observations above lower limit of quantification (NALQ) = 0, summary statistics were not presented. |
| Serum Maximum Concentration (Cmax) for Avelumab | One hour post-dose on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1 | Cmax was defined as maximum observed plasma concentration. The determination method of Cmax was observing directly from data. |
| Plasma Ctrough for Talazoparib | Predose on Cycle 1 Days 1, 15 and Cycle 3 Day 1 | Ctrough was defined as predose concentration during multiple dosing. The determination method of Ctrough was observing directly from data. The lower limit of quantification (LLQ) was 25 pg/mL. For Cycle 1 Day 1, as the number of observations above lower limit of quantification (NALQ) = 0, summary statistics were not presented. Evaluable participants were participants with non-missing Ctrough concentrations at each specific time point and meeting 2 conditions: participants received 14 consecutive days of talazoparib dose without dosing interruption prior to sample collection (except on Cycle 1 Day 1) and sample collection within 24 hours ± 10% (2 hours and 24 minutes) after the previous day's dose and no more than 5 minutes (0.083 hours) after the administration of the dose on the day of PK sample collection. Predose PK samples on Cycle 1 Day 1 must have been collected prior to dose. |
| Plasma Post-dose Concentrations for Talazoparib | Postdose (samples collected within 2 hours post dose plus/minus 12 minutes) on Days 1,15 of Cycle 1, and Day 1 of Cycle 3 | In this OM, the post-dose concentrations for talazoparib in plasma were reported. |
| Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | Predose (within 2 hours before start of avelumab infusion) on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1 | Blood samples were assayed for ADA using a validated assay. ADA never-positive = no positive ADA results at any time point. ADA ever-positive =at least one positive ADA result at any time point. Baseline ADA positive =a positive ADA result at baseline. Treatment-boosted ADA =a positive ADA result at baseline and the titer \>=8×baseline titer at least once after treatment with avelumab. Treatment-induced ADA = participant was ADA-negative at baseline and had at least one positive post-baseline ADA result; or the participant had at least one positive post-baseline ADA result if no baseline sample. Transient ADA response = participants with treatment-induced ADA had (a single positive ADA result or duration between first and last positive result \<16 weeks) and ADA result at the last assessment was not positive. Persistent ADA response =participants with treatment-induced ADA had duration between first and last positive ADA result \>=16 weeks or a positive ADA result at the last assessment. |
| Number of Participants With Neutralizing Antibodies (Nab) Levels Against Avelumab Ever-Positive | Predose (within 2 hours before start of avelumab infusion) on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1 | Nab ever-positive was defined as at least one positive Nab result at any time point. Samples positive for ADA with persistent treatment-induced ADA response could be analyzed for Nab. |
| Percentage of Participants With Confirmed OR as Assessed by The Investigator | From the first dose of study treatment until the date of first documented disease progression or date of death from any cause, whichever comes first, assessed up to approximately 24 months | For participants with solid tumors, except mCRPC, OR was defined as a CR or PR per RECIST v1.1, both confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. For participants with mCRPC, OR was defined as the percentage of participants with a best overall soft tissue response of CR or PR per RECIST v1.1 with no evidence of confirmed bone disease progression per PCWG3 criteria. Per RECIST v1.1, CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. Non-target PR lesions must be non-PD, where PD was unequivocal progression of pre-existing lesions. |
| Time to Tumor Response (TTR) as Assessed by BICR | Baseline up to approximately 24 months | For participants with solid tumors, except mCRPC: TTR was defined for participants with confirmed objective response (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response. For participants with mCRPC: TTR was defined as the time from the first dose of study treatment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3. Soft tissue response was defined as a Best Overall Response (BOR) of CR or PR per RECIST v1.1. |
| TTR as Assessed by Investigator | Baseline up to approximately 24 months | For participants with solid tumors, except mCRPC: TTR was defined for participants with confirmed objective response (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response. For participants with mCRPC: TTR was defined as the time from the first dose of study treatment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3. Soft tissue response was defined as a BOR of CR or PR per RECIST v1.1. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately | An adverse event (AE) was any untoward medical occurrence in a clinical investigation where participants administered a product or medical device. TEAEs were those events with onset dates occurring during the on-treatment period. A Serious Adverse Event (SAE) was any untoward medical occurrence at any dose that: resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or resulted in congenital anomaly/birth defect. A treatment-related AE was any untoward medical occurrence attributed to the study drug in a participant who received study drug. TEAEs were graded by the investigator using National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. |
| DoR as Assessed by Investigator | Baseline up to approximately 24 months | For participants with solid tumors, except mCRPC: DoR was defined for participants with confirmed objective response (CR or PR) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. For participants with mCRPC: DoR was defined for participants with confirmed objective response (CR or PR) as the time from the first objective evidence of soft tissue response (subsequently confirmed) per RECIST v1.1 and no evidence of confirmed bone disease progression by PCWG3 to the first subsequent objective evidence of radiographic progression or death due to any cause, whichever occurred first. Radiographic progression was defined as soft tissue progression evaluated per RECIST v1.1 or bone disease progression evaluated per PCWG3. |
| Progression Free Survival (PFS) as Assessed by BICR | Baseline up to approximately 24 months | For participants with solid tumors, except mCRPC: PFS was defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurred first. For participants with mCRPC: PFS was defined as the time from the first dose of study treatment to documentation of radiographic progression in soft tissue evaluated per RECIST v1.1, in bone evaluated per PCWG3, or death, whichever occurred first. |
| PFS as Assessed by Investigator | Baseline up to approximately 24 months | For participants with solid tumors, except mCRPC: PFS was defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurred first. For participants with mCRPC: PFS was defined as the time from the first dose of study treatment to documentation of radiographic progression in soft tissue evaluated per RECIST v1.1, in bone evaluated per PCWG3, or death, whichever occurred first. |
| Overall Survival (OS) for All Participants | Baseline up to approximately 24 months | OS was defined as the time from the first dose of study treatment to the date of death. Participants without an event (death) were censored at the date of last contact. |
| Time to Prostate-Specific Antigen (PSA) Progression for Participants With mCRPC | Baseline up to approximately 24 months | For participants with mCRPC, time to PSA progression was defined as the time from the first dose to the date that a \>=25% increase in PSA with an absolute increase of \>=2 μg/L (2 ng/mL) above the nadir (or baseline for participants with no PSA decline) was documented, confirmed by a second consecutive PSA value obtained \>=3 weeks (21 days) later. |
| Number of Participants With Confirmed PSA Response | Baseline up to approximately 24 months | For participants with mCRPC, PSA response was defined as confirmed PSA decline \>=50% compared to baseline. PSA response was calculated as a decline from baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50%. A PSA response must have been confirmed by a second consecutive value at least 3 weeks later. |
| Number of Participants With Circulating Tumor Cell (CTC) Count Conversion | Day 1 of Cycle 1 to Cycle 4 | For participants with mCRPC, CTC count conversion was defined as a decrease in CTC count from \>=5 CTC per 7.5 mL of blood at baseline to \<5 CTC per 7.5 mL of blood anytime on study. |
| Number of Participants With Cancer Antigen 125 (CA-125) Response | Baseline, Day 1 of each treatment Cycle, maximum up to 4.3 years approximately | For participants with ovarian cancer, CA-125 response was defined as at least a 50% reduction in CA-125 levels from baseline. The response must have been confirmed and maintained for at least 28 days. |
| Number of Participants With Positive Programmed Death Ligand 1 (PD-L1) Expression in Baseline Tumor Tissue | Baseline | PD-L1 expression on tumor and infiltrating immune cells was measured by immunohistochemistry (IHC). PD-L1 expression level was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and inflammatory cells in regions of interest. This OM reported the number of participants classified as positive according to scoring algorithms and cut-offs established from external sources. |
| Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | Baseline | Participants were enrolled in the two cohorts based on BRCA 1/2 and ATM defect status assessed by the local laboratory. The participant BRCA and ATM status was assessed retrospectively by central laboratory, that may differ from the status assessed by the local laboratory. The ATM participants with a negative ATM status per the central laboratory were reported to have a positive ATM status per the local laboratory. Therefore, participants with negative ATM status might have been included in the ATM defect cohort. For defects in BRCA1, BRCA2 and ATM by central laboratory analysis, participants were classified as positive, negative, not analyzable or missing. The number of participants in each category of BRCA 1 defect, BRCA 2 defect, BRCA 1 or BRCA 2 defect and ATM defect were presented. |
| Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline | Baseline | TMB was defined as the total number of mutations in the tumor genome, or number of mutations per megabase of DNA if derived from targeted sequencing. TMB categories were defined as high, low for a number of mutations per megabase \>=10 and \<10, respectively. The TMB category 'Not analyzable' included participants with available samples but not evaluable. The TMB category 'Missing' included participants with no sample available. The number of participants in each category at only baseline were tabulated. |
| Duration of Response (DoR) as Assessed by BICR | Baseline up to approximately 24 months | For participants with solid tumors, except mCRPC: DoR was defined for participants with confirmed objective response (CR or PR) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occured first. For participants with mCRPC: DoR was defined for participants with confirmed objective response (CR or PR) as the time from the first objective evidence of soft tissue response (subsequently confirmed) per RECIST v1.1 and no evidence of confirmed bone disease progression by PCWG3 to the first subsequent objective evidence of radiographic progression or death due to any cause, whichever occured first. Radiographic progression was defined as soft tissue progression evaluated per RECIST v1.1 or bone disease progression evaluated per PCWG3. |
Countries
Belgium, Denmark, France, Italy, Japan, Netherlands, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 270 participants were screened for this study, 202 participants were enrolled and assigned to study treatment but 2 participants never started the treatment. In total 200 participants were treated (159 in Cohort 1 and 41 in Cohort 2).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (BRCA 1/2 Defect) Participants with locally advanced or metastatic solid tumors with one or more defects in the BRCA1 or BRCA2 genes were enrolled in Cohort 1. Talazoparib was self-administered orally at a starting dose of 1 mg QD for participants with normal renal function or mild renal impairment until End of Treatment. Participants with moderate renal impairment received starting dose of 0.75 mg QD. Avelumab was administered as a 1-hour IV infusion Q2W on Days 1 and 15 of each 28-day cycle at a dose of 800 mg after administration of talazoparib and the premedication. | 159 |
| Cohort 2 (ATM Defect) Participants with locally advanced or metastatic solid tumors with one or more defects in the ATM gene without concurrent BRCA1/2 defect were enrolled in Cohort 2. Talazoparib was self-administered orally at a starting dose of 1 mg QD for participants with normal renal function or mild renal impairment until End of Treatment. Participants with moderate renal impairment received starting dose of 0.75 mg QD. Avelumab was administered as a 1-hour IV infusion Q2W on Days 1 and 15 of each 28-day cycle at a dose of 800 mg after administration of talazoparib and the premedication. | 41 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 2 |
| Overall Study | Death | 3 | 0 |
| Overall Study | Global deterioration of health status | 14 | 4 |
| Overall Study | Other | 11 | 0 |
| Overall Study | Progressive disease | 121 | 29 |
| Overall Study | Withdrawal by Subject | 2 | 6 |
Baseline characteristics
| Characteristic | Cohort 2 (ATM Defect) | Total | Cohort 1 (BRCA 1/2 Defect) |
|---|---|---|---|
| Age, Continuous | 61.76 Years STANDARD_DEVIATION 12.47 | 58.25 Years STANDARD_DEVIATION 12.89 | 57.35 Years STANDARD_DEVIATION 12.88 |
| Age, Customized 65 - <75 years | 11 Participants | 45 Participants | 34 Participants |
| Age, Customized < 65 years | 25 Participants | 135 Participants | 110 Participants |
| Age, Customized 75 - <85 years | 3 Participants | 18 Participants | 15 Participants |
| Age, Customized >=85 years | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 13 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 170 Participants | 131 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 17 Participants | 17 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 15 Participants | 15 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 11 Participants | 8 Participants |
| Race/Ethnicity, Customized Not reported | 1 Participants | 19 Participants | 18 Participants |
| Race/Ethnicity, Customized White | 37 Participants | 154 Participants | 117 Participants |
| Sex: Female, Male Female | 24 Participants | 132 Participants | 108 Participants |
| Sex: Female, Male Male | 17 Participants | 68 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 159 | 3 / 41 |
| other Total, other adverse events | 153 / 159 | 40 / 41 |
| serious Total, serious adverse events | 50 / 159 | 7 / 41 |
Outcome results
Primary
Percentage of Participants With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR)
For participants with solid tumors, except metastatic Castration Resistant Prostate Cancer (mCRPC), OR was defined as a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), both confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. For participants with mCRPC, OR was defined as the percentage of participants with a best overall soft tissue response of CR or PR per RECIST v1.1 with no evidence of confirmed bone disease progression per Prostate Cancer Working Group 3 (PCWG3) criteria. Per RECIST v1.1, CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. Non-target PR lesions must be non-Progressive Disease (PD), where PD was unequivocal progression of pre-existing lesions.
Time frame: From the first dose of study treatment until the date of first documented disease progression or date of death from any cause, whichever came first, assessed up to approximately 24 months
Population: The analysis set included all enrolled participants who received at least 1 dose of study treatment. Participants were classified according to the cohort assigned at enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Percentage of Participants With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR) | 27.7 Percentage of participants |
| Cohort 2 (ATM Defect) | Percentage of Participants With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR) | 7.3 Percentage of participants |
Secondary
DoR as Assessed by Investigator
For participants with solid tumors, except mCRPC: DoR was defined for participants with confirmed objective response (CR or PR) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. For participants with mCRPC: DoR was defined for participants with confirmed objective response (CR or PR) as the time from the first objective evidence of soft tissue response (subsequently confirmed) per RECIST v1.1 and no evidence of confirmed bone disease progression by PCWG3 to the first subsequent objective evidence of radiographic progression or death due to any cause, whichever occurred first. Radiographic progression was defined as soft tissue progression evaluated per RECIST v1.1 or bone disease progression evaluated per PCWG3.
Time frame: Baseline up to approximately 24 months
Population: The analysis population included all enrolled participants who received at least 1 dose of study treatment and with confirmed CR or PR as assessed by investigator.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | DoR as Assessed by Investigator | 8.8 Months |
| Cohort 2 (ATM Defect) | DoR as Assessed by Investigator | 7.1 Months |
Secondary
Duration of Response (DoR) as Assessed by BICR
For participants with solid tumors, except mCRPC: DoR was defined for participants with confirmed objective response (CR or PR) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occured first. For participants with mCRPC: DoR was defined for participants with confirmed objective response (CR or PR) as the time from the first objective evidence of soft tissue response (subsequently confirmed) per RECIST v1.1 and no evidence of confirmed bone disease progression by PCWG3 to the first subsequent objective evidence of radiographic progression or death due to any cause, whichever occured first. Radiographic progression was defined as soft tissue progression evaluated per RECIST v1.1 or bone disease progression evaluated per PCWG3.
Time frame: Baseline up to approximately 24 months
Population: The analysis population included all enrolled participants who received at least 1 dose of study treatment and with confirmed CR or PR as assessed by BICR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Duration of Response (DoR) as Assessed by BICR | 12.5 Months |
| Cohort 2 (ATM Defect) | Duration of Response (DoR) as Assessed by BICR | NA Months |
Secondary
Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories
Blood samples were assayed for ADA using a validated assay. ADA never-positive = no positive ADA results at any time point. ADA ever-positive =at least one positive ADA result at any time point. Baseline ADA positive =a positive ADA result at baseline. Treatment-boosted ADA =a positive ADA result at baseline and the titer \>=8×baseline titer at least once after treatment with avelumab. Treatment-induced ADA = participant was ADA-negative at baseline and had at least one positive post-baseline ADA result; or the participant had at least one positive post-baseline ADA result if no baseline sample. Transient ADA response = participants with treatment-induced ADA had (a single positive ADA result or duration between first and last positive result \<16 weeks) and ADA result at the last assessment was not positive. Persistent ADA response =participants with treatment-induced ADA had duration between first and last positive ADA result \>=16 weeks or a positive ADA result at the last assessment.
Time frame: Predose (within 2 hours before start of avelumab infusion) on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1
Population: Number of Participants Analyzed = participants in the immunogenicity analysis set who had at least 1 ADA sample collected for avelumab. Number Analyzed (N0) = participants with at least one valid ADA result at any time point; (N1) = participants with valid baseline ADA result; (N2) = participants with valid baseline ADA results and at least one valid post-baseline ADA result; (N3) = participants with at least one valid post-baseline ADA result and without positive baseline ADA result.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | Baseline ADA positive (n/N1) | 5 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | Treatment-induced ADA (n/N3) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | ADA ever-positive (n/N0) | 6 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | Transient ADA response (n/N3) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | Treatment-boosted ADA (n/N2) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | Persistent ADA response (n/N3) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | ADA never-positive (n/N0) | 153 Participants |
| Cohort 2 (ATM Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | Persistent ADA response (n/N3) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | ADA never-positive (n/N0) | 39 Participants |
| Cohort 2 (ATM Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | ADA ever-positive (n/N0) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | Baseline ADA positive (n/N1) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | Treatment-boosted ADA (n/N2) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | Treatment-induced ADA (n/N3) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants by Avelumab Anti-drug Antibody (ADA) Categories | Transient ADA response (n/N3) | 0 Participants |
Secondary
Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline
TMB was defined as the total number of mutations in the tumor genome, or number of mutations per megabase of DNA if derived from targeted sequencing. TMB categories were defined as high, low for a number of mutations per megabase \>=10 and \<10, respectively. The TMB category 'Not analyzable' included participants with available samples but not evaluable. The TMB category 'Missing' included participants with no sample available. The number of participants in each category at only baseline were tabulated.
Time frame: Baseline
Population: The biomarker analysis set included all participants who received at least 1 dose of study treatment and had at least 1 screening biomarker assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline | TMB status high | 9 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline | TMB status low | 95 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline | TMB status not analyzable | 34 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline | TMB status missing | 21 Participants |
| Cohort 2 (ATM Defect) | Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline | TMB status missing | 8 Participants |
| Cohort 2 (ATM Defect) | Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline | TMB status high | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline | TMB status not analyzable | 8 Participants |
| Cohort 2 (ATM Defect) | Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline | TMB status low | 23 Participants |
Secondary
Number of Participants With Cancer Antigen 125 (CA-125) Response
For participants with ovarian cancer, CA-125 response was defined as at least a 50% reduction in CA-125 levels from baseline. The response must have been confirmed and maintained for at least 28 days.
Time frame: Baseline, Day 1 of each treatment Cycle, maximum up to 4.3 years approximately
Population: The analysis population included all participants with ovarian cancer who received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Cancer Antigen 125 (CA-125) Response | 9 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Cancer Antigen 125 (CA-125) Response | 0 Participants |
Secondary
Number of Participants With Circulating Tumor Cell (CTC) Count Conversion
For participants with mCRPC, CTC count conversion was defined as a decrease in CTC count from \>=5 CTC per 7.5 mL of blood at baseline to \<5 CTC per 7.5 mL of blood anytime on study.
Time frame: Day 1 of Cycle 1 to Cycle 4
Population: The analysis population included all enrolled participants with mCRPC who received at least 1 dose of study treatment, and with CTC count \>=5 CTC per 7.5 mL of blood at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Circulating Tumor Cell (CTC) Count Conversion | 11 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Circulating Tumor Cell (CTC) Count Conversion | 1 Participants |
Secondary
Number of Participants With Confirmed PSA Response
For participants with mCRPC, PSA response was defined as confirmed PSA decline \>=50% compared to baseline. PSA response was calculated as a decline from baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50%. A PSA response must have been confirmed by a second consecutive value at least 3 weeks later.
Time frame: Baseline up to approximately 24 months
Population: The analysis population included all participants with mCRPC who received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Confirmed PSA Response | 17 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Confirmed PSA Response | 2 Participants |
Secondary
Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM
Participants were enrolled in the two cohorts based on BRCA 1/2 and ATM defect status assessed by the local laboratory. The participant BRCA and ATM status was assessed retrospectively by central laboratory, that may differ from the status assessed by the local laboratory. The ATM participants with a negative ATM status per the central laboratory were reported to have a positive ATM status per the local laboratory. Therefore, participants with negative ATM status might have been included in the ATM defect cohort. For defects in BRCA1, BRCA2 and ATM by central laboratory analysis, participants were classified as positive, negative, not analyzable or missing. The number of participants in each category of BRCA 1 defect, BRCA 2 defect, BRCA 1 or BRCA 2 defect and ATM defect were presented.
Time frame: Baseline
Population: The biomarker analysis set included all participants who received at least 1 dose of study treatment and had at least 1 screening biomarker assessment.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA1 status | Positive | 52 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA1 status | Negative | 65 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA1 status | Not analyzable | 21 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA1 status | Missing | 21 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA2 status | Positive | 53 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA2 status | Negative | 64 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA2 status | Not analyzable | 21 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA2 status | Missing | 21 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA status | Positive | 105 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA status | Negative | 12 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA status | Not analyzable | 21 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA status | Missing | 21 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | ATM status | Positive | 2 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | ATM status | Negative | 115 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | ATM status | Not analyzable | 21 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | ATM status | Missing | 21 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | ATM status | Missing | 8 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA1 status | Positive | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA status | Positive | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA1 status | Negative | 29 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | ATM status | Positive | 26 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA1 status | Not analyzable | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA status | Negative | 28 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA1 status | Missing | 8 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | ATM status | Not analyzable | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA2 status | Positive | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA status | Not analyzable | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA2 status | Negative | 28 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | ATM status | Negative | 3 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA2 status | Not analyzable | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA status | Missing | 8 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM | BRCA2 status | Missing | 8 Participants |
Secondary
Number of Participants With Neutralizing Antibodies (Nab) Levels Against Avelumab Ever-Positive
Nab ever-positive was defined as at least one positive Nab result at any time point. Samples positive for ADA with persistent treatment-induced ADA response could be analyzed for Nab.
Time frame: Predose (within 2 hours before start of avelumab infusion) on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1
Population: The immunogenicity analysis set included participants who had at least 1 Nab sample collected for avelumab. Nabs data were not collected due to insufficient number of participants with persistent treatment-induced ADA response. Therefore, the number of participants analyzed for this OM was 0.
Secondary
Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period
The laboratory results were graded according to the CTCAE v4.03 severity grade whenever applicable. Laboratory test abnormalities were summarized according to worst toxicity grade observed for each laboratory test. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. On-treatment period was defined as the time from the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy - 1 day).
Time frame: From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately
Population: The safety analysis set included all enrolled participants who received at least 1 dose of study treatment. The number analyzed for each parameter in each treatment group was the number of participants evaluable for each parameter. Number of participants analyzed = participants evaluable for this outcome measure (OM), number analyzed = participants evaluable for the specific lab parameter per CTCAE criteria.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: serum amylase increased) | 2 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: creatinine increased) | 12 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: alanine aminotransferase increased) | 6 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: creatinine increased) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: serum amylase increased) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: creatinine increased) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hyponatremia) | 11 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: gamma glutamyl transferase [GGT] increased) | 23 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: blood bilirubin increased) | 7 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: GGT increased) | 16 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypomagnesemia) | 2 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: GGT increased) | 26 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hyponatremia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: GGT increased) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: alkaline phosphatase increased) | 21 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypercalcemia) | 11 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: blood bilirubin increased) | 7 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypercalcemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: aspartate aminotransferase increased) | 13 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypercalcemia) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypermagnesemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: aspartate aminotransferase increased) | 2 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypernatremia) | 8 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: aspartate aminotransferase increased) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hyperkalemia) | 6 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: alkaline phosphatase increased) | 7 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hyperkalemia) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypophosphatemia) | 2 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hyperkalemia) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: CPK increased) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypermagnesemia) | 9 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypomagnesemia) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypermagnesemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypokalemia) | 24 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypermagnesemia) | 3 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypophosphatemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: blood bilirubin increased) | 2 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypernatremia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: alkaline phosphatase increased) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypernatremia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: blood bilirubin increased) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypernatremia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: lipase increased) | 13 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypoalbuminemia) | 21 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: creatine phosphokinase [CPK] increased) | 22 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypoalbuminemia) | 10 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypomagnesemia) | 24 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypoalbuminemia) | 2 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: CPK increased) | 8 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypoalbuminemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: lipase increased) | 9 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypocalcemia) | 27 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: CPK increased) | 2 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypocalcemia) | 6 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypomagnesemia) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypocalcemia) | 3 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: lipase increased) | 7 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypocalcemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypercalcemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypoglycemia) | 10 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: alanine aminotransferase increased) | 30 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypoglycemia) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hyperglycemia) | 23 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypoglycemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hyponatremia) | 29 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypoglycemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hyperglycemia) | 2 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: serum amylase increased) | 16 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: alanine aminotransferase increased) | 3 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypokalemia) | 4 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hyperglycemia) | 3 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypokalemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: alanine aminotransferase increased) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hyperglycemia) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: alkaline phosphatase increased) | 25 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: serum amylase increased) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypokalemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hyperkalemia) | 13 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hyponatremia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypophosphatemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypophosphatemia) | 18 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: creatinine increased) | 87 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: aspartate aminotransferase increased) | 35 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: lipase increased) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypermagnesemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypokalemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypokalemia) | 8 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: alanine aminotransferase increased) | 10 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: alkaline phosphatase increased) | 5 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: alkaline phosphatase increased) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: aspartate aminotransferase increased) | 5 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypomagnesemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hyponatremia) | 10 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hyponatremia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hyponatremia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypophosphatemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypophosphatemia) | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypophosphatemia) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypophosphatemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: lipase increased) | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: lipase increased) | 3 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: lipase increased) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: lipase increased) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: serum amylase increased) | 3 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: serum amylase increased) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: serum amylase increased) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: serum amylase increased) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypomagnesemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: blood bilirubin increased) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: aspartate aminotransferase increased) | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypomagnesemia) | 5 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: aspartate aminotransferase increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypomagnesemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: blood bilirubin increased) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: blood bilirubin increased) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: blood bilirubin increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: creatine phosphokinase [CPK] increased) | 3 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: CPK increased) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: CPK increased) | 3 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypercalcemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypercalcemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hyperglycemia) | 5 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hyperglycemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hyperglycemia) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hyperglycemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: CPK increased) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: creatinine increased) | 24 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: creatinine increased) | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: creatinine increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: creatinine increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: gamma glutamyl transferase [GGT] increased) | 8 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: GGT increased) | 5 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: GGT increased) | 7 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: GGT increased) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypercalcemia) | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypercalcemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: aspartate aminotransferase increased) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hyperkalemia) | 3 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hyperkalemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hyperkalemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hyperkalemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypermagnesemia) | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypermagnesemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypermagnesemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypernatremia) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypernatremia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypernatremia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypernatremia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypoalbuminemia) | 6 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypoalbuminemia) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypoalbuminemia) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypoalbuminemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypocalcemia) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypocalcemia) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypocalcemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypocalcemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hypoglycemia) | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hypoglycemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypoglycemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypoglycemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: alanine aminotransferase increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hypokalemia) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: alanine aminotransferase increased) | 3 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: alanine aminotransferase increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: alkaline phosphatase increased) | 12 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hypokalemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hyponatremia) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Chemistry Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: alkaline phosphatase increased) | 0 Participants |
Secondary
Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period
The laboratory results were graded according to the CTCAE v4.03 severity grade whenever applicable. Laboratory test abnormalities were summarized according to worst toxicity grade observed for each laboratory test. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. On-treatment period was defined as the time from the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy - 1 day).
Time frame: From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately
Population: The safety analysis set included all enrolled participants who received at least 1 dose of study treatment. The number analyzed for each parameter in each treatment group was the number of participants evaluable for each parameter. Number of participants analyzed = participants evaluable for this outcome measure (OM), number analyzed = participants evaluable for the specific lab parameter per CTCAE criteria.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: white blood cell decreased) | 52 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: anemia) | 27 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: neutrophil count decreased) | 3 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: anemia) | 33 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: white blood cell decreased) | 15 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: anemia) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: neutrophil count decreased) | 15 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hemoglobin increased) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: white blood cell decreased) | 2 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: platelet count decreased) | 59 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: anemia) | 61 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hemoglobin increased) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: platelet count decreased) | 16 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: INR increased) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hemoglobin increased) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: INR increased) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: neutrophil count decreased) | 42 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: INR increased) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hemoglobin increased) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: lymphocyte count decreased) | 15 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: platelet count decreased) | 14 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: lymphocyte count decreased) | 58 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: International Normalized Ratio [INR] increased) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: lymphocyte count decreased) | 34 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: activated partial thromboplastin time prolonged) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: lymphocyte count decreased) | 3 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: lymphocyte count increased) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: lymphocyte count increased) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: activated partial thromboplastin time prolonged) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: lymphocyte count increased) | 3 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: lymphocyte count increased) | 1 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: white blood cell decreased) | 45 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: activated partial thromboplastin time prolonged) | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: neutrophil count decreased) | 16 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: platelet count decreased) | 11 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: activated partial thromboplastin time prolonged) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: neutrophil count decreased) | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: lymphocyte count increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: neutrophil count decreased) | 8 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: neutrophil count decreased) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: platelet count decreased) | 3 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: platelet count decreased) | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: white blood cell decreased) | 14 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: white blood cell decreased) | 11 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: white blood cell decreased) | 5 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: white blood cell decreased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: hemoglobin increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: hemoglobin increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: hemoglobin increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: activated partial thromboplastin time prolonged) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: activated partial thromboplastin time prolonged) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: activated partial thromboplastin time prolonged) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: activated partial thromboplastin time prolonged) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: anemia) | 9 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: anemia) | 12 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: anemia) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: anemia) | 6 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: hemoglobin increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: lymphocyte count increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: International Normalized Ratio [INR] increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: INR increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: INR increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: INR increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: lymphocyte count decreased) | 6 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 2 (Parameter: lymphocyte count decreased) | 15 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: lymphocyte count decreased) | 7 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 4 (Parameter: lymphocyte count decreased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: lymphocyte count increased) | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: neutrophil count decreased) | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 1 (Parameter: platelet count decreased) | 16 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: platelet count decreased) | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With New or Worsening Hematology Laboratory Test Results During the On-Treatment Period | New or worsened to grade 3 (Parameter: lymphocyte count increased) | 0 Participants |
Secondary
Number of Participants With Positive Programmed Death Ligand 1 (PD-L1) Expression in Baseline Tumor Tissue
PD-L1 expression on tumor and infiltrating immune cells was measured by immunohistochemistry (IHC). PD-L1 expression level was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and inflammatory cells in regions of interest. This OM reported the number of participants classified as positive according to scoring algorithms and cut-offs established from external sources.
Time frame: Baseline
Population: The biomarker analysis set included all participants who received at least 1 dose of study treatment and had at least 1 screening biomarker assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Positive Programmed Death Ligand 1 (PD-L1) Expression in Baseline Tumor Tissue | 27 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Positive Programmed Death Ligand 1 (PD-L1) Expression in Baseline Tumor Tissue | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a clinical investigation where participants administered a product or medical device. TEAEs were those events with onset dates occurring during the on-treatment period. A Serious Adverse Event (SAE) was any untoward medical occurrence at any dose that: resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or resulted in congenital anomaly/birth defect. A treatment-related AE was any untoward medical occurrence attributed to the study drug in a participant who received study drug. TEAEs were graded by the investigator using National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE.
Time frame: From baseline up to 30 days after last dose of study treatment, maximum up to 4.3 years approximately
Population: The safety analysis set included all enrolled participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs | 156 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | treatment-related TEAEs | 148 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | grade >=3 TEAEs | 114 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | grade >=3 treatment-related TEAEs | 85 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | treatment-related TEAEs leading to discontinuation of all study drugs | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to death | 14 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | treatment-related TEAEs leading to death | 0 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation of all study drugs | 5 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | SAEs | 50 Participants |
| Cohort 1 (BRCA 1/2 Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | treatment-related SAEs | 12 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | treatment-related TEAEs leading to death | 0 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs | 40 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | treatment-related TEAEs leading to discontinuation of all study drugs | 1 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | treatment-related TEAEs | 34 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | treatment-related SAEs | 4 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | grade >=3 TEAEs | 22 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to death | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | grade >=3 treatment-related TEAEs | 17 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation of all study drugs | 2 Participants |
| Cohort 2 (ATM Defect) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | SAEs | 7 Participants |
Secondary
Overall Survival (OS) for All Participants
OS was defined as the time from the first dose of study treatment to the date of death. Participants without an event (death) were censored at the date of last contact.
Time frame: Baseline up to approximately 24 months
Population: All efficacy analyses were performed based on the full analysis set. The full analysis set included all enrolled participants who received at least 1 dose of study treatment. Participants were classified according to the cohort assigned at enrollment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Overall Survival (OS) for All Participants | 11.9 Months |
| Cohort 2 (ATM Defect) | Overall Survival (OS) for All Participants | 16.4 Months |
Secondary
Percentage of Participants With Confirmed OR as Assessed by The Investigator
For participants with solid tumors, except mCRPC, OR was defined as a CR or PR per RECIST v1.1, both confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. For participants with mCRPC, OR was defined as the percentage of participants with a best overall soft tissue response of CR or PR per RECIST v1.1 with no evidence of confirmed bone disease progression per PCWG3 criteria. Per RECIST v1.1, CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. Non-target PR lesions must be non-PD, where PD was unequivocal progression of pre-existing lesions.
Time frame: From the first dose of study treatment until the date of first documented disease progression or date of death from any cause, whichever comes first, assessed up to approximately 24 months
Population: All efficacy analyses were performed based on the full analysis set. The full analysis set included all enrolled participants who received at least 1 dose of study treatment. Participants were classified according to the cohort assigned at enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Percentage of Participants With Confirmed OR as Assessed by The Investigator | 34.6 Percentage of participants |
| Cohort 2 (ATM Defect) | Percentage of Participants With Confirmed OR as Assessed by The Investigator | 14.6 Percentage of participants |
Secondary
PFS as Assessed by Investigator
For participants with solid tumors, except mCRPC: PFS was defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurred first. For participants with mCRPC: PFS was defined as the time from the first dose of study treatment to documentation of radiographic progression in soft tissue evaluated per RECIST v1.1, in bone evaluated per PCWG3, or death, whichever occurred first.
Time frame: Baseline up to approximately 24 months
Population: All efficacy analyses were performed based on the full analysis set. The full analysis set included all enrolled participants who received at least 1 dose of study treatment. Participants were classified according to the cohort assigned at enrollment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | PFS as Assessed by Investigator | 5.3 Months |
| Cohort 2 (ATM Defect) | PFS as Assessed by Investigator | 3.7 Months |
Secondary
Plasma Ctrough for Talazoparib
Ctrough was defined as predose concentration during multiple dosing. The determination method of Ctrough was observing directly from data. The lower limit of quantification (LLQ) was 25 pg/mL. For Cycle 1 Day 1, as the number of observations above lower limit of quantification (NALQ) = 0, summary statistics were not presented. Evaluable participants were participants with non-missing Ctrough concentrations at each specific time point and meeting 2 conditions: participants received 14 consecutive days of talazoparib dose without dosing interruption prior to sample collection (except on Cycle 1 Day 1) and sample collection within 24 hours ± 10% (2 hours and 24 minutes) after the previous day's dose and no more than 5 minutes (0.083 hours) after the administration of the dose on the day of PK sample collection. Predose PK samples on Cycle 1 Day 1 must have been collected prior to dose.
Time frame: Predose on Cycle 1 Days 1, 15 and Cycle 3 Day 1
Population: The talazoparib PK concentration analysis set included all participants (Cohort 1 and Cohort 2 combined) who received at least 1 dose of study intervention and had at least one Ctrough concentration measurement for talazoparib. Number of participants analyzed = number of participants evaluable for this OM. Number analyzed = participants evaluable at the specific time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Plasma Ctrough for Talazoparib | CYCLE3DAY1 (Starting Dose: 1 mg QD) | 3313 picogram(pg)/mL | Geometric Coefficient of Variation 113 |
| Cohort 1 (BRCA 1/2 Defect) | Plasma Ctrough for Talazoparib | CYCLE1DAY1 (Starting Dose: 0.75 mg QD) | NA picogram(pg)/mL | — |
| Cohort 1 (BRCA 1/2 Defect) | Plasma Ctrough for Talazoparib | CYCLE1DAY15 (Starting Dose: 0.75 mg QD) | 7612 picogram(pg)/mL | — |
| Cohort 1 (BRCA 1/2 Defect) | Plasma Ctrough for Talazoparib | CYCLE3DAY1 (Starting Dose: 0.75 mg QD) | 4314 picogram(pg)/mL | Geometric Coefficient of Variation 42 |
| Cohort 1 (BRCA 1/2 Defect) | Plasma Ctrough for Talazoparib | CYCLE1DAY1 (Starting Dose: 1 mg QD) | NA picogram(pg)/mL | — |
| Cohort 1 (BRCA 1/2 Defect) | Plasma Ctrough for Talazoparib | CYCLE1DAY15 (Starting Dose: 1 mg QD) | 4649 picogram(pg)/mL | Geometric Coefficient of Variation 61 |
Secondary
Plasma Post-dose Concentrations for Talazoparib
In this OM, the post-dose concentrations for talazoparib in plasma were reported.
Time frame: Postdose (samples collected within 2 hours post dose plus/minus 12 minutes) on Days 1,15 of Cycle 1, and Day 1 of Cycle 3
Population: The Analysis Population included all participants (Cohort 1 and Cohort 2 combined) who received at least 1 dose of talazoparib, had at least one non-missing concentration measurement at any collection scheduled time point, received 14 consecutive days of talazoparib dose without dosing interruption prior to sample collection (except on Cycle 1 Day 1) and sample collection was performed within ± 10% (12 minutes) of nominal time post-dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Plasma Post-dose Concentrations for Talazoparib | CYCLE1DAY1 (Starting Dose: 1 mg QD) | 1833 pg/mL | Geometric Coefficient of Variation 275 |
| Cohort 1 (BRCA 1/2 Defect) | Plasma Post-dose Concentrations for Talazoparib | CYCLE1DAY15 (Starting Dose: 1 mg QD) | 7985 pg/mL | Geometric Coefficient of Variation 79 |
| Cohort 1 (BRCA 1/2 Defect) | Plasma Post-dose Concentrations for Talazoparib | CYCLE3DAY1 (Starting Dose: 1 mg QD) | 7800 pg/mL | Geometric Coefficient of Variation 69 |
| Cohort 1 (BRCA 1/2 Defect) | Plasma Post-dose Concentrations for Talazoparib | CYCLE1DAY1 (Starting Dose: 0.75 mg QD) | 1663 pg/mL | Geometric Coefficient of Variation 100 |
| Cohort 1 (BRCA 1/2 Defect) | Plasma Post-dose Concentrations for Talazoparib | CYCLE1DAY15 (Starting Dose: 0.75 mg QD) | 12590 pg/mL | Geometric Coefficient of Variation 47 |
| Cohort 1 (BRCA 1/2 Defect) | Plasma Post-dose Concentrations for Talazoparib | CYCLE3DAY1 (Starting Dose: 0.75 mg QD) | 8366 pg/mL | Geometric Coefficient of Variation 53 |
Secondary
Progression Free Survival (PFS) as Assessed by BICR
For participants with solid tumors, except mCRPC: PFS was defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurred first. For participants with mCRPC: PFS was defined as the time from the first dose of study treatment to documentation of radiographic progression in soft tissue evaluated per RECIST v1.1, in bone evaluated per PCWG3, or death, whichever occurred first.
Time frame: Baseline up to approximately 24 months
Population: All efficacy analyses were performed based on the full analysis set. The full analysis set included all enrolled participants who received at least 1 dose of study treatment. Participants were classified according to the cohort assigned at enrollment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Progression Free Survival (PFS) as Assessed by BICR | 3.7 Months |
| Cohort 2 (ATM Defect) | Progression Free Survival (PFS) as Assessed by BICR | 3.5 Months |
Secondary
Serum Lowest (Trough) Concentration (Ctrough) of Avelumab
Ctrough was defined as predose concentration during multiple dosing. The determination method of Ctrough was observing directly from data. The lower limit of quantification (LLQ) was 0.2 mcg/mL. For Cycle 1 Day 1, as the number of observations above lower limit of quantification (NALQ) = 0, summary statistics were not presented.
Time frame: Predose on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1
Population: The avelumab PK concentration analysis set included all participants (Cohort 1 and Cohort 2 combined) who received at least 1 dose of study intervention and had at least one concentration measurement for avelumab. Number of participants analyzed = number of participants evaluable for this OM. Number analyzed = participants evaluable at the specific time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Serum Lowest (Trough) Concentration (Ctrough) of Avelumab | CYCLE1DAY1 | NA microgram(mcg)/milliliter(mL) | — |
| Cohort 1 (BRCA 1/2 Defect) | Serum Lowest (Trough) Concentration (Ctrough) of Avelumab | CYCLE1DAY15 | 21.06 microgram(mcg)/milliliter(mL) | Geometric Coefficient of Variation 58 |
| Cohort 1 (BRCA 1/2 Defect) | Serum Lowest (Trough) Concentration (Ctrough) of Avelumab | CYCLE3DAY1 | 32.65 microgram(mcg)/milliliter(mL) | Geometric Coefficient of Variation 63 |
| Cohort 1 (BRCA 1/2 Defect) | Serum Lowest (Trough) Concentration (Ctrough) of Avelumab | CYCLE6DAY1 | 36.23 microgram(mcg)/milliliter(mL) | Geometric Coefficient of Variation 60 |
| Cohort 1 (BRCA 1/2 Defect) | Serum Lowest (Trough) Concentration (Ctrough) of Avelumab | CYCLE12DAY1 | 41.80 microgram(mcg)/milliliter(mL) | Geometric Coefficient of Variation 60 |
| Cohort 1 (BRCA 1/2 Defect) | Serum Lowest (Trough) Concentration (Ctrough) of Avelumab | CYCLE18DAY1 | 35.19 microgram(mcg)/milliliter(mL) | Geometric Coefficient of Variation 54 |
| Cohort 1 (BRCA 1/2 Defect) | Serum Lowest (Trough) Concentration (Ctrough) of Avelumab | CYCLE24DAY1 | 37.21 microgram(mcg)/milliliter(mL) | Geometric Coefficient of Variation 54 |
Secondary
Serum Maximum Concentration (Cmax) for Avelumab
Cmax was defined as maximum observed plasma concentration. The determination method of Cmax was observing directly from data.
Time frame: One hour post-dose on Day 1 of Cycles 1, 3, 6, 12, 18, 24 and Day 15 of Cycle 1
Population: The avelumab PK concentration analysis set included all participants (Cohort 1 and Cohort 2 combined) who received at least 1 dose of study intervention and had at least one concentration measurement for avelumab. Number of participants analyzed = number of participants evaluable for this OM. Number analyzed = participants evaluable at the specific time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Serum Maximum Concentration (Cmax) for Avelumab | CYCLE1DAY1 | 223.0 mcg/mL | Geometric Coefficient of Variation 39 |
| Cohort 1 (BRCA 1/2 Defect) | Serum Maximum Concentration (Cmax) for Avelumab | CYCLE1DAY15 | 221.6 mcg/mL | Geometric Coefficient of Variation 38 |
| Cohort 1 (BRCA 1/2 Defect) | Serum Maximum Concentration (Cmax) for Avelumab | CYCLE3DAY1 | 225.6 mcg/mL | Geometric Coefficient of Variation 34 |
| Cohort 1 (BRCA 1/2 Defect) | Serum Maximum Concentration (Cmax) for Avelumab | CYCLE6DAY1 | 222.3 mcg/mL | Geometric Coefficient of Variation 37 |
| Cohort 1 (BRCA 1/2 Defect) | Serum Maximum Concentration (Cmax) for Avelumab | CYCLE12DAY1 | 248.2 mcg/mL | Geometric Coefficient of Variation 25 |
| Cohort 1 (BRCA 1/2 Defect) | Serum Maximum Concentration (Cmax) for Avelumab | CYCLE18DAY1 | 265.9 mcg/mL | Geometric Coefficient of Variation 20 |
| Cohort 1 (BRCA 1/2 Defect) | Serum Maximum Concentration (Cmax) for Avelumab | CYCLE24DAY1 | 286.1 mcg/mL | Geometric Coefficient of Variation 21 |
Secondary
Time to Prostate-Specific Antigen (PSA) Progression for Participants With mCRPC
For participants with mCRPC, time to PSA progression was defined as the time from the first dose to the date that a \>=25% increase in PSA with an absolute increase of \>=2 μg/L (2 ng/mL) above the nadir (or baseline for participants with no PSA decline) was documented, confirmed by a second consecutive PSA value obtained \>=3 weeks (21 days) later.
Time frame: Baseline up to approximately 24 months
Population: The analysis population included all participants with mCRPC who received at least 1 dose of study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Time to Prostate-Specific Antigen (PSA) Progression for Participants With mCRPC | 6.5 Months |
| Cohort 2 (ATM Defect) | Time to Prostate-Specific Antigen (PSA) Progression for Participants With mCRPC | 11.3 Months |
Secondary
Time to Tumor Response (TTR) as Assessed by BICR
For participants with solid tumors, except mCRPC: TTR was defined for participants with confirmed objective response (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response. For participants with mCRPC: TTR was defined as the time from the first dose of study treatment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3. Soft tissue response was defined as a Best Overall Response (BOR) of CR or PR per RECIST v1.1.
Time frame: Baseline up to approximately 24 months
Population: The analysis population included all enrolled participants who received at least 1 dose of study treatment and with confirmed CR or PR as assessed by BICR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | Time to Tumor Response (TTR) as Assessed by BICR | 1.82 Months |
| Cohort 2 (ATM Defect) | Time to Tumor Response (TTR) as Assessed by BICR | 5.52 Months |
Secondary
TTR as Assessed by Investigator
For participants with solid tumors, except mCRPC: TTR was defined for participants with confirmed objective response (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response. For participants with mCRPC: TTR was defined as the time from the first dose of study treatment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3. Soft tissue response was defined as a BOR of CR or PR per RECIST v1.1.
Time frame: Baseline up to approximately 24 months
Population: The analysis population included all enrolled participants who received at least 1 dose of study treatment and with confirmed CR or PR as assessed by investigator.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (BRCA 1/2 Defect) | TTR as Assessed by Investigator | 1.84 Months |
| Cohort 2 (ATM Defect) | TTR as Assessed by Investigator | 3.99 Months |