| October 16, 2017
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| November 6, 2017
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| February 10, 2023
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| June 12, 2023
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| October 13, 2023
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| October 19, 2017
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| February 22, 2022 (Final data collection date for primary outcome measure)
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- Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Cycle 1; 28 days ]
DLTs=occurrence of any of the following AEs attributable to any study treatment in Cycle 1:Hematologic: grade(G)4 neutropenia lasting >5 days (absolute neutrophil count [ANC]< 0.5*10^9/L); febrile neutropenia; neutropenic infection (ANC<1.0*10^9/L, and G>3 infection); G>=3 thrombocytopenia (platelet count [PC] <50.0*10^9/L) with bleeding; G4 thrombocytopenia (PC<25.0*10^9/L); G4 anemia (life-threatening; urgent intervention indicated). Non-hematologic: G>=3 toxicities unless predefined in the protocol; potential Hy's law cases. Non-adherence to treatment schedule: failure to deliver at least 75% of the planned doses of talazoparib during the first cycle of treatment due to treatment-related toxicities; G3 non-hematologic toxicity that delayed administration of either study drug for more than 2 weeks. Dose reductions: any adverse event (AE) that resulted in a dose reduction of talazoparib.
- Phase 2: Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment [ Time Frame: From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 4.3 years approximately) ]
This outcome measure (OM) is reported for participants with solid tumors except mCRPC; for those participants, OR was defined as a complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors (RECIST) version(v) 1.1 by investigator. CR: Complete disappearance of all target and non-target lesions with the exception of nodal disease; all target and non-target nodes must decrease to normal size (short axis <10 mm); all lesions must be assessed. PR: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions; all target lesions must be assessed. Non-target PR lesions must be non-progressive disease (PD), where PD is unequivocal progression of pre-existing lesions.
- Phase 2: Percentage of Participants With Confirmed Objective Response (OR) as Per RECIST v1.1 and Prostate Cancer Working Group 3 (PCWG3) by Investigator Assessment [ Time Frame: From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 4.3 years approximately) ]
This OM is reported for participants with mCRPC; for those participants, OR was defined as the proportion of participants with a best overall soft tissue response of CR or PR per RECIST v1.1 and with no evidence of confirmed bone disease progression per PCWG3 criteria by investigator. CR: Complete disappearance of all target and non-target lesions with the exception of nodal disease; all target and non-target nodes must decrease to normal size (short axis <10 mm); all lesions must be assessed. PR: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions; all target lesions must be assessed. Non-target PR lesions must be non-PD.
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- Dose Limiting Toxicity (DLT) [ Time Frame: Cycle 1 Days 1-28 (28 days from date of first dose of study treatment) ]
Phase 1b: DLT during the DLT evaluation period (Cycle 1)
- Overall Response (OR) [ Time Frame: From date of 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 ]
Phase 2: Confirmed OR, as assessed by the Investigator using RECIST v1.1 in patients with locally advanced or metastatic solid tumors and RECIST v1.1 and PCWG3 in patients with metastatic CRPC
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- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately) ]
Adverse event (AE) was any untoward medical occurrence in a participant who received any study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related AEs were those related to any study drug (ie, at least one of the study drugs).
- Number of Participants With Grade >=3 TEAEs [ Time Frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately) ]
AE was any untoward medical occurrence in a participant who received any study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. TEAEs were graded by the investigator using National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. In this outcome measure, number of participants with Grade 3 or higher TEAEs were reported.
- Number of Participants With Serious TEAEs [ Time Frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately) ]
TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related AEs were those related to any study drug (ie, at least one of the study drugs). A serious TEAE was any untoward medical occurrence that at any dose resulted in any of following outcomes/considered to be an important medical event: death; life-threatening experience (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); congenital anomaly/birth defect.
- Number of Participants With TEAEs Leading to Discontinuation of Either Study Drug [ Time Frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately) ]
Either study drug = avelumab only or talazoparib only. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related AEs were those related to any study drug (ie, at least one of the study drugs).
- Number of Participants With TEAEs Leading to Discontinuation of All Study Drugs [ Time Frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately) ]
All study drugs = all study drugs in the combination. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related AEs were those related to any study drug (ie, at least one of the study drugs).
- Number of Participants With TEAEs Leading to Death [ Time Frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately) ]
TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first.
- Number of Participants With New or Worsening Hematology Laboratory Test Results to Grade >=1 During the On-Treatment Period [ Time Frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately) ]
The number of participants with newly occurring or worsening hematology abnormalities during the on-treatment period were summarized by worst grade on-treatment. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. NCI-CTCAE criteria version 4.03 is used. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death.
- Number of Participants With New or Worsening Hematology Laboratory Test Results to Grade >=3 During the On-Treatment Period [ Time Frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately) ]
The number of participants with newly occurring or worsening hematology abnormalities during the on-treatment period were summarized by worst grade on-treatment. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. NCI-CTCAE criteria version 4.03 is used. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death.
- Number of Participants With New or Worsening Chemistry Laboratory Test Results to Grade >=1 During the On-Treatment Period [ Time Frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately) ]
The number of participants with newly occurring or worsening chemistry abnormalities during the on-treatment period were summarized by worst grade on-treatment. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. NCI-CTCAE criteria version 4.03 is used. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death.
- Number of Participants With New or Worsening Chemistry Laboratory Test Results to Grade >=3 During the On-Treatment Period [ Time Frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately) ]
The number of participants with newly occurring or worsening chemistry abnormalities during the on-treatment period were summarized by worst grade on-treatment. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. NCI-CTCAE criteria version 4.03 is used. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death.
- Trough Concentrations (Ctrough)/Predose and Maximum Concentrations (Cmax) of Serum Avelumab Concentrations (μg/mL) by Visit (Excluding Site 1055) [ Time Frame: Predose/0 Hour (H) and 1 H on Days 1 and 15 of Cycle 1 and on Day 1 of Cycles 2-4, and additionally on Day 1 of Cycles 6, 9, 12, 18, and 24. ]
Pharmacokinetics (PK) data analyses included descriptive summary statistics of the pre-dose/Ctrough concentrations for both investigational products and post-dose (for talazoparib) or Cmax concentrations (for avelumab) for each cycle.
- Predose and Postdose Plasma Talazoparib Concentrations (pg/mL) by Visit (Excluding Site 1055) [ Time Frame: Pre-dose and post-dose (at the end of the avelumab infusion) on Days 1 and 15 of Cycle 1 and on Day 1 of Cycles 2-4. ]
Pharmacokinetics (PK) data analyses included descriptive summary statistics of the pre-dose/Ctrough concentrations for both investigational products and post-dose (for talazoparib) or Cmax concentrations (for avelumab) for each cycle. Cmax=maximum concentration. Ctrough=trough concentration. Participants with moderate renal impairment were started at a lower, 0.75 mg QD, dose to compensate for decreased talazoparib clearance.
- Number of Participants With at Least 1 Valid Anti-drug Antibody (ADA) Result at: Any Time Point (N0), Baseline (N1), Baseline and Post-Baseline (N2), and Post-Baseline and Without Positive Baseline ADA Result (N3) [ Time Frame: Pre-dose (within 2 hours of talazoparib dose) on Day 1 and Day 15 of Cycle 1, on Day 1 of Cycle 2-4 and then on Day 1 of Cycles 6, 9, 12, 18, 24, and at the end of treatment (EOT) ]
Immunogenicity blood samples were assayed for ADA using a validated assay. The sample analysis followed a tiered approach of screening, confirmation, and titer determination. Samples tested positive for ADA were further analyzed for neutralizing antibodies (Nab) using a validated assay. Baseline was defined as the last assessment prior to the date/time of the first dose of avelumab. N0, N1, N2, and N3=Number of participants with at least 1 valid ADA result at any time point, baseline (pre-dose on Day 1), baseline and post-baseline, and post-baseline, respectively.
- Number of Participants by ADA Categories [ Time Frame: Pre-dose (within 2 hours of talazoparib dose) on Day 1 and Day 15 of Cycles 1, on Day 1 of Cycle 2-4 and then on Day 1 of Cycles 6, 9, 12, 18, 24, and at the end of treatment (EOT) ]
Immunogenicity blood samples were assayed for ADA using a validated assay. The sample analysis followed a tiered approach of screening, confirmation, and titer determination. Samples tested positive for ADA were further analyzed for neutralizing antibodies (Nab) using a validated assay. Baseline was defined as the last assessment prior to the date/time of the first dose of avelumab. N0, N1, N2, and N3=Number of participants with at least 1 valid ADA Result at any time point, baseline (pre-dose on Day 1), baseline and post-baseline, and post-baseline, respectively. n=number of participants in each category.
- Phase 1b: Percentage of Participants With Confirmed OR as Per RECIST v1.1 and PCWG3 by Investigator Assessment [ Time Frame: From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately) ]
This OM is reported for participants in Phase 1b; OR was defined as the proportion of participants with a best overall soft tissue response of CR or PR per RECIST v1.1 and with no evidence of confirmed bone disease progression per Prostate Cancer Working Group 3 (PCWG3) criteria by investigator. CR: Complete disappearance of all target and non-target lesions with the exception of nodal disease; all target and non-target nodes must decrease to normal size (short axis <10 mm); all lesions must be assessed. PR: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions; all target lesions must be assessed. Non-target PR lesions must be non-PD.
- Phase 1b: Time to Response (TTR) in Participants With Confirmed CR or PR [ Time Frame: From the first dose of study treatment to the first documentation of objective tumor response/the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression (<=5.2 years approximately) ]
For participants with solid tumors except mCRPC, TTR was defined for participants with confirmed OR (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 as assessed by Investigator using RECIST v1.1.
- Phase 2: TTR in Participants With Confirmed CR or PR [ Time Frame: From the first dose of study treatment to the first documentation of objective tumor response/the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression (<= 5.2 years approximately) ]
For participants with solid tumors except mCRPC, TTR was defined for participants with confirmed OR (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 as assessed by Investigator using RECIST v1.1.
- Phase 2: Duration of Response (DR) in Participants With Confirmed CR or PR [ Time Frame: From the first objective tumor response/soft tissue response to the first objective tumor progression/subsequent objective evidence of radiographic progression or death due to any cause, whichever occurred first (<=5.2 years approximately) ]
For participants with solid tumors except mCRPC, DR was defined for participants with confirmed OR (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.
- Phase 1b: Progression-Free Survival (PFS) in Participants With Confirmed CR or PR [ Time Frame: From the first dose of study treatment to the date of disease progression/radiographic progression in soft tissue or bone, or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately) ]
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 as assessed by Investigator using RECIST v1.1, in bone as assessed by Investigator using PCWG3, or death, whichever occurred first
- Phase 2: PFS in Participants With Confirmed CR or PR (RECIST v1.1) [ Time Frame: From the first dose of study treatment to the date of disease progression/radiographic progression in soft tissue or bone, or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately) ]
This OM is reported for participants with solid tumors except mCRPC; for those participants, 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.
- Phase 2: PFS in Participants With Confirmed CR or PR (RECIST v1.1 and PCWG3) [ Time Frame: From the first dose of study treatment to the date of disease progression/radiographic progression in soft tissue or bone, or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately) ]
This OM was reported for participants with mCRPC; for these participants, PFS was defined as the time from the first dose of study treatment to documentation of radiographic progression in soft tissue as assessed by Investigator using RECIST v1.1, in bone as assessed by Investigator using PCWG3, or death, whichever occurred first.
- Phase 2: Time to Prostate-Specific Antigen (PSA) Progression for Participants With mCRPC [ Time Frame: 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 (maximum up to 5.2 years approximately) ]
Time to PSA progression for participants with mCRPC 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.
- Phase 1b: Overall Survival [ Time Frame: From the first dose of study treatment to the date of death (maximum up to 5.2 years approximately) ]
Overall survival (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.
- Phase 2: Overall Survival [ Time Frame: From the first dose of study treatment to the date of death (maximum up to 5.2 years approximately) ]
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.
- Phase 2: Percentage of Participants With PSA Response [ Time Frame: From baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50% (maximum up to 5.2 years approximately) ]
PSA response was defined as the proportion of participants with 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 be confirmed by a second consecutive value at least 3 weeks later.
- Phase 1b: Percentage of Participants With CA-125 Response [ Time Frame: From baseline to at least a 50% reduction in CA-125 level (maximum up to 5.2 years approximately) ]
Cancer Antigen 125 (CA-125) response is defined as at least a 50% reduction in CA-125 levels from baseline. The response must be confirmed and maintained for at least 28 days.
- Phase 2: Percentage of Participants With CA-125 Response [ Time Frame: From baseline to at least a 50% reduction in CA-125 level (maximum up to 5.2 years approximately) ]
CA-125 response is defined as at least a 50% reduction in CA-125 levels from baseline. The response must be confirmed and maintained for at least 28 days.
- Number of Participants With Different Programmed Death-Ligand 1 (PD-L1) Status at Baseline [ Time Frame: At baseline (the last available assessment prior to the start of study treatment was defined as 'baseline' value or 'baseline' assessment) ]
PD-L1 expression on tumor and infiltrating immune cells were measured by immunohistochemistry (IHC). PD-L1 expression level corresponds to the percentage of positive cells. The PD-L1 Positive category does not apply to cohorts A1 and A2. The PD-L1 High/Low categories only apply to cohorts A1 and A2. Participants were considered positive if their baseline tumor tissue sample demonstrated cell surface PD-L1 expression: 1) for Cohorts E1, E2, and F: >=1% tumor cells (TC) or >= 5% immune cells (IC); 2) for Cohort D: TC/IC>=25%; 3) for Cohorts B1, B2, C1, C2: IC>=5%; otherwise were considered negative. Categories based on PD-L1 expression level ≥50% and <50% were defined as High and Low, respectively.
- Number of Participants With Different Tumor Mutational Burden (TMB) at Baseline [ Time Frame: At baseline (the last available assessment prior to the start of study treatment was defined as 'baseline' value or 'baseline' assessment) ]
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. High: TMB score >=20 muts/mb (number of mutations per megabase of DNA); Medium: TMB score >=10 muts/mb and <20 muts/mb; Low: TMB score <10 muts/mb.
- Number of Participants With Different DNA Damage Repair (DDR) Status at Baseline [ Time Frame: At baseline (the last available assessment prior to the start of study treatment was defined as 'baseline' value or 'baseline' assessment) ]
DDR defect positive was determined by presence of one or more pathogenic or likely pathogenic mutations in tissue, DNA and/or blood samples.
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- Serum concentrations of avelumab [ Time Frame: Day 1 Cycles 1-4, 6, 9, 12, 18, 24 and Day 15 Cycle 1 ]
Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
- Anti drug antibody (ADA) levels of avelumab [ Time Frame: Day 1 Cycles 1-4, 6,9,12,18, 24 and Day 15 Cycle 1 ]
Immunogenicity assessment of avelumab
- OR [ Time Frame: From the start of treatment until disease progression/recurrence up to approximately 24 months ]
Phase 1b: Confirmed OR, as assessed by the Investigator using RECIST v1.1 in patients with locally advanced or metastatic solid tumors and RECIST v1.1 and PCWG3 in patients with metastatic CRPC.
- PSA Tumor Marker [ Time Frame: Baseline, Day1 of each cycle (each cycle is 28 days), and End of Treatment ( up to approximately 24 months) ]
PSA response greater than or equal to 50% for patients with metastatic CRPC.
- CA-125 Tumor Marker [ Time Frame: Baseline, Day1 of each cycle (each cycle is 28 days), and End of Treatment (up to approximately 24 months) ]
CA-125 response for patients with ovarian cancer.
- Biomarker PD-L1 [ Time Frame: Baseline ]
PD-L1 expression level in baseline tumor tissue.
- Genomic [ Time Frame: Baseline ]
Genomic scarring and the presence of defects in select genes, considered critical to effective DDR, in baseline tumor tissue.
- Serum concentrations of avelumab [ Time Frame: Day 1 Cycles 1-4, 6,9,12,18, 24 and Day 15 Cycle 1 ]
Pharmacokinetic parameters: maximum concentrations (Cmax)
- Plasma concentrations of talazoparib [ Time Frame: Day 1 Cycles 1-4 and Day 15 Cycle 1 ]
Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
- Plasma concentration of talazoparib [ Time Frame: Day 1 Cycles 1-4 and Day 15 Cycle 1 ]
Pharmacokinetic parameters: post-dose concentrations
- Neutralizing antibodies (Nab) levels against avelumab. [ Time Frame: Day 1 Cycles 1-4, 6, 9, 12, 18, 24 and Day 15 Cycle 1 ]
Immunogenicity assessment of avelumab
- Time to Tumor Response (TTR) [ Time Frame: Baseline up to approximately 24 months ]
Time to Tumor Response (TTR) is defined for patients 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.
- Duration of response (DR) [ Time Frame: Baseline up to approximately 24 months ]
Duration of Response (DR) is defined for patients with confirmed objective response (complete response [CR] or partial response [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 occurs first.
- Progression-Free Survival (PFS) [ Time Frame: Baseline up to approximately 24 months ]
Progression Free Survival (PFS) is 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 occurs first.
- Prostate-Specific Antigen (PSA) response [ Time Frame: Baseline up to approximately 24 months ]
PSA response is defined as the proportion of patients with confirmed PSA decline greater than or equal to 50% compared to baseline.
- Overall Survival (OS) [ Time Frame: Baseline up to approximately 24 months ]
OS is defined as the time from the first dose of study treatment to the date of death.
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| Not Provided
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| Not Provided
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| Javelin Parp Medley: Avelumab Plus Talazoparib In Locally Advanced Or Metastatic Solid Tumors
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| A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND ANTI TUMOR ACTIVITY OF AVELUMAB IN COMBINATION WITH THE POLY(ADENOSINE DIPHOSPHATE [ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR TALAZOPARIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS
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| Avelumab in combination with talazoparib will be investigated in patients with locally advanced (primary or recurrent) or metastatic solid tumors, including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), hormone receptor positive (HR+) breast cancer, recurrent platinum sensitive ovarian cancer, urothelial cancer (UC), and castration resistant prostate cancer (CRPC).
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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, including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), hormone receptor positive (HR+) breast cancer, recurrent platinum sensitive ovarian cancer, urothelial cancer (UC), and castration resistant prostate cancer (CRPC).
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| Interventional
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Phase 1
Phase 2
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Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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| Avelumab in Combination With Talazoparib Will be Investigated in Patients With Locally Advanced (Primary or Recurrent) or Metastatic Solid Tumors
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- Drug: Avelumab Phase 1b
Avelumab
Other Name: MSB0010718C
- Drug: Talazoparib Phase 1b
Talazoparib
Other Name: MDV3800, BMN 673
- Drug: Avelumab Phase 2
The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.
Other Name: MSB0010718C
- Drug: Talazoparib Phase 2
The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.
Other Name: MDV3800, BMN 673
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- Experimental: Dose Level 0 Phase 1b
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 1b
- Drug: Talazoparib Phase 1b
- Experimental: Dose Level -1 Phase 1b
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 1b
- Drug: Talazoparib Phase 1b
- Experimental: Dose Level -2 Phase 1b
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 1b
- Drug: Talazoparib Phase 1b
- Experimental: A1. NSCLC Phase 2
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 2
- Drug: Talazoparib Phase 2
- Experimental: A2. NSCLC PD-L1 Resistant DDR+ Phase 2
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 2
- Drug: Talazoparib Phase 2
- Experimental: B1. TNBC Phase 2
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 2
- Drug: Talazoparib Phase 2
- Experimental: B2. HR+BC DDR Defect +Assay Phase 2
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 2
- Drug: Talazoparib Phase 2
- Experimental: C1. Ovarian CA Recurrent Plat-Sensitive Phase 2
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 2
- Drug: Talazoparib Phase 2
- Experimental: C2.Ovarian CA Recurrent Plat-Sensitive BRCA defect Phase 2
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 2
- Drug: Talazoparib Phase 2
- Experimental: D.Urothelial CA Phase 2
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 2
- Drug: Talazoparib Phase 2
- Experimental: E1. CRPC Phase 2
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 2
- Drug: Talazoparib Phase 2
- Experimental: E2. CRPC DDR Defect +Assay Phase 2
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 2
- Drug: Talazoparib Phase 2
- Experimental: F: Advanced Solid Tumors with BRCA or ATM defect Phase 2
Drug: Avelumab
Drug: Talazoparib Interventions:
- Drug: Avelumab Phase 2
- Drug: Talazoparib Phase 2
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| Yap TA, Bardia A, Dvorkin M, Galsky MD, Beck JT, Wise DR, Karyakin O, Rubovszky G, Kislov N, Rohrberg K, Joy AA, Telli ML, Schram AM, Conte U, Chappey C, Stewart R, Stypinski D, Michelon E, Cesari R, Konstantinopoulos PA. Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial. JAMA Oncol. 2023 Jan 1;9(1):40-50. doi: 10.1001/jamaoncol.2022.5228.
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| Terminated
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| 223
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| 296
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| January 4, 2023
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| February 22, 2022 (Final data collection date for primary outcome measure)
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Inclusion Criteria:
- Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent in adult patients with: NSCLC, TNBC, HR+ breast cancer, recurrent platinum sensitive ovarian cancer, UC, CRPC, and other advanced solid tumors with a BRCA or ATM gene defect
- Mandatory primary or metastatic tumor biopsy. If archival tumor tissue is available from a biopsy/surgery the tumor tissue may be submitted without repeating a tumor biopsy during the screening period.
- Minimum age in Japan is 20 years.
- ECOG performance status 0 or 1.
- Resolved acute effects of prior therapy
- Adequate bone marrow, renal, and liver function.
- Negative serum pregnancy test at screening.
- Pregnant, breastfeeding females or female patients able to have children must agree to use highly effective method of contraception throughout the study and for at least 30 days after the last dose of avelumab and for at least 7 months after the last dose of talazoparib; fertile male patients must use a condom during treatment and for at least 4 months after the last dose of talazoparib.
- Signed and dated informed consent.
Exclusion Criteria:
- Prior treatment with a PARP inhibitor.
- Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, OX 40, GITR, LAG 3, IDO, TDO,TIM 3, CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways. Prior treatment with Sipuleucel-T for patients with mCRPC is allowed. For cohort A2 NSCLC patients prior treatment with anti-PD-1/L1 is allowed
- Prior anti-cancer therapy within 2 weeks prior to study enrollment. Prior radiation therapy within 2 weeks prior to enrollment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed 2 days prior to study enrollment and no clinically significant toxicities are expected (eg, mucositis, esophagitis).
- Major surgery within 4 weeks prior to study enrollment.
- Current use of immunosuppressive medication at the time of study enrollment.
- Known prior or suspected hypersensitivity to investigational products.
- 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.
- Vaccination within 4 weeks of study enrollment and while on trial is prohibited except for administration of inactivated vaccines.
- Diagnosis of Myelodysplastic Syndrome.
- Patients with known brain metastases requiring steroids.
- Participation in other studies involving investigational drug(s) within 4 weeks prior to study participation and/or during study participation.
- Persisting toxicity related to prior therapy >Grade 1
- Known HIV or AIDs-related illness.
- Positive HBV or HCV test indicating acute or chronic infection.
- Active infection requiring systemic therapy.
- Clinically significant cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months prior to study entry; unstable angina, congestive heart failure or a serious cardiac arrhythmia requiring medication.
- Current or anticipated use within 7 days prior to first dose of study drug, or anticipated use during the study of a strong P-gp inhibitor.
- Other acute or chronic medical or psychiatric conditions.
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| Sexes Eligible for Study: |
All |
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| 18 Years and older (Adult, Older Adult)
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| No
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| Contact information is only displayed when the study is recruiting subjects
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| Australia, Belgium, Canada, Denmark, Hungary, Korea, Republic of, Russian Federation, United Kingdom, United States
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| NCT03330405
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B9991025
2017-001509-33 ( EudraCT Number )
JAVELIN PARP MEDLEY ( Other Identifier: Alias Study Number )
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| No
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| Studies a U.S. FDA-regulated Drug Product: |
Yes |
| Studies a U.S. FDA-regulated Device Product: |
No |
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| Plan to Share IPD: |
Yes |
| Plan Description: |
Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests. |
| URL: |
https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests |
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| Pfizer
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| Same as current
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| Pfizer
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| Same as current
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| Not Provided
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| Study Director: |
Pfizer CT.gov Call Center |
Pfizer |
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| Pfizer
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| October 2023
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