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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 223
- 试验地点
- 61
- 主要终点
- Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
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).
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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.
研究组 & 干预措施
C2.Ovarian CA Recurrent Plat-Sensitive BRCA defect Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 2 (Drug)
Dose Level 0 Phase 1b
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 1b (Drug)
Dose Level 0 Phase 1b
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 1b (Drug)
Dose Level -1 Phase 1b
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 1b (Drug)
Dose Level -1 Phase 1b
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 1b (Drug)
Dose Level -2 Phase 1b
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 1b (Drug)
Dose Level -2 Phase 1b
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 1b (Drug)
A1. NSCLC Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 2 (Drug)
A1. NSCLC Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 2 (Drug)
A2. NSCLC PD-L1 Resistant DDR+ Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 2 (Drug)
A2. NSCLC PD-L1 Resistant DDR+ Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 2 (Drug)
B1. TNBC Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 2 (Drug)
B1. TNBC Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 2 (Drug)
B2. HR+BC DDR Defect +Assay Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 2 (Drug)
B2. HR+BC DDR Defect +Assay Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 2 (Drug)
C1. Ovarian CA Recurrent Plat-Sensitive Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 2 (Drug)
C1. Ovarian CA Recurrent Plat-Sensitive Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 2 (Drug)
C2.Ovarian CA Recurrent Plat-Sensitive BRCA defect Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 2 (Drug)
D.Urothelial CA Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 2 (Drug)
D.Urothelial CA Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 2 (Drug)
E1. CRPC Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 2 (Drug)
E1. CRPC Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 2 (Drug)
E2. CRPC DDR Defect +Assay Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 2 (Drug)
E2. CRPC DDR Defect +Assay Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 2 (Drug)
F: Advanced Solid Tumors with BRCA or ATM defect Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Avelumab Phase 2 (Drug)
F: Advanced Solid Tumors with BRCA or ATM defect Phase 2
Drug: Avelumab
Drug: Talazoparib
干预措施: Talazoparib Phase 2 (Drug)
结局指标
主要结局
Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- Trough Concentrations (Ctrough)/Predose and Maximum Concentrations (Cmax) of Serum Avelumab Concentrations (μg/mL) by Visit (Excluding Site 1055)(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.)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)(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))
- Number of Participants With Grade >=3 TEAEs(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))
- Number of Participants With TEAEs Leading to Discontinuation of Either Study Drug(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))
- Number of Participants With New or Worsening Hematology Laboratory Test Results to Grade >=1 During the On-Treatment Period(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))
- Number of Participants With Serious TEAEs(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))
- Number of Participants With New or Worsening Hematology Laboratory Test Results to Grade >=3 During the On-Treatment Period(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))
- Number of Participants With New or Worsening Chemistry Laboratory Test Results to Grade >=1 During the On-Treatment Period(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))
- Predose and Postdose Plasma Talazoparib Concentrations (pg/mL) by Visit (Excluding Site 1055)(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.)
- Number of Participants With TEAEs Leading to Discontinuation of All Study Drugs(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))
- Number of Participants With New or Worsening Chemistry Laboratory Test Results to Grade >=3 During the On-Treatment Period(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))
- Number of Participants With TEAEs Leading to Death(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))
- 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)(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))
- Number of Participants by ADA Categories(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))
- Phase 1b: Percentage of Participants With Confirmed OR as Per RECIST v1.1 and PCWG3 by Investigator Assessment(From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately))
- Phase 1b: Time to Response (TTR) in Participants With Confirmed CR or PR(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))
- Phase 2: TTR in Participants With Confirmed CR or PR(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))
- Phase 2: Duration of Response (DR) in Participants With Confirmed CR or PR(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))
- Phase 1b: Progression-Free Survival (PFS) in Participants With Confirmed CR or PR(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))
- Phase 2: PFS in Participants With Confirmed CR or PR (RECIST v1.1)(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))
- Phase 2: PFS in Participants With Confirmed CR or PR (RECIST v1.1 and PCWG3)(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))
- Phase 2: Time to Prostate-Specific Antigen (PSA) Progression for Participants With mCRPC(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))
- Phase 1b: Overall Survival(From the first dose of study treatment to the date of death (maximum up to 5.2 years approximately))
- Phase 2: Overall Survival(From the first dose of study treatment to the date of death (maximum up to 5.2 years approximately))
- Phase 2: Percentage of Participants With PSA Response(From baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50% (maximum up to 5.2 years approximately))
- Phase 1b: Percentage of Participants With CA-125 Response(From baseline to at least a 50% reduction in CA-125 level (maximum up to 5.2 years approximately))
- Phase 2: Percentage of Participants With CA-125 Response(From baseline to at least a 50% reduction in CA-125 level (maximum up to 5.2 years approximately))
- Number of Participants With Different Programmed Death-Ligand 1 (PD-L1) Status at Baseline(At baseline (the last available assessment prior to the start of study treatment was defined as 'baseline' value or 'baseline' assessment))
- Number of Participants With Different Tumor Mutational Burden (TMB) at Baseline(At baseline (the last available assessment prior to the start of study treatment was defined as 'baseline' value or 'baseline' assessment))
- Number of Participants With Different DNA Damage Repair (DDR) Status at Baseline(At baseline (the last available assessment prior to the start of study treatment was defined as 'baseline' value or 'baseline' assessment))