A PHASE 2 STUDY TO EVALUATE SAFETY AND ANTI-TUMOR ACTIVITY OF AVELUMAB IN COMBINATION WITH TALAZOPARIB IN PATIENTS WITH BRCA OR ATM MUTANT TUMORS JAVELIN BRCA/ATM
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 202
- 试验地点
- 86
- 主要终点
- Percentage of Participants With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR)
研究概览
简要总结
Avelumab in combination with talazoparib will be investigated in patients with locally advanced or metastatic solid tumors with a BRCA or ATM defect.
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 with a BReast CAncer susceptibility gene (BRCA)1, or BRCA2, or ataxia telangiectasia mutated (ATM) gene defect.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Open label
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
- •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
- •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.
排除标准
- •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 >
- •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.
研究组 & 干预措施
Combination of avelumab and talazoparib
Single arm open label
干预措施: Avelumab (Drug)
Combination of avelumab and talazoparib
Single arm open label
干预措施: Talazoparib (Drug)
结局指标
主要结局
Percentage of Participants With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR)
时间窗: 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.
次要结局
- 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)
- 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)
- Plasma Ctrough for Talazoparib(Predose on Cycle 1 Days 1, 15 and Cycle 3 Day 1)
- Duration of Response (DoR) as Assessed by BICR(Baseline up to approximately 24 months)
- 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)
- Time to Tumor Response (TTR) as Assessed by BICR(Baseline up to approximately 24 months)
- DoR as Assessed by Investigator(Baseline up to approximately 24 months)
- 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)
- Number of Participants by Status of Tumor Mutational Burden (TMB) at Baseline(Baseline)
- 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)
- 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)
- 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)
- 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)
- PFS as Assessed by Investigator(Baseline up to approximately 24 months)
- Number of Participants With Circulating Tumor Cell (CTC) Count Conversion(Day 1 of Cycle 1 to Cycle 4)
- 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)
- TTR as Assessed by Investigator(Baseline up to approximately 24 months)
- Overall Survival (OS) for All Participants(Baseline up to approximately 24 months)
- Time to Prostate-Specific Antigen (PSA) Progression for Participants With mCRPC(Baseline up to approximately 24 months)
- Number of Participants With Cancer Antigen 125 (CA-125) Response(Baseline, Day 1 of each treatment Cycle, maximum up to 4.3 years approximately)
- Progression Free Survival (PFS) as Assessed by BICR(Baseline up to approximately 24 months)
- Number of Participants With Confirmed PSA Response(Baseline up to approximately 24 months)
- Number of Participants With Positive Programmed Death Ligand 1 (PD-L1) Expression in Baseline Tumor Tissue(Baseline)
- Number of Participants With Different Status for Defects in BRCA1, BRCA2 and ATM(Baseline)