A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND CLINICAL ACTIVITY OF COMBINATIONS OF AVELUMAB, BINIMETINIB AND TALAZOPARIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC RAS-MUTANT SOLID TUMORS
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 36
- 试验地点
- 16
- 主要终点
- Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b
研究概览
简要总结
This Phase 1b/2 study will examine the effects of the study drugs, avelumab, binimetinib and talazoparib when given in a 2 (doublet) or 3 (triplet) drug combination, in patients with locally advanced or metastatic RAS-mutant solid tumors. The Phase 1b part of the study will assess if the different study drugs can be given together safely and which doses to use for further research. Phase 2 will test if the study treatments have an effect on tumor size and growth, and gather more information about potential side effects.
详细描述
This is a Phase 1b/2, open label, multi-center, safety, clinical activity, pharmacokinetic (PK), and pharmacodynamics (PD) study of combinations of avelumab, binimetinib and talazoparib in adult patients with metastatic pancreatic ductal adenocarcinoma and other locally advanced or metastatic KRAS- or NRAS-mutant solid tumors.
The Phase 1b part of this study will initially assess doublet drug combinations to determine a recommended dose for further investigation. Following this, the recommended dose for the combination of avelumab, binimetinib and talazoparib (triplet) will be determined. The recommended doses for the doublet and triplet combinations will be used in the Phase 2 part of the study, which will assess the safety and preliminary anti-tumor activity of the study treatments.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 as follows:
- •Metastatic pancreatic ductal adenocarcinoma; or
- •Phase 2 only: Stage IIIb/IV NSCLC or other advanced solid tumors with documented positive KRAS or NRAS mutation as determined using a validated test performed in a CAP/CLIA-certified laboratory (or other comparable local or regional certification).
- •Have had disease progression during or following at least 1 and not more than 2 prior lines of treatment for advanced or metastatic disease.
- •Patients with NSCLC must have previously received treatment with an anti-PD-1 or anti-PD-L1 agent for advanced disease.
- •Measurable disease as per RECIST v1.1 criteria.
- •Provision of a baseline tumor sample.
- •Age ≥18 years (Japanese patients must be ≥20 years old)
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or
- •Adequate bone marrow, renal and liver functions.
- •Adequate cardiac function.
- •Informed consent provided.
排除标准
- •Prior treatment with avelumab, a PARP inhibitor or MEK inhibitor.
- •Prior systemic anti-cancer therapy within 2 weeks prior to study enrollment.
- •Persisting toxicity related to prior therapy.
- •Current use of immunosuppressive medication.
- •Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis, uveitis or iritis.
- •Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent.
- •Diagnosis of myelodysplastic syndrome (MDS).
- •Known symptomatic brain metastases requiring steroids.
- •Known history of testing positive for HIV or hepatitis.
- •Clinically significant (ie, active) cardiovascular disease.
- •History of thromboembolic or cerebrovascular events.
- •Current or anticipated use of a P-gp inhibitor, inducer, or inhibitor of breast cancer resistance protein (BCRP)
- •Uncontrolled hypertension.
- •Concurrent neuromuscular disorder that is associated with the potential of elevated creatinine kinase.
- •Known history of Gilbert's syndrome.
- •History or current evidence of retinal degenerative disease, retinal vein occlusion (RVO) or current risk factors for RVO.
- •Other acute or chronic medical or psychiatric condition.
研究组 & 干预措施
Avelumab and binimetinib
Open label
干预措施: Avelumab (Drug)
Avelumab and binimetinib
Open label
干预措施: Binimetinib (Drug)
Avelumab, binimetinib and talazoparib
Open label
干预措施: Avelumab (Drug)
Avelumab, binimetinib and talazoparib
Open label
干预措施: Binimetinib (Drug)
Avelumab, binimetinib and talazoparib
Open label
干预措施: Talazoparib (Drug)
Binimetinib and talazoparib.
Open label.
干预措施: Binimetinib (Drug)
Binimetinib and talazoparib.
Open label.
干预措施: Talazoparib (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b
时间窗: From date of first study treatment to day 28 of study treatment (Up to 28 days)
Any adverse events (AEs) occurring in the first cycle of treatment (28 days) which were attributable to study drugs and met DLT criteria. DLT was defined as hematologic: Grade 4 neutropenia lasting\>5 days; febrile neutropenia; neutropenic infection; Grade \>=3 thrombocytopenia with bleed; Grade 4 thrombocytopenia; Grade 4 anemia; non-hematologic: Grade ≥3 toxicities (with some exceptions) ; Grade≥3 creatinine phosphokinase (CPK) with creatinine \>= 1.5xbaseline; Grade 3 troponin increase with cardiac toxicity; potential Hy's Law cases; eye disorders: retinopathy or retinal detachment Grade≥3; retinal vascular disorder; Grade≥3 uveitis, blurred vision, flashing lights, floaters or others for \>21 consecutive days; other Grade 4; cardiac disorders: absolute LVEF decrease \>10% and the LVEF was below LLN; other Grade≥3; respiratory disorders: interstitial lung disease Grade≥2; bronchospasm Grade 3; skin and subcutaneous tissue disorders; non-adherence to treatment schedule; dose reductions.
Phase 2: Confirmed Objective Response (OR) Based on Investigator Assessment Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
时间窗: From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).
Confirmed OR, defined as a complete response (CR) or partial response (PR) per RECIST v1.1. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Both CR and PR must be confirmed by repeated assessments performed no less than 4 weeks after the criteria for response were first met.
次要结局
- Number of Participants With Adverse Events During the On-Treatment Period(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) assessed for a maximum duration of up to 31 months)
- Number of Participants With Hematology Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03(Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months))
- Predose Concentration During Multiple Dosing (Ctrough) for Binimetinib(Predose on Day 15 of Cycle 1 (each cycle is 28 days), Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 3 for avelumab+binimetinib groups, and on Day 8 and Day 15 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycle 3 for binimetinib+talazoparib groups)
- Predose Concentration During Multiple Dosing (Ctrough) for Talazoparib(Pre-dose on Days 1, 8 and Day 15 of Cycle 1 (each cycle is 28 days), and on Day 1 of Cycle 2 and Cycle 3)
- Maximum Observed Plasma Concentration (Cmax) for Avelumab(Post dose on Day 1, and Day 15 of Cycle 1 (each cycle is 28 days); Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 3, 5, 9 and 12)
- Maximum Observed Plasma Concentration (Cmax) for Binimetinib(Post dose on Day 1 and Day 8 of Cycle 1)
- Number of Participants With Anti-drug Antibody (ADA) Categories(from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months)
- Predose Concentration During Multiple Dosing (Ctrough) for Avelumab(Pre-dose on Day 1, and Day 15 of Cycle 1 (each cycle is 28 days); Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 3, 5, 9 and 12.)
- Number of Participants With Chemistry Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03(Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months))
- Neutralizing Antibodies (nAb) Against Avelumab(from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months)
- Percentage of Participants With Confirmed Objective Response (OR) in Phase 1b Based on Investigator Assessment (RECIST v1.1)(From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).)
- Progression-Free Survival (PFS) Based on Investigator Assessment (RECIST v1.1) in Phase 1b(From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).)
- Overall Survival (OS) in Phase 1b(From date of first study treatment until the date of death due to any cause (assessed for a maximum duration of up to 31 months).)
- Time-to-Tumor Response (TTR) in Phase 1b(From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).)
- Duration of Response (DR) in Phase 1b(From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).)
- Phase 2: Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression, DNA Damage Repair (DDR) Gene Alterations, and Tumor Mutational Burden (TMB) in Baseline Tumor Tissue.(Baseline)