A Phase Ib Study Evaluating Cobimetinib Plus Atezolizumab in Patients With Advanced BRAF V600 Wild-Type Melanoma Who Have Progressed During or After Treatment With Anti-PD-1 Therapy and Atezolizumab Monotherapy in Patients With Previously Untreated Advanced BRAF V600 Wild-Type Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 155
- 试验地点
- 42
- 主要终点
- Investigator-Assessed Disease Control Rate (DCR)
研究概览
简要总结
This study will evaluate the preliminary efficacy, safety, and pharmacokinetics of cobimetinib and atezolizumab in participants with advanced BRAF V600-wild type (WT), metastatic, or unresectable locally advanced melanoma who have progressed on prior anti-PD-1 therapy. In addition, this study will evaluate the efficacy, safety, and pharmacokinetics of atezolizumab monotherapy in participants with BRAFV600-WT metastatic or unresectable locally advanced melanoma, who have not been previously treated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Cohorts A and B:
- •Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc BRAF V600 WT (locally advanced) melanoma
- •Documentation of BRAF V600 mutation-negative status in melanoma tumor tissue (archival [< 5 years old] or newly obtained) through use of a clinical mutation test approved by the local health authority
- •Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
- •Disease progression on or after treatment with a programmed death (PD)-1 inhibitor either as monotherapy or in combination with other agent(s)
- •Additional Disease-Specific Inclusion Criteria in Cohort B (Biopsy Cohort):
- •Progressed on or after anti-PD-1 therapy within 12 weeks before study start
- •Received a minimum of two cycles of anti-PD-1 therapy
- •Meet the following criteria for resistance to an anti-PD-1 agent: primary resistance defined as disease progression, according to RECIST v1.1, as best response; secondary resistance defined as disease progression after initial confirmed response according to RECIST v1.1
- •Consent to undergo tumor biopsies of accessible lesions, before and during treatment and at radiographic progression, for biomarker analyses.
- •Have at least two accessible lesions that are amenable to excisional or core-needle (minimum three cores and minimum diameter 18 gauge; however, 16 gauge is desirable) biopsy without unacceptable risk of a major procedural complication. Exceptions may be made if patient has only one lesion that allows multiple biopsies.
- •Disease-Specific Inclusion Criteria: Cohort C:
- •Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc BRAFV600-WT (locally advanced) melanoma
- •Naive to prior systemic anti-cancer therapy for melanoma
- •Documentation of BRAFV600 mutation-negative status in melanoma tumor tissue (archival [< 5 years old] or newly obtained) through use of a clinical mutation test approved by the local health authority
- •A representative, formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or 20 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study entry.
- •Measurable disease according to RECIST v1.
- •General Inclusion Criteria:
- •Ability to comply with the study protocol, in the investigator's judgment
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •Available and adequate baseline tumor tissue sample
- •Life expectancy ≥ 18 weeks
- •Adequate hematologic and end-organ function, defined by laboratory test results, obtained within 14 days before initiation of study treatment
- •For women of childbearing potential: abstinent or use an effective form of contraceptive method for at least 3 months for cobimetinib and at least 5 months for atezolizumab. Women must refrain from donating eggs during this same period.
- •For men: abstinent or use contraceptive measures and agreement to refrain from donating sperm for at least 3 months after cobimetinib and atezolizumab
- •Exclusion criteria
- •Prior treatment with a mitogen activated-protein kinase (MAPK) inhibitor
- •Ocular melanoma
- •Major surgical procedure other than for diagnosis within 4 weeks before initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study
- •Traumatic injury within 2 weeks before initiation of study treatment
- •Palliative radiotherapy within 14 days before initiation of study treatment
- •Active malignancy (other than BRAF V600 mutation-negative melanoma) or malignancy within 3 years
- •Treatment with any anti-cancer agent 14 days prior to Cycle, Day 1 other than aPD-1 based therapy
- •Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤
- •Clinically stable patients with manageable immune-related adverse events resulting from prior cancer immunotherapy may be eligible for the study.
- •For Cohort C only: any prior anti-cancer therapy for advanced melanoma
- •History or evidence of ongoing serous retinopathy or retinal vein occlusion (RVO) at baseline
- •History of clinically significant cardiac dysfunction
- •Active or untreated central nervous system (CNS) metastases
- •History of metastases to brain stem, midbrain, pons, or medulla, or within 10 millimeter (mm) of the optic apparatus (optic nerves and chiasm)
- •History of leptomeningeal metastatic disease
- •Human immunodeficiency virus (HIV) infection
- •Active tuberculosis
- •Severe infection within 4 weeks before initiation of study treatment
- •Signs or symptoms of infection within 2 weeks before initiation of study treatment
- •Treatment with oral or intravenous (IV) antibiotics within 2 weeks prior to Day 1 of Cycle 1
- •Active or chronic viral hepatitis B or C infection
- •Active or history of autoimmune disease or immune deficiency
- •Prior allogeneic stem cell or solid organ transplantation
- •History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
- 另有 18 项未显示
排除标准
- 未提供
研究组 & 干预措施
Cohort A
Participants with disease progression on or after treatment with an anti-PD-1 agent will receive cobimetinib and atezolizumab treatment during 28-day cycles.
干预措施: Atezolizumab (Biological)
Cohort A
Participants with disease progression on or after treatment with an anti-PD-1 agent will receive cobimetinib and atezolizumab treatment during 28-day cycles.
干预措施: Cobimetinib (Drug)
Cohort B
Participants with disease progression on or after treatment with an anti-PD-1 agent will receive cobimetinib prior to initiating atezolizumab treatment during Cycle 1. During subsequent 28-day cycles participants will initiate both atezolizumab and cobimetinib on Day 1 of each cycle. Participants in this cohort will undergo tumor biopsies before and during treatment.
干预措施: Cobimetinib (Drug)
Cohort B
Participants with disease progression on or after treatment with an anti-PD-1 agent will receive cobimetinib prior to initiating atezolizumab treatment during Cycle 1. During subsequent 28-day cycles participants will initiate both atezolizumab and cobimetinib on Day 1 of each cycle. Participants in this cohort will undergo tumor biopsies before and during treatment.
干预措施: Atezolizumab (Biological)
Cohort C
Participants with advanced melanoma, who have not received previous treatment, will receive atezolizumab monotherapy during 21-day cycles.
干预措施: Atezolizumab (Biological)
结局指标
主要结局
Investigator-Assessed Disease Control Rate (DCR)
时间窗: Week 16
DCR is defined as the percentage of participants with CR, PR, or stable disease (SD) at 16 weeks. Per RECIST v1.1, CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions.
Investigator-Assessed Objective Response Rate (ORR)
时间窗: Up to approximately 2 years
ORR is defined as the percentage of participants with confirmed objective response (OR). Confirmed OR is defined as complete response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
次要结局
- Overall Survival (OS)(Up to approximately 2 years)
- Serum Concentration of Atezolizumab(Cycle 1, Day 15; Day 1 of Cycles 2, 3, 4, 8)
- Cohort C: IRC-Assessed DOR(Approximately 21 months)
- Investigator-Assessed Duration of Response (DOR)(Up to approximately 2 years)
- Investigator-Assessed Progression-Free Survival (PFS)(Up to approximately 2 years)
- Plasma Concentration of Cobimetinib(Cycle 1, Day 15)
- Percentage of Participants With Adverse Events(Baseline through follow up)
- Cohort C: Independent-Review-Committee-Assessed (IRC) ORR(Approximately 2 years for Cohorts A and B and 19 months for Cohort C)
- Cohort C: IRC-Assessed DCR(Approximately 21 months)
- Change From Baseline in Percentage of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab(Cycle 1 Day 1 pre-dose to 120 days after the last dose of study medication)
- Cohort C: IRC-Assessed PFS(Approximately 21 months)