A Phase II Two Cohort Study Evaluating the Safety and Efficacy of Cobimetinib Plus Atezolizumab in BRAFV600 Wild-type Melanoma With Central Nervous System Metastases and Cobimetinib Plus Atezolizumab and Vemurafenib in BRAFV600 Mutation-positive Melanoma With Central Nervous System Metastases
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 80
- 试验地点
- 22
- 主要终点
- Intracranial Objective Response Rate (ORR)
研究概览
简要总结
This study will evaluate the efficacy and safety of cobimetinib plus atezolizumab in participants with BRAFV600 wild-type melanoma with central nervous system (CNS) metastases and of cobimetinib plus atezolizumab and vemurafenib in BRAFV600 mutation-positive melanoma patients with CNS metastases.
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
- •Disease-specific inclusion criteria:
- •Histologically confirmed melanoma with radiologically confirmed brain metastases
- •Documented BRAFV600 mutation status of melanoma tumour tissue using a validated genetic test.
- •Measurable brain metastases
- •Prior systemic therapy for metastatic melanoma is allowed with exceptions as detailed in the exclusion criteria
- •Prior SRT or surgical therapy of ≤ 10 brain metastases is allowed but prior WBRT is not allowed
- •Adverse effects of all prior systemic or local treatment must have either returned to baseline or become stable and manageable prior to initiation of study treatment.
- •General inclusion criteria:
- •Age ≥18 years
- •Able to comply with the study protocol, in the investigator's judgment
- •ECOG Performance Status ≤ 2
- •Life expectancy of > 3 months
- •Willing and able to complete health and quality of life questionnaires required by the protocol
- •Adequate hematologic and end-organ function
- •Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use two effective forms of contraception during the course of this study and for at least six months after completion of study therapy.
- •Male patients must agree to refrain from donating sperm for at least six months after the last dose of cobimetinib
- •Exclusion criteria:
- •Disease-specific exclusion criteria:
- •Ocular melanoma
- •Leptomeningeal involvement
- •Uncontrolled tumour-related pain
- •Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once every 28 days.
- •Prior WBRT treatment for CNS disease
- •Increasing corticosteroid dose during the seven days prior to initiation of study treatment or current dexamethasone or equivalent dose of > 8 mg/day
- •Prior treatment with a BRAF or MEK inhibitor
- •For patients assigned to Cohort 1 only: prior immunotherapy in the metastatic setting is not allowed. Prior immunotherapy is allowed in the adjuvant setting, provided it is completed ≥ 90 days prior to study treatment initiation.
- •For patients assigned to Cohort 2 only: prior immunotherapy in either the adjuvant or metastatic setting is not allowed.
- •Major surgical procedure other than for diagnosis within four weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study
- •Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells or to any formulation component of cobimetinib or atezolizumab or, for patients assigned to Cohort 2 only, vemurafenib
- •Any anti-cancer therapy, including chemotherapy, hormonal therapy and radiotherapy, within two weeks prior to initiation of study treatment
- •Patients assigned to Cohort 2 only: Concomitant treatment with anticonvulsants other than gabapentin, vigabatrin and levetiracetam
- •Patients assigned to Cohort 2 only: acetaminophen is prohibited within seven days prior to initiation of study treatment unless the patient has an absolute contraindication to the to the use of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin
- •Active malignancy (other than melanoma) or a prior malignancy within the past three years
- •General exclusion criteria:
- •Known risk factors for ocular toxicity
- •History of clinically significant cardiac dysfunction
- •Inability to swallow medications
- •Malabsorption condition that would alter the absorption of orally administered medications
- •Traumatic injury within two weeks prior to initiation of study treatment
- •Prior allogeneic stem cell or solid organ transplantation
- •Active or history of autoimmune disease or immune deficiency
- •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
- •Uncontrolled diabetes or symptomatic hyperglycaemia
- •Any Grade ≥ 3 haemorrhage or bleeding event within 28 days of study treatment initiation
- •History of stroke, reversible ischemic neurological defect, or transient ischemic attack within six months prior to study treatment initiation
- •Positive human immunodeficiency virus (HIV) test at screening
- •Hepatitis B virus (HBV) infection (chronic or acute)
- •Active hepatitis C virus (HCV) infection
- •Active tuberculosis
- •History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
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排除标准
- 未提供
研究组 & 干预措施
Cohort 1- cobimetinib and atezolizumab
Participants with BRAFV600 wild-type disease will be administered cobimetinib on Days 1-21 of each 28-day cycle; and atezolizumab on Days 1 and 15 of each treatment cycle.
干预措施: Cobimetinib (Drug)
Cohort 1- cobimetinib and atezolizumab
Participants with BRAFV600 wild-type disease will be administered cobimetinib on Days 1-21 of each 28-day cycle; and atezolizumab on Days 1 and 15 of each treatment cycle.
干预措施: Atezolizumab (Drug)
Cohort 2 - cobimetinib, atezolizumab and vemurafenib
Participants with BRAFV600 mutation-positive disease will be administered cobimetinib, atezolizumab and vemurafenib in 28-day treatment cycles. Treatment includes a 28-day run-in period where participants will receive cobimetinib and vemurafenib only. Upon completion of the 28-day run-in period, atezolizumab will be added to their treatment regimen.
干预措施: Cobimetinib (Drug)
Cohort 2 - cobimetinib, atezolizumab and vemurafenib
Participants with BRAFV600 mutation-positive disease will be administered cobimetinib, atezolizumab and vemurafenib in 28-day treatment cycles. Treatment includes a 28-day run-in period where participants will receive cobimetinib and vemurafenib only. Upon completion of the 28-day run-in period, atezolizumab will be added to their treatment regimen.
干预措施: Atezolizumab (Drug)
Cohort 2 - cobimetinib, atezolizumab and vemurafenib
Participants with BRAFV600 mutation-positive disease will be administered cobimetinib, atezolizumab and vemurafenib in 28-day treatment cycles. Treatment includes a 28-day run-in period where participants will receive cobimetinib and vemurafenib only. Upon completion of the 28-day run-in period, atezolizumab will be added to their treatment regimen.
干预措施: Vemurafenib (Drug)
结局指标
主要结局
Intracranial Objective Response Rate (ORR)
时间窗: Baseline up to cut of date (approximately 2.5 years)
Intracranial ORR is defined as the percentage of participants with either a complete response (CR) or a partial response (PR) in their intracranial disease based on two consecutive assessments \>= 4 weeks apart. Disease status for this endpoint will be determined by an Independent Review Committee (IRC) in accordance with Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) with modified measurability definition for intracranial lesions (\>= 0.5 cm by MRI) and allowing up to five intracranial target lesions. CR is defined as disappearance of all lesions. PR is defined as \>=30% decrease in tumor burden, in the absence of CR. The primary endpoint is analyzed on the BRAFV600 mutation positive (Cohort 2) only as the Sponsor had discontinued enrolment into Cohort 1. Data for Cohort 1 was not collected nor analyzed for this outcome measure.
次要结局
- Duration of Response (DOR)(Baseline up to cut of date (approximately 2.5 years))
- Time to Cognitive Symptom Deterioration(Up to 48 months)
- Percentage of Participants With Adverse Events(Baseline up to 4 years, 4 months)
- Disease Control Rate (DCR)(At 16 weeks)
- Overall Survival (OS)(Baseline up to 4 years, 4 months)
- Duration of Stable/Improved Health-related Quality of Life (HRQoL) Scores(Baseline up to cut of date (approximately 2.5 years))
- Overall ORR(Baseline up to cut of date (approximately 2.5 years))
- Extracranial ORR(Baseline up to cut of date (approximately 2.5 years))
- Progression-Free Survival (PFS)(Baseline up to cut of date (approximately 2.5 years))
- Time to Symptom and Function Deterioration(Up to 48 months)