A Phase III, Open-Label, Multicenter, Two Arm, Randomized Study to Investigate the Efficacy and Safety of Cobimetinib Plus Atezolizumab Versus Pembrolizumab in Patients With Previously Untreated Advanced BRAF V600 Wild-Type Melanoma
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 446
- 试验地点
- 121
- 主要终点
- Progression Free Survival (PFS) as Determined by the Independent Review Committee (IRC)
研究概览
简要总结
This is a Phase III, multicenter, open-label, randomized study designed to evaluate the efficacy, safety, and pharmacokinetics of cobimetinib plus atezolizumab compared with pembrolizumab in treatment-naive participants with advanced BRAFV600 wild-type melanoma.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 locally advanced and unresectable or metastatic melanoma
- •Naive to prior systemic anti-cancer therapy for melanoma
- •Documentation of BRAFV600 wild-type status in melanoma tumor tissue 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. If 20 slides are not available or the tissue block is not of sufficient size, the patient may still be eligible for the study, after discussion with and approval by the Medical Monitor
- •Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
- •Age >=18 years at time of signing Informed Consent Form
- •Ability to comply with the study protocol, in the investigator's judgment
- •Histologically or cytologically confirmed BRAFV600 wild-type melanoma
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •Life expectancy >=3 months
- •Adequate hematologic and end-organ function
- •For women of childbearing potential: agreement to remain abstinent or use at least two forms of effective contraceptive with a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of cobimetinib and at least 5 months after the last dose of atezolizumab or pembrolizumab
- •For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures (e.g. condom), and agreement to refrain from donating sperm, for at least 3 months after the last dose of cobimetinib
- •Willingness and ability of patients to report selected study outcomes (e.g., GHS and HRQoL) using an electronic device or paper backup questionnaires.
排除标准
- •General Exclusion Criteria
- •Inability to swallow medications
- •Malabsorption condition that would alter the absorption of orally administered medications
- •Pregnancy, breastfeeding, or intention of becoming pregnant during the study
- •History of severe hypersensitivity reactions to components of the cobimetinib, atezolizumab, or pembrolizumab formulations
- •Current or recent treatment with therapeutic antibiotics, live attenuated vaccines or systemic immunostimulatory/immunosuppresive medication
- •Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study Cancer-Related Exclusion Criteria
- •Ocular melanoma
- •Major surgery or radiotherapy within 21 days prior to Day 1 of Cycle 1 or anticipation of needing such procedure while receiving study treatment
- •Uncontrolled tumor-related pain
- •Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once every 28 days
- •Active or untreated central nervous system (CNS) metastases Exclusions Related to Cardiovascular Disease
- •Unstable angina, new-onset angina within last 3 months, myocardial infarction within the last 6 months prior to Day 1 of Cycle 1, or current congestive heart failure classified as New York Heart Association Class II or higher
- •Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or <50%, whichever is lower
- •Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic baseline hypertension consistently above 159/99 mmHg despite optimal medical management
- •History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third degree heart block, or evidence of prior myocardial infarction Exclusions Related to Infections
- •HIV infection
- •Active tuberculosis infection
- •Severe infections within 4 weeks prior to Day 1 of Cycle 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- •Signs or symptoms of clinically relevant infection within 2 weeks prior to Day 1 of Cycle 1
- •Treatment with oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1
- •Active or chronic viral hepatitis B or C infection Exclusions Related to Ocular Disease
- •Known risk factors for ocular toxicity Exclusions Related to Autoimmune Conditions and Immunomodulatory Drugs
- •Active or history of autoimmune disease or immune deficiency
- •Prior allogeneic stem cell or solid organ transplantation
- •History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
- •Treatment with systemic immunosuppressive medications within 2 weeks prior to Day 1, Cycle 1 Exclusions Related to Other Medical Conditions or Medications
- •Active malignancy (other than melanoma) or a prior malignancy within the past 3 years
- •Any Grade >=3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1
- •History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to Day 1
- •Proteinuria >3.5 gm/24 hr
- •Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme inducers or inhibitors at least 7 days prior to Day 1 of Cycle 1 and during study treatment
研究组 & 干预措施
Cobimetinib and Atezolizumab
Participants will receive 60 mg of cobimetinib orally from Days 1 to 21 along with 840 mg of atezolizumab by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurs first. There will be no cobimetinib administration for 7 days (Days 22-28) in each cycle.
干预措施: Cobimetinib (Drug)
Cobimetinib and Atezolizumab
Participants will receive 60 mg of cobimetinib orally from Days 1 to 21 along with 840 mg of atezolizumab by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurs first. There will be no cobimetinib administration for 7 days (Days 22-28) in each cycle.
干预措施: Atezolizumab (Drug)
Pembrolizumab
Participants will receive 200 mg of pembrolizumab administered by IV infusion every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurs first.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Progression Free Survival (PFS) as Determined by the Independent Review Committee (IRC)
时间窗: Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months
PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.
次要结局
- Serum Concentration of Atezolizumab(Day 1 of Cycles 1, 2, and 3)
- Objective Response as Determined by IRC(Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months)
- Objective Response as Determined by the Investigator(Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months)
- PFS as Determined by the Investigator(Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months)
- Overall Survival (OS)(From randomization up to approximately 3 years)
- Duration of Objective Response Determined by the Investigator(Up to 3 years)
- Number of Participants With Adverse Events (AEs)(Up to approximately 16 months)
- Plasma Concentration of Cobimetinib(Days 1 and 15 of Cycle 1)
- Duration of Objective Response Determined by the IRC(Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months)
- Two-year Landmark Survival(At 2 years)
- Change From Baseline in Health-related Quality of Life (HRQoL) Scores(Up to approximately 16 months. Follow up is reported at weeks after participant treatment discontinuation, which could occur at any time during the study. Total time frame does not exceed 16 months.)
- Disease Control Rate (DCR)(Week 16)
- Number of Participants With Abnormal Vital Signs(From baseline up to approximately 3 years)
- Number of Participants With Laboratory Abnormalities(Up to approximately 16 months)
- Percentage of Participants With Anti-drug Antibodies (ADAs)(Day 1 of Cycle 1, 2, 3 and 30 days after treatment discontinuation)