A Study of Cobimetinib Plus Atezolizumab Versus Pembrolizumab in Participants With Previously Untreated Advanced BRAFv600 Wild-Type Melanoma

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Advanced BRAFV600 Wild-type Melanoma

Intervention / Treatment
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* Drug: Cobimetinib
* Drug: Atezolizumab
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cobimetinib and Atezolizumab<br>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. | Drug: Cobimetinib<br>* Cobimetinib 60 mg tablets orally once daily on a 21 days on, 7 days off schedule.<br>Drug: Atezolizumab<br>* Atezolizumab 840 mg as IV infusion once in every 2 weeks.<br>|
| Active Comparator: Pembrolizumab<br>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. | Drug: Pembrolizumab<br>* Pembrolizumab 200 mg as IV infusion once in every 3 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) as Determined by the Independent Review Committee (IRC) | 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. | Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS as Determined by the Investigator | PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator 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. | Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months | 
| Objective Response as Determined by the Investigator | Objective response rate is defined as the percentage of participants with a complete response (CR) or a partial response (PR) on two consecutive occasions >/=4 weeks apart, as determined by the investigator through the use of RECIST v1.1. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). | Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months | 
| Objective Response as Determined by IRC | Objective response, defined as a complete response or partial response on two consecutive occasions ≥4 weeks apart, as determined by IRC according to RECIST v1.1 | Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months | 
| Disease Control Rate (DCR) | DCR is defined as the proportion of participants with a complete response, a partial response, or stable disease at 16 weeks. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). Stable disease (SD): neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. | Week 16 | 
| Overall Survival (OS) | OS is defined as the time from randomization to death from any cause. | From randomization up to approximately 3 years | 
| Duration of Objective Response Determined by the IRC | Duration of objective response, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first. | Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months | 
| Duration of Objective Response Determined by the Investigator | Duration of objective response is defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator through use of RECIST v1.1, or death from any cause, whichever occurs first. | Up to 3 years | 
| Two-year Landmark Survival | Two-year landmark survival is defined as the rate of survival at 2 years. Two-year landmark survival is defined as the rate of survival at 2 years and was calculated using Kaplan-Meier analysis, which is commonly used to estimate the probability of an event at time 't.' | At 2 years | 
| Change From Baseline in Health-related Quality of Life (HRQoL) Scores | HRQoL scores are assessed through global health status (GHS)/ quality of life (QoL) subscale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30). These are based on questions 29 and 30 of the EORTC QLQ-C30. These questions on global health status/QoL scale are coded on 7-point scale (1=very poor to 7=excellent). Raw scores will be linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher (better) level of functioning. | 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. | 
| Number of Participants With Adverse Events (AEs) | An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | Up to approximately 16 months | 
| Number of Participants With Abnormal Vital Signs | Vital signs will include temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure. | From baseline up to approximately 3 years | 
| Number of Participants With Laboratory Abnormalities | Participants with laboratory abnormalities (values outside of a defined range) will be reported. | Up to approximately 16 months | 
| Plasma Concentration of Cobimetinib |  | Days 1 and 15 of Cycle 1 | 
| Serum Concentration of Atezolizumab |  | Day 1 of Cycles 1, 2, and 3 | 
| Percentage of Participants With Anti-drug Antibodies (ADAs) | Participants with ADAs during the study relative to the prevalence of ADAs at baseline will be reported. | Day 1 of Cycle 1, 2, 3 and 30 days after treatment discontinuation |