Cobimetinib (Targeted Therapy) Plus Atezolizumab (Immunotherapy) in Participants With Advanced Melanoma Whose Cancer Has Worsened During or After Treatment With Previous Immunotherapy and Atezolizumab Monotherapy in Participants With Previously Untreated Advanced Melanoma
- Registration Number
- NCT03178851
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 155
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 v1.1.
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 ≤ 1. 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
- Treatment with systemic immunosuppressive medications with the following exceptions:
- Patients who have received acute, low-dose systemic immunosuppressant medication (≤ 10 mg/day oral prednisone or equivalent) or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor approval has been obtained.
- Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
- Current severe, uncontrolled systemic disease other than cancer
- 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
- Anticipated use of any concomitant medication during or within 7 days before initiation of study treatment that is known to cause QT prolongation
- Any psychological, familial, sociological, or geographic condition that may hamper compliance with the protocol and follow-up after treatment discontinuation
- History of malabsorption or other clinically significant metabolic dysfunction that may interfere with absorption of oral study treatment
- Pregnant or breastfeeding, or intending to become pregnant during the study
- Known clinically significant liver disease
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the participant at high risk for treatment complications
- Treatment with a live, attenuated vaccine within 4 weeks before initiation of study treatment, or anticipation of need for such a vaccine during the course of the study
- Known hypersensitivity to any component of the atezolizumab or cobimetinib formulations
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- Treatment with any other investigational agent or participation in another clinical study with therapeutic intent
- Inability or unwillingness to swallow pills
- Requirement for concomitant therapy or food that is prohibited during the study
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort C Atezolizumab Participants with advanced melanoma, who have not received previous treatment, will receive atezolizumab monotherapy during 21-day cycles. Cohort A Atezolizumab Participants with disease progression on or after treatment with an anti-PD-1 agent will receive cobimetinib and atezolizumab treatment during 28-day cycles. Cohort B Atezolizumab 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. Cohort A Cobimetinib Participants with disease progression on or after treatment with an anti-PD-1 agent will receive cobimetinib and atezolizumab treatment during 28-day cycles. Cohort B Cobimetinib 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.
- Primary Outcome Measures
Name Time Method Investigator-Assessed Disease Control Rate (DCR) 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) 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.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) Up to approximately 2 years OS is defined as the time from Cycle 1, Day 1 to death from any cause.
Serum Concentration of Atezolizumab Cycle 1, Day 15; Day 1 of Cycles 2, 3, 4, 8 Cohort C: IRC-Assessed DOR Approximately 21 months DOR is defined as the time from the first occurrence of documented OR to disease progression, as determined by an independent review committee (IRC) according to RECIST v1.1, or death from any cause, whichever occurs first. 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 Duration of Response (DOR) Up to approximately 2 years DOR is defined as the time from the first occurrence of documented OR to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. 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 Progression-Free Survival (PFS) Up to approximately 2 years PFS is defined as the time from Cycle 1, Day 1 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. 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.
Plasma Concentration of Cobimetinib Cycle 1, Day 15 Percentage of Participants With Adverse Events Baseline through follow up An adverse event is any untoward medical occurrence in a participant 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.
Cohort C: Independent-Review-Committee-Assessed (IRC) ORR Approximately 2 years for Cohorts A and B and 19 months for Cohort C ORR is defined as the percentage of participants with confirmed objective response (OR), as determined by an independent review committee (IRC) according to RECIST v1.1. Confirmed OR is defined as complete response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart, as determined by an independent review committee (IRC) 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.
Cohort C: IRC-Assessed DCR Approximately 21 months DCR is defined as the percentage of participants with CR, PR, or stable disease (SD), as determined by an independent review committee (IRC) according to 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.
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 To evaluate the immune response to atezolizumab the percentage of participants with ADAs to atezolizumab will be determined at baseline and during the study.
Cohort C: IRC-Assessed PFS Approximately 21 months PFS is defined as the time from Cycle 1, Day 1 to the first occurrence of disease progression, as determined by an independent review committee (IRC) according to RECIST v1.1, or death from any cause, whichever occurs first. 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.
Trial Locations
- Locations (42)
Baylor University Medical Center
🇺🇸Dallas, Texas, United States
Cancercare
🇿🇦Port Elizabeth, South Africa
Peter Maccallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Clínica Universidad de Navarra
🇪🇸Pamplona, Navarra, Spain
Lviv State Oncology Regional Treatment and Diagnostic Centre
🇺🇦Lviv, Ukraine
University of Colorado Hospital - Anschutz Cancer Pavilion
🇺🇸Aurora, Colorado, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
HonorHealth Research Institute - Bisgrove
🇺🇸Scottsdale, Arizona, United States
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
Blacktown Hospital
🇦🇺Blacktown, New South Wales, Australia
Mid North Coast Cancer Institute
🇦🇺Port Macquarie, New South Wales, Australia
Melanoma Institute Australia
🇦🇺North Sydney, New South Wales, Australia
Greenslopes Private Hospital; Clinic Pharmacy
🇦🇺Greenslopes, Queensland, Australia
Flinders Medical Centre
🇦🇺Bedford Park, South Australia, Australia
University Clinical Centre of the Republic of Srpska
🇧🇦Banja Luka, Bosnia and Herzegovina
University Clinic Ctr Sarajevo
🇧🇦Sarajevo, Bosnia and Herzegovina
Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Instituto de Ensino e Pesquisa Clinica do Ceara
🇧🇷Fortaleza, CE, Brazil
Hospital Sao Vicente de Paulo
🇧🇷Passo Fundo, RS, Brazil
Instituto Nacional de Cancer - INCa; Oncologia
🇧🇷Rio de Janeiro, RJ, Brazil
Cenantron - Centro Avancado de Tratamento Oncologico
🇧🇷Belo Horizonte, MG, Brazil
Hospital Sao Lucas - PUCRS
🇧🇷Porto Alegre, RS, Brazil
Hospital das Clinicas - UFRGS
🇧🇷Porto Alegre, RS, Brazil
GVI Constantiaberg
🇿🇦Cape Town, South Africa
Hospital Amaral Carvalho
🇧🇷Jau, SP, Brazil
Cape Town Oncology Trials
🇿🇦Cape Town, South Africa
Johese Clinical Research
🇿🇦Centurion, South Africa
Wits Clinical Research; Charlotte Maxeke Johannesburg Academic Hospital
🇿🇦Johannesburg, South Africa
Hospital Clinico Universitario de Santiago
🇪🇸Santiago de Compostela, LA Coruña, Spain
Hospital Universitario Virgen Macarena
🇪🇸Seville, Sevilla, Spain
Steve Biko Academic Hospital; Oncology
🇿🇦Pretoria, South Africa
Hospital Universitari Quiron Dexeus
🇪🇸Barcelona, Spain
Hospital Clinic I Provincial
🇪🇸Barcelona, Spain
Hospital Universitario Ramón y Cajal; Pharmacy
🇪🇸Madrid, Spain
Hospital Universitario La Paz; Servicio de Oncologia
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre; Servicio de Oncologia
🇪🇸Madrid, Spain
Central Municipal Hospital - Uzhgorod State University
🇺🇦Uzhgorod, Chernihiv Governorate, Ukraine
Sumy Regional Clinical Onc Ctr
🇺🇦Sumy, Ukraine
MD Anderson Cancer Center
🇪🇸Madrid, Spain
National Cancer Institute MOH of Ukraine
🇺🇦Kiev, Ukraine
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Public Institution: City Multispecialty Clinical Hospital #4 under Dnipropetrovsk Regional Council
🇺🇦Dnipropetrovsk, Ukraine