Clinical trial NCT03178851: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Melanoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-06-07
Enrollment: 155
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion criteria

Disease-Specific Inclusion Criteria: 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

Primary outcomes:
measure: Investigator-Assessed Objective Response Rate (ORR)
timeFrame: Up to approximately 2 years
measure: Investigator-Assessed Disease Control Rate (DCR)
timeFrame: Week 16
Secondary outcomes:
measure: Investigator-Assessed Duration of Response (DOR)
timeFrame: Up to approximately 2 years
measure: Overall Survival (OS)
timeFrame: Up to approximately 2 years
measure: Investigator-Assessed Progression-Free Survival (PFS)
timeFrame: Up to approximately 2 years
measure: Serum Concentration of Atezolizumab
timeFrame: Cycle 1, Day 15; Day 1 of Cycles 2, 3, 4, 8
measure: Plasma Concentration of Cobimetinib
timeFrame: Cycle 1, Day 15
measure: Percentage of Participants With Adverse Events
timeFrame: Baseline through follow up
measure: Change From Baseline in Percentage of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab
timeFrame: Cycle 1 Day 1 pre-dose to 120 days after the last dose of study medication
measure: Cohort C: Independent-Review-Committee-Assessed (IRC) ORR
timeFrame: Approximately 2 years for Cohorts A and B and 19 months for Cohort C
measure: Cohort C: IRC-Assessed DCR
timeFrame: Approximately 21 months
measure: Cohort C: IRC-Assessed DOR
timeFrame: Approximately 21 months
measure: Cohort C: IRC-Assessed PFS
timeFrame: Approximately 21 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: HonorHealth Research Institute - Bisgrove
state: Arizona
city: Aurora
country: United States
facility: University of Colorado Hospital - Anschutz Cancer Pavilion
state: Colorado
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Blacktown
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: North Sydney
country: Australia
facility: Melanoma Institute Australia
state: New South Wales
city: Port Macquarie
country: Australia
facility: Mid North Coast Cancer Institute
state: New South Wales
city: Greenslopes
country: Australia
facility: Greenslopes Private Hospital; Clinic Pharmacy
state: Queensland
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Banja Luka
country: Bosnia and Herzegovina
facility: University Clinical Centre of the Republic of Srpska
city: Sarajevo
country: Bosnia and Herzegovina
facility: University Clinic Ctr Sarajevo
city: Fortaleza
country: Brazil
facility: Instituto de Ensino e Pesquisa Clinica do Ceara
state: CE
city: Belo Horizonte
country: Brazil
facility: Cenantron - Centro Avancado de Tratamento Oncologico
state: MG
city: Rio de Janeiro
country: Brazil
facility: Instituto Nacional de Cancer - INCa; Oncologia
state: RJ
city: Passo Fundo
country: Brazil
facility: Hospital Sao Vicente de Paulo
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital das Clinicas - UFRGS
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas - PUCRS
state: RS
city: Jau
country: Brazil
facility: Hospital Amaral Carvalho
state: SP
city: Cape Town
country: South Africa
facility: Cape Town Oncology Trials
city: Cape Town
country: South Africa
facility: GVI Constantiaberg
city: Centurion
country: South Africa
facility: Johese Clinical Research
city: George
country: South Africa
facility: Cancercare
city: Johannesburg
country: South Africa
facility: Wits Clinical Research; Charlotte Maxeke Johannesburg Academic Hospital
city: Port Elizabeth
country: South Africa
facility: Cancercare
city: Pretoria
country: South Africa
facility: Steve Biko Academic Hospital; Oncology
city: Santiago de Compostela
country: Spain
facility: Hospital Clinico Universitario de Santiago
state: LA Coruña
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
state: Navarra
city: Seville
country: Spain
facility: Hospital Universitario Virgen Macarena
state: Sevilla
city: Barcelona
country: Spain
facility: Hospital Universitari Quiron Dexeus
city: Barcelona
country: Spain
facility: Hospital Clinic I Provincial
city: Madrid
country: Spain
facility: MD Anderson Cancer Center
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal; Pharmacy
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario La Paz; Servicio de Oncologia
city: Uzhgorod
country: Ukraine
facility: Central Municipal Hospital - Uzhgorod State University
state: Chernihiv Governorate
city: Dnipropetrovsk
country: Ukraine
facility: Public Institution: City Multispecialty Clinical Hospital #4 under Dnipropetrovsk Regional Council
city: Kiev
country: Ukraine
facility: National Cancer Institute MOH of Ukraine
city: Lviv
country: Ukraine
facility: Lviv State Oncology Regional Treatment and Diagnostic Centre
city: Sumy
country: Ukraine
facility: Sumy Regional Clinical Onc Ctr
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Barteselli G, Goodman GR, Patel Y, Caro I, Xue C, McCallum S. Characterization of Serous Retinopathy Associated with Cobimetinib: Integrated Safety Analysis of Four Studies. Drug Saf. 2022 Dec;45(12):1491-1499. doi: 10.1007/s40264-022-01248-2. Epub 2022 Oct 30.
citation: de Azevedo SJ, de Melo AC, Roberts L, Caro I, Xue C, Wainstein A. First-line atezolizumab monotherapy in patients with advanced BRAFV600 wild-type melanoma. Pigment Cell Melanoma Res. 2021 Sep;34(5):973-977. doi: 10.1111/pcmr.12960. Epub 2021 Feb 15.