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

Malignant Melanoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03178851
• Other study ID #: CO39721
• Secondary ID: 2016-004402-34
• Status: Completed
• Phase: Phase 1
• Start date: June 20, 2017
• Est. completion date: September 21, 2020

Study information

• Verified date: November 2021
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 155
• Est. completion date: September 21, 2020
• Est. primary completion date: May 29, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Malignant Melanoma
• Melanoma

Intervention

Biological:
• Atezolizumab
Atezolizumab, 840 mg intravenously every two weeks (Q2W) on Days 1 and 15 of each 28-day cycle, until loss of clinical benefit

Drug:
• Cobimetinib
Cobimetinib, 60 mg orally once daily (QD) on Days 1-21 of each 28-day cycle, until loss of clinical benefit

Biological:
• Atezolizumab
Atezolizumab, 840 mg intravenously on Day 15 of Cycle 1; thereafter Q2W on Days 1 and 15 of Cycle 2 and all subsequent 28-day cycles, until loss of clinical benefit
• Atezolizumab
Atezolizumab, 1200 mg intravenously every three weeks (Q3W) on Day 1 of each 21-day cycle, until loss of clinical benefit

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Blacktown Hospital	Blacktown	New South Wales
Australia	Greenslopes Private Hospital; Clinic Pharmacy	Greenslopes	Queensland
Australia	Alfred Hospital	Melbourne	Victoria
Australia	Peter Maccallum Cancer Centre	Melbourne	Victoria
Australia	Melanoma Institute Australia	North Sydney	New South Wales
Australia	Mid North Coast Cancer Institute	Port Macquarie	New South Wales
Bosnia and Herzegovina	University Clinical Centre of the Republic of Srpska	Banja Luka
Bosnia and Herzegovina	University Clinic Ctr Sarajevo	Sarajevo
Brazil	Cenantron - Centro Avancado de Tratamento Oncologico	Belo Horizonte	MG
Brazil	Instituto de Ensino e Pesquisa Clinica do Ceara	Fortaleza	CE
Brazil	Hospital Amaral Carvalho	Jau	SP
Brazil	Hospital Sao Vicente de Paulo	Passo Fundo	RS
Brazil	Hospital das Clinicas - UFRGS	Porto Alegre	RS
Brazil	Hospital Sao Lucas - PUCRS	Porto Alegre	RS
Brazil	Instituto Nacional de Cancer - INCa; Oncologia	Rio de Janeiro	RJ
South Africa	Cape Town Oncology Trials	Cape Town
South Africa	GVI Constantiaberg	Cape Town
South Africa	Johese Clinical Research	Centurion
South Africa	Cancercare	George
South Africa	Wits Clinical Research; Charlotte Maxeke Johannesburg Academic Hospital	Johannesburg
South Africa	Cancercare	Port Elizabeth
South Africa	Steve Biko Academic Hospital; Oncology	Pretoria
Spain	Hospital Clinic I Provincial	Barcelona
Spain	Hospital Universitari Quiron Dexeus	Barcelona
Spain	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid
Spain	Hospital Universitario La Paz; Servicio de Oncologia	Madrid
Spain	Hospital Universitario Ramón y Cajal; Pharmacy	Madrid
Spain	MD Anderson Cancer Center	Madrid
Spain	Clínica Universidad de Navarra	Pamplona	Navarra
Spain	Hospital Clinico Universitario de Santiago	Santiago de Compostela	LA Coruña
Spain	Hospital Universitario Virgen Macarena	Seville	Sevilla
Ukraine	Public Institution: City Multispecialty Clinical Hospital #4 under Dnipropetrovsk Regional Council	Dnipropetrovsk
Ukraine	National Cancer Institute MOH of Ukraine	Kiev
Ukraine	Lviv State Oncology Regional Treatment and Diagnostic Centre	Lviv
Ukraine	Sumy Regional Clinical Onc Ctr	Sumy
Ukraine	Central Municipal Hospital - Uzhgorod State University	Uzhgorod	Chernihiv Governorate
United States	University of Colorado Hospital - Anschutz Cancer Pavilion	Aurora	Colorado
United States	Baylor University Medical Center	Dallas	Texas
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	HonorHealth Research Institute - Bisgrove	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Bosnia and Herzegovina,  Brazil,  South Africa,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Investigator-Assessed Objective Response Rate (ORR)	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.	Up to approximately 2 years
Primary	Investigator-Assessed Disease Control Rate (DCR)	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.	Week 16
Secondary	Investigator-Assessed Duration of Response (DOR)	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.	Up to approximately 2 years
Secondary	Overall Survival (OS)	OS is defined as the time from Cycle 1, Day 1 to death from any cause.	Up to approximately 2 years
Secondary	Investigator-Assessed Progression-Free Survival (PFS)	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.	Up to approximately 2 years
Secondary	Serum Concentration of Atezolizumab		Cycle 1, Day 15; Day 1 of Cycles 2, 3, 4, 8
Secondary	Plasma Concentration of Cobimetinib		Cycle 1, Day 15
Secondary	Percentage of Participants With Adverse Events	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.	Baseline through follow up
Secondary	Change From Baseline in Percentage of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab	To evaluate the immune response to atezolizumab the percentage of participants with ADAs to atezolizumab will be determined at baseline and during the study.	Cycle 1 Day 1 pre-dose to 120 days after the last dose of study medication
Secondary	Cohort C: Independent-Review-Committee-Assessed (IRC) ORR	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.	Approximately 2 years for Cohorts A and B and 19 months for Cohort C
Secondary	Cohort C: IRC-Assessed DCR	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.	Approximately 21 months
Secondary	Cohort C: IRC-Assessed DOR	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.	Approximately 21 months
Secondary	Cohort C: IRC-Assessed PFS	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.	Approximately 21 months