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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

NCT03178851

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: CO39721
  • SECONDARY ID: 2016-004402-34
  • NCT ID: NCT03178851

Conditions

  • Malignant Melanoma

Interventions

DrugSynonymsArms
AtezolizumabTecentriqCohort A
CobimetinibCotellicCohort A
AtezolizumabTecentriqCohort B
AtezolizumabTecentriqCohort C

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimentalParticipants with disease progression on or after treatment with an anti-PD-1 agent will receive cobimetinib and atezolizumab treatment during 28-day cycles.
  • Atezolizumab
  • Cobimetinib
Cohort BExperimentalParticipants 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.
  • Cobimetinib
  • Atezolizumab
Cohort CExperimentalParticipants with advanced melanoma, who have not received previous treatment, will receive atezolizumab monotherapy during 21-day cycles.
  • Atezolizumab

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:Up to approximately 2 years
Safety Issue:
Description: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

Measure:Duration of Response (DOR)
Time Frame:Up to approximately 2 years
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:Up to approximately 2 years
Safety Issue:
Description:OS is defined as the time from Cycle 1, Day 1 to death from any cause.
Measure:Progression-Free Survival (PFS)
Time Frame:Up to approximately 2 years
Safety Issue:
Description: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.
Measure:Clearance of Atezolizumab
Time Frame:Cohort A: Cycle 1, Day 1 - pre-dose, 30 minutes (min) post-dose. Cohort B: Cycle 1, Day 15 - pre-dose, 30 min post-dose. Cohorts A and B: Cycles 2, 3, 4, 8, 12, and 16 - pre-dose, discontinuation, 120 days after last dose. Each cycle is 28 days.
Safety Issue:
Description:Clearance is the process of drug elimination from the body.
Measure:Clearance of Cobimetinib
Time Frame:Cohort A: Cycle 1, Day 1 - 2-4 hours (hr) post-dose, Cycle 1, Day 15 - pre-dose, 2-4 hr post-dose. Cohort B: Cycle 1, Day 15 - pre-dose, 2-4 hr post-dose. Each cycle is 28 days.
Safety Issue:
Description:Clearance is the process of drug elimination from the body.
Measure:Percentage of Participants with Adverse Events
Time Frame:Up to approximately 2 years
Safety Issue:
Description: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.
Measure:Change from Baseline in Percentage of Participants with Anti-drug Antibodies (ADAs) to Atezolizumab
Time Frame:Cohorts A and C: Cycle 1, Day 1 pre-dose. Cohort B: Cycle 1, Day 15 pre-dose. Cohorts A, B and C: Cycles, 2, 3, 4, 8, 12, and 16 pre-dose, discontinuation, 120 days after last dose. Cohorts A and B: each cycle is 28 days. Cohort C: each cycle is 21 days.
Safety Issue:
Description:To evaluate the immune response to atezolizumab the percentage of participants with ADAs to atezolizumab will be determined at baseline and during the study.
Measure:Cohort C: Objective Response Rate (ORR)
Time Frame:Up to approximately 4 years
Safety Issue:
Description: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.
Measure:Cohort C: Disease Control Rate (DCR)
Time Frame:Up to approximately 4 years
Safety Issue:
Description: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.
Measure:Cohort C: Duration of Response (DOR)
Time Frame:Up to approximately 4 years
Safety Issue:
Description: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.
Measure:Cohort C: Progression-free Survival (PFS)
Time Frame:Up to approximately 4 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

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