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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

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ClinicalTrials.gov Identifier: NCT03178851
Recruitment Status : Active, not recruiting
First Posted : June 7, 2017
Last Update Posted : October 3, 2019
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Malignant Melanoma Biological: Atezolizumab Drug: Cobimetinib Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 152 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 20, 2017
Actual Primary Completion Date : May 29, 2019
Estimated Study Completion Date : December 15, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Cohort A
Participants with disease progression on or after treatment with an anti-PD-1 agent will receive cobimetinib and atezolizumab treatment during 28-day cycles.
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
Other Name: Tecentriq

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

Experimental: Cohort B
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.
Drug: Cobimetinib
Cobimetinib, 60 mg orally once daily (QD) on Days 1−21 of each 28-day cycle, until loss of clinical benefit
Other Name: Cotellic

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
Other Name: Tecentriq

Experimental: Cohort C
Participants with advanced melanoma, who have not received previous treatment, will receive atezolizumab monotherapy during 21-day cycles.
Biological: Atezolizumab
Atezolizumab, 1200 mg intravenously every three weeks (Q3W) on Day 1 of each 21-day cycle, until loss of clinical benefit
Other Name: Tecentriq




Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 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.

  2. Disease Control Rate (DCR) [ Time Frame: 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.


Secondary Outcome Measures :
  1. Duration of Response (DOR) [ Time Frame: 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.

  2. Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]
    OS is defined as the time from Cycle 1, Day 1 to death from any cause.

  3. Progression-Free Survival (PFS) [ Time Frame: 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.

  4. 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. ]
    Clearance is the process of drug elimination from the body.

  5. 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. ]
    Clearance is the process of drug elimination from the body.

  6. Percentage of Participants with Adverse Events [ Time Frame: Up to approximately 2 years ]
    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.

  7. 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. ]
    To evaluate the immune response to atezolizumab the percentage of participants with ADAs to atezolizumab will be determined at baseline and during the study.

  8. Cohort C: Objective Response Rate (ORR) [ Time Frame: Up to approximately 4 years ]
    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.

  9. Cohort C: Disease Control Rate (DCR) [ Time Frame: Up to approximately 4 years ]
    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.

  10. Cohort C: Duration of Response (DOR) [ Time Frame: Up to approximately 4 years ]
    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.

  11. Cohort C: Progression-free Survival (PFS) [ Time Frame: Up to approximately 4 years ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03178851


  Show 52 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03178851     History of Changes
Other Study ID Numbers: CO39721
2016-004402-34 ( EudraCT Number )
First Posted: June 7, 2017    Key Record Dates
Last Update Posted: October 3, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs