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A Study Evaluating the Safety and Efficacy of Cobimetinib Plus Atezolizumab in BRAFV600 Wild-type Melanoma With Central Nervous System Metastases and Cobimetinib Plus Atezolizumab and Vemurafenib in BRAFV600 Mutation-positive Melanoma With Central Nervous System Metastases

NCT03625141

Description:

This study will evaluate the efficacy and safety of cobimetinib plus atezolizumab in participants with BRAFV600 wild-type melanoma with central nervous system (CNS) metastases and of cobimetinib plus atezolizumab and vemurafenib in BRAFV600 mutation-positive melanoma patients with CNS metastases.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating the Safety and Efficacy of Cobimetinib Plus Atezolizumab in BRAFV600 Wild-type Melanoma With Central Nervous System Metastases and Cobimetinib Plus Atezolizumab and Vemurafenib in BRAFV600 Mutation-positive Melanoma With Central Nervous System Metastases
  • Official Title: A Phase II Two Cohort Study Evaluating the Safety and Efficacy of Cobimetinib Plus Atezolizumab in BRAFV600 Wild-type Melanoma With Central Nervous System Metastases and Cobimetinib Plus Atezolizumab and Vemurafenib in BRAFV600 Mutation-positive Melanoma With Central Nervous System Metastases

Clinical Trial IDs

  • ORG STUDY ID: MO39136
  • NCT ID: NCT03625141

Conditions

  • Metastatic Melanoma

Interventions

DrugSynonymsArms
CobimetinibCotellicCohort 1- cobimetinib and atezolizumab
AtezolizumabTecentriqCohort 1- cobimetinib and atezolizumab
VemurafenibZelborafCohort 2 - cobimetinib, atezolizumab and vemurafenib

Purpose

This study will evaluate the efficacy and safety of cobimetinib plus atezolizumab in participants with BRAFV600 wild-type melanoma with central nervous system (CNS) metastases and of cobimetinib plus atezolizumab and vemurafenib in BRAFV600 mutation-positive melanoma patients with CNS metastases.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1- cobimetinib and atezolizumabExperimentalParticipants with BRAFV600 wild-type disease will be administered cobimetinib on Days 1−21 of each 28-day cycle; and atezolizumab on Days 1 and 15 of each treatment cycle.
  • Cobimetinib
  • Atezolizumab
Cohort 2 - cobimetinib, atezolizumab and vemurafenibExperimentalParticipants with BRAFV600 mutation-positive disease will be administered cobimetinib, atezolizumab and vemurafenib in 28-day treatment cycles. Treatment includes a 28-day run-in period where participants will receive cobimetinib and vemurafenib only. Upon completion of the 28-day run-in period, atezolizumab will be added to their treatment regimen.
  • Cobimetinib
  • Atezolizumab
  • Vemurafenib

Eligibility Criteria

        Inclusion Criteria:

        Disease-specific inclusion criteria:

          -  Histologically confirmed melanoma with radiologically confirmed brain metastases

          -  Documented BRAFV600 mutation status of melanoma tumour tissue using a validated
             genetic test.

          -  Measurable brain metastases

          -  Prior systemic therapy for metastatic melanoma is allowed with exceptions as detailed
             in the exclusion criteria

          -  Prior SRT or surgical therapy of ≤ 10 brain metastases is allowed but prior WBRT is
             not allowed

          -  Adverse effects of all prior systemic or local treatment must have either returned to
             baseline or become stable and manageable prior to initiation of study treatment.

        General inclusion criteria:

          -  Age ≥18 years

          -  Able to comply with the study protocol, in the investigator's judgment

          -  ECOG Performance Status ≤ 2

          -  Life expectancy of > 3 months

          -  Willing and able to complete health and quality of life questionnaires required by the
             protocol

          -  Adequate hematologic and end-organ function

          -  Female patients of childbearing potential and male patients with partners of
             childbearing potential must agree to always use two effective forms of contraception
             during the course of this study and for at least six months after completion of study
             therapy.

          -  Male patients must agree to refrain from donating sperm for at least six months after
             the last dose of cobimetinib

        Exclusion criteria:

        Disease-specific exclusion criteria:

          -  Ocular melanoma

          -  Leptomeningeal involvement

          -  Uncontrolled tumour-related pain

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated
             drainage more than once every 28 days.

          -  Prior WBRT treatment for CNS disease

          -  Increasing corticosteroid dose during the seven days prior to initiation of study
             treatment or current dexamethasone or equivalent dose of > 8 mg/day

          -  Prior treatment with a BRAF or MEK inhibitor

          -  For patients assigned to Cohort 1 only: prior immunotherapy in the metastatic setting
             is not allowed. Prior immunotherapy is allowed in the adjuvant setting, provided it is
             completed ≥ 90 days prior to study treatment initiation.

        For patients assigned to Cohort 2 only: prior immunotherapy in either the adjuvant or
        metastatic setting is not allowed.

          -  Major surgical procedure other than for diagnosis within four weeks prior to
             initiation of study treatment, or anticipation of need for a major surgical procedure
             during the course of the study

          -  Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary
             cells or to any formulation component of cobimetinib or atezolizumab or, for patients
             assigned to Cohort 2 only, vemurafenib

          -  Any anti-cancer therapy, including chemotherapy, hormonal therapy and radiotherapy,
             within two weeks prior to initiation of study treatment

          -  Patients assigned to Cohort 2 only: Concomitant treatment with anticonvulsants other
             than gabapentin, vigabatrin and levetiracetam

          -  Patients assigned to Cohort 2 only: acetaminophen is prohibited within seven days
             prior to initiation of study treatment unless the patient has an absolute
             contraindication to the to the use of non-steroidal anti-inflammatory drugs (NSAIDs)
             or aspirin

          -  Active malignancy (other than melanoma) or a prior malignancy within the past three
             years

        General exclusion criteria:

          -  Known risk factors for ocular toxicity

          -  History of clinically significant cardiac dysfunction

          -  Inability to swallow medications

          -  Malabsorption condition that would alter the absorption of orally administered
             medications

          -  Traumatic injury within two weeks prior to initiation of study treatment

          -  Prior allogeneic stem cell or solid organ transplantation

          -  Active or history of autoimmune disease or immune deficiency

          -  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

          -  Uncontrolled diabetes or symptomatic hyperglycaemia

          -  Any Grade ≥ 3 haemorrhage or bleeding event within 28 days of study treatment
             initiation

          -  History of stroke, reversible ischemic neurological defect, or transient ischemic
             attack within six months prior to study treatment initiation

          -  Positive human immunodeficiency virus (HIV) test at screening

          -  Hepatitis B virus (HBV) infection (chronic or acute)

          -  Active hepatitis C virus (HCV) infection

          -  Active tuberculosis

          -  History of severe allergic, anaphylactic or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  Severe infection within four weeks prior to initiation of study treatment

          -  Signs or symptoms of infection within two weeks prior to initiation of study treatment

          -  Any serious medical condition or abnormality in clinical laboratory tests that, in the
             investigator's judgment, precludes the patient's safe participation in, and completion
             of, the study

          -  Any psychological, familial, sociological, or geographical condition that may hamper
             compliance with the protocol and follow-up after treatment discontinuation

          -  Pregnancy, breastfeeding, or intention of becoming pregnant during the study. Women of
             childbearing potential must have a negative serum pregnancy test result within seven
             days prior to initiation of study treatment.

          -  Treatment with therapeutic oral or IV antibiotics within two weeks prior to initiation
             of study treatment

          -  Administration of a live, attenuated vaccine within four weeks prior to initiationof
             study treatment or anticipation of need for such a vaccine during the study

          -  Treatment with systemic immunostimulatory agents within 28 days or 5 half-lives of the
             drug, whichever is shorter, prior to study treatment initiation

          -  Treatment with systemic immunosuppressive medications within two weeks prior to study
             treatment initiation

          -  Treatment with investigational drug within 28 days or 5 half-lives of the drug,
             whichever is longer, prior to initiation of study treatment

          -  For patients to be assigned to Cohort 2 only: anticipated use of any concomitant
             medication during or within seven days prior to initiation of study treatment that is
             known to cause QT prolongation

          -  Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme
             inducers or inhibitors at least seven days prior to initiation of study treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Intracranial Objective Response Rate (ORR)
Time Frame:Up to 48 months
Safety Issue:
Description:Intracranial ORR is defined as the proportion of patients with either a complete response (CR) or a partial response (PR) in their intracranial disease based on two consecutive assessments ≥ 4 weeks apart. Disease status for this endpoint will be determined by an Independent Review Committee (IRC) in accordance with Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) with modified measurability definition for intracranial lesions (≥ 0.5 cm by MRI) and allowing up to five intracranial target lesions. CR is defined as disappearance of all lesions. PR is defined as ≥30% decrease in tumor burden, in the absence of CR.

Secondary Outcome Measures

Measure:Extracranial ORR
Time Frame:Up to 48 months
Safety Issue:
Description:Extracranial ORR, defined as the proportion of patients with either a CR or PR in their extracranial disease based on two consecutive assessments ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1.
Measure:Overall ORR
Time Frame:Up to 48 months
Safety Issue:
Description:Overall ORR, defined as the proportion of patients with either a CR or PR in their overall disease (i.e. including intracranial and extracranial disease) based on two consecutive assessments ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1.
Measure:Progression-Free Survival (PFS)
Time Frame:Up to 48 months
Safety Issue:
Description:Intracranial, extracranial and overall PFS defined as the time from study treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1.
Measure:Duration of Response (DOR)
Time Frame:Up to 48 months
Safety Issue:
Description:Intracranial, extracranial and overall DOR, defined as the time from the first occurrence of a documented objective response based on two consecutive assessments ≥ 4 weeks apart to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1.
Measure:Disease Control Rate (DCR)
Time Frame:Up to 48 months
Safety Issue:
Description:Intracranial, extracranial and overall DCR, defined as the proportion of patients with a CR or PR or stable disease (SD) at 16 weeks from study treatment initiation, as determined by the investigator according to RECIST v1.1. SD is defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for disease progression. Disease progression is defined as ≥20% increase in tumor burden.
Measure:Overall Survival (OS)
Time Frame:Up to 48 months
Safety Issue:
Description:OS is defined as the time from study treatment initiation to death from any cause.
Measure:Time to cognitive symptom deterioration
Time Frame:Up to 48 months
Safety Issue:
Description:Time from study treatment initiation to cognitive symptom deterioration, defined as a change (≥ 10 points on a 0-100 scale) on selected scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-BN20) (visual disorder, motor dysfunction, communication deficit, headaches, seizures and drowsiness).
Measure:Time to symptom and function deterioration
Time Frame:Up to 48 months
Safety Issue:
Description:Time from study treatment initiation to symptom and function deterioration defined as a change (≥ 10 points on a 0-100 scale) in fatigue, physical functioning, cognitive functioning, or role functioning as measured by the Fatigue, Physical, Cognitive, Role Functioning scales of the EORTC QLQ-C30.
Measure:Duration of Stable/Improved Health-related Quality of Life (HRQoL) scores
Time Frame:Up to 48 months
Safety Issue:
Description:Duration of Stable/Improved HRQoL scores as assessed through use of the two-item Global Health Status (GHS)/HRQoL subscale (Questions 29 and 30) of the EORTC QLQ-C30.
Measure:Occurrence and Severity of Adverse Events
Time Frame:Up to 48 months
Safety Issue:
Description:The safety profile of Cobimetinib plus Atezolizumab and Cobimetinib plus Atezolizumab plus Vemurafenib is evaluated in terms of occurrence and severity of AEs. Severity will be determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0)
Measure:Number of participants reporting change from baseline in targeted vital signs
Time Frame:Up to 48 months
Safety Issue:
Description:The safety profile of Cobimetinib plus Atezolizumab and Cobimetinib plus Atezolizumab plus Vemurafenib is evaluated in terms of number of participants reporting change from baseline in targeted vital signs e.g. ECG and blood pressure.
Measure:Number of participants reporting change from baseline in targeted lab values.
Time Frame:Up to 48 months
Safety Issue:
Description:The safety profile of Cobimetinib plus Atezolizumab and Cobimetinib plus Atezolizumab plus Vemurafenib is evaluated in terms of umber of participants reporting change from baseline in targeted lab values.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Hoffmann-La Roche

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