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A Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFv600 Mutation-Positive Patients With Metastatic or Unresectable Locally Advanced Melanoma

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ClinicalTrials.gov Identifier: NCT02908672
Recruitment Status : Active, not recruiting
First Posted : September 21, 2016
Last Update Posted : November 25, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE September 19, 2016
First Posted Date  ICMJE September 21, 2016
Last Update Posted Date November 25, 2019
Actual Study Start Date  ICMJE January 13, 2017
Actual Primary Completion Date October 11, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 19, 2016)
Progression-Free Survival (PFS), as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 90 months) ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02908672 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 8, 2018)
  • Progression-Free Survival (PFS), as Determined by Independent Review Committee Using RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 90 months) ]
  • Percentage of Participants With Objective Response, as Determined by Investigator Using RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 90 months) ]
  • Duration of Response, as Determined by Investigator Using RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 90 months) ]
  • Overall Survival [ Time Frame: Baseline up to death due to any cause (up to approximately 90 months) ]
  • Percentage of Participants who Have Survived at 2 Years [ Time Frame: 2 years ]
  • Time to Deterioration in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status Scale Score [ Time Frame: Baseline up to end of treatment (approximately 90 months) ]
  • Time to Deterioration in Physical Functioning Using EORTC QLQ-C30 Physical Functioning Scale Score [ Time Frame: Baseline up to end of treatment (approximately 90 months) ]
  • Percentage of Participants with Adverse Events and Serious Adverse Events [ Time Frame: Baseline up to 6 months after the last dose of study treatment (approximately 90 months) ]
  • Serum Concentration of Atezolizumab [ Time Frame: Pre-infusion Day 1 of Cycles 1-4; 30 minutes post-infusion Day 1 of Cycles 1 and 4; at Atezolizumab discontinuation (up to approximately 90 months)(1 Cycle = 28 days) ]
  • Plasma Concentration of Cobimetinib [ Time Frame: Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days) ]
  • Plasma Concentration of Vemurafenib [ Time Frame: Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days) ]
  • Percentage of Participants With Anti-Drug Antibodies (ADA) to Atezolizumab [ Time Frame: Pre-infusion Day 1 of Cycles 1-4; at Atezolizumab discontinuation (up to approximately 90 months)(1 Cycle=28 days) (approximately up to 90 months) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2016)
  • Progression-Free Survival (PFS), as Determined by Independent Review Committee Using RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 90 months) ]
  • Percentage of Participants With Objective Response, as Determined by Investigator Using RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 90 months) ]
  • Duration of Response, as Determined by Investigator Using RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 90 months) ]
  • Overall Survival [ Time Frame: Baseline up to death due to any cause (up to approximately 90 months) ]
  • Percentage of Participants Who are Alive at Year 2 [ Time Frame: 2 years ]
  • Time to Deterioration in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30) Global Health Status Scale Score [ Time Frame: Baseline up to end of treatment (approximately 90 months) ]
  • Time to Deterioration in Physical Functioning Using EORTC QLQ-30 Physical Functioning Scale Score [ Time Frame: Baseline up to end of treatment (approximately 90 months) ]
  • Percentage of Participants with Adverse Events and Serious Adverse Events [ Time Frame: Baseline up to 6 months after the last dose of study treatment (approximately 90 months) ]
  • Serum Concentration of ATZ [ Time Frame: Pre-infusion (0 hour) and 30 minutes (min) post-infusion (infusion duration=30-60 min) on Day 1 (D1) of Cycles (Cy) 1-4; Pre-infusion on D1 of Cy 8 & every 8 Cy thereafter up to ATZ discontinuation (approximately 90 months overall) (1 Cy=28 days) ]
  • Plasma Concentration of Cobimetinib [ Time Frame: Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days) ]
  • Plasma Concentration of Vemurafenib [ Time Frame: Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days) ]
  • Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to Atezolizumab [ Time Frame: Pre-infusion (0 hour) on D1 of Cy 1-4; Pre-infusion on D1 of Cy 8 & every 8 Cy thereafter up to atezolizumab discontinuation (approximately 90 months overall) (1 Cy=28 days) (approximately up to 90 months) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFv600 Mutation-Positive Patients With Metastatic or Unresectable Locally Advanced Melanoma
Official Title  ICMJE A Phase III, Double-Blinded, Randomized, Placebo-Controlled Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFV600 Mutation-Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma
Brief Summary This is a Phase III, double-blinded, placebo-controlled, randomized, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of atezolizumab + cobimetinib + vemurafenib compared with placebo + cobimetinib + vemurafenib in patients with previously untreated BRAFv600 mutation-positive metastatic or unresectable locally advanced melanoma.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Melanoma
Intervention  ICMJE
  • Drug: Atezolizumab
    Will be administered as per the schedule described in individual arm.
  • Drug: Atezolizumab Placebo
    Will be administered as per the schedule described in individual arm.
  • Drug: Cobimetinib
    Will be administered as per the schedule described in individual arm.
  • Drug: Vemurafenib
    Will be administered as per the schedule described in individual arm.
  • Drug: Vemurafenib Placebo
    Will be administered as per the schedule described in individual arm.
Study Arms  ICMJE
  • Experimental: Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo
    Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
    Interventions:
    • Drug: Atezolizumab
    • Drug: Cobimetinib
    • Drug: Vemurafenib
    • Drug: Vemurafenib Placebo
  • Experimental: Atezolizumab Placebo + Cobimetinib + Vemurafenib
    Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.
    Interventions:
    • Drug: Atezolizumab Placebo
    • Drug: Cobimetinib
    • Drug: Vemurafenib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 20, 2018)
513
Original Estimated Enrollment  ICMJE
 (submitted: September 19, 2016)
500
Estimated Study Completion Date  ICMJE July 29, 2023
Actual Primary Completion Date October 11, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Females of child bearing potential and males with female partners must and use of contraceptive methods with a failure rate of less than or equal to (</=)1% per year is required during treatment and for 6 months post treatment. Males should not expose pregnant partners to sperm and refrain from donating sperm for 6 months post treatment. Women must refrain from donating eggs during this same period
  • Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) melanoma
  • Naive to prior systemic anti-cancer therapy for melanoma (example: chemotherapy, hormonal therapy, targeted therapy, immunotherapy, or other biologic therapies) except adjuvant treatment with interferon (IFN), interleukin (IL)-2, or vaccine therapies or herbal therapies
  • Documentation of BRAFv600 mutation-positive status in melanoma tumor tissue (archival or newly obtained) through use of a clinical mutation test approved by the local health authority
  • Eastern Cooperative Oncology Group Performance (ECOG) Status of 0 or 1
  • Measurable disease according to RECIST v1.1 (must be outside central nervous system (CNS))
  • Life expectancy >/=18 weeks
  • For participants not receiving therapeutic anticoagulation: International normalized ratio (INR) or activated partial thromboplastin time (aPTT) less than or equal to (</=) 1.5*upper limit of normal (ULN) within 28 days prior to initiation of study treatment
  • For participants receiving therapeutic anticoagulation: stable anticoagulant regimen and stable INR during the 28 days immediately preceding initiation of study treatment

Exclusion Criteria:

Cancer-Related Exclusion Criteria:

  • Major surgical procedure within 4 weeks prior study treatment initiation
  • Traumatic injury or palliative radiotherapy within 2 weeks prior study treatment initiation
  • Active malignancy (other than BRAFv600 mutation-positive melanoma) or malignancy within 3 years prior to screening are excluded, with the exception of resected melanoma, resected basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage bladder cancer, or any other curatively treated malignancies from which the participant has been disease-free for at least 3 years

Ocular Exclusion Criteria:

  • History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration

Cardiac Exclusion Criteria:

  • History of clinically significant cardiac dysfunction
  • Left ventricular ejection fraction (LVEF) below the institutional lower limit of normal or below 50%

Central Nervous System (CNS) Exclusion Criteria:

  • Untreated or actively progressing CNS lesions (carcinomatous meningitis)
  • History of metastases to brain stem, midbrain, pons, or medulla, or within 10 millimeter (mm) of the optic apparatus (optic nerves and chiasm); or leptomeningeal metastatic disease; or intracranial hemorrhage

Additional Exclusion Criteria:

  • Uncontrolled diabetes or symptomatic hyperglycemia
  • Current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular, pulmonary, or renal disease) other than cancer
  • History of malabsorption or other clinically significant metabolic dysfunction
  • Pregnant or breastfeeding, or intending to become pregnant during the study
  • Prior allogeneic stem cell or solid organ transplantation
  • History of idiopathic pulmonary fibrosis, organizing pneumonia (example: bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
  • Active or history of autoimmune disease or immune deficiency
  • Known clinically significant liver disease, inherited liver disease and active viral disease
  • Active tuberculosis
  • Treatment with therapeutic oral or intravenous (IV) antibiotics; or with a live, attenuated vaccine; or systemic immunosuppressive medication
  • Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells or any component of the atezolizumab, cobimetinib, or vemurafenib formulations
  • Any grade >/=3 hemorrhage or bleeding event within 4 weeks prior to initiation of study treatment
  • History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to initiation of study treatment
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Brazil,   Canada,   France,   Germany,   Greece,   Hungary,   Israel,   Italy,   Korea, Republic of,   Netherlands,   New Zealand,   Poland,   Portugal,   Russian Federation,   Spain,   United Kingdom,   United States
Removed Location Countries Switzerland
 
Administrative Information
NCT Number  ICMJE NCT02908672
Other Study ID Numbers  ICMJE CO39262
2016-002482-54 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP