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.
Active, not recruiting
Phase 3
| Drug | Synonyms | Arms |
|---|---|---|
| Atezolizumab | Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo | |
| Atezolizumab Placebo | Atezolizumab Placebo + Cobimetinib + Vemurafenib | |
| Cobimetinib | Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo | |
| Vemurafenib | Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo | |
| Vemurafenib Placebo | Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo |
| Name | Type | Description | Interventions |
|---|---|---|---|
| Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo | Experimental | 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. |
|
| Atezolizumab Placebo + Cobimetinib + Vemurafenib | Experimental | 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. |
|
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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | 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 33 months) |
| Safety Issue: | |
| Description: | PFS is defined as the time from randomization 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 |
| Measure: | 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 33 months) |
| Safety Issue: | |
| Description: | PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first |
| Measure: | 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 33 months) |
| Safety Issue: | |
| Description: | Objective response is defined as a CR or PR on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1 |
| Measure: | 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 33 months) |
| Safety Issue: | |
| Description: | DOR, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first |
| Measure: | Overall Survival |
| Time Frame: | Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months) |
| Safety Issue: | |
| Description: | OS is defined as the time from randomization to death from any cause |
| Measure: | Percentage of Participants Who Have Survived at 2 Years |
| Time Frame: | 2 years |
| Safety Issue: | |
| Description: | 2-year landmark survival, defined as survival at 2 years |
| Measure: | 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 disease progression or death due to any cause, whichever occurs first (up to approximately 33 months) |
| Safety Issue: | |
| Description: | Time to deterioration in global health status/healthrelated quality of life (GHS/HRQoL), defined as the time from randomization to first observed ≥ 10-point decrease in EORTC QLQ-C30 linearly transformed GHS/HRQoL scale score that is sustained for two consecutive assessments or followed by death while the participant is on treatment. The score range for each EORTC QLQ-C30 scale is from 0 to 100, with higher scores indicating better functioning and better GHS/HRQoL. |
| Measure: | Time to Deterioration in Physical Functioning Using EORTC QLQ-C30 Physical Functioning Scale Score |
| Time Frame: | Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months) |
| Safety Issue: | |
| Description: | Time to deterioration in physical functioning, defined as the time from randomization to first observed ≥ 10-point decrease in EORTC QLQ-C30 linearly transformed physical functioning scale score that is sustained for two consecutive assessments or followed by death while the participant is on treatment. The score range for each EORTC QLQ-C30 scale is from 0 to 100, with higher scores indicating better functioning and better GHS/HRQoL. |
| Measure: | 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 33 months) |
| Safety Issue: | |
| Description: |
| Measure: | 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 33 months)(1 Cycle = 28 days) |
| Safety Issue: | |
| Description: |
| Measure: | Plasma Concentration of Cobimetinib Dose: 20/40 mg |
| 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) |
| Safety Issue: | |
| Description: |
| Measure: | Plasma Concentration of Cobimetinib Dose: 60 mg |
| 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) |
| Safety Issue: | |
| Description: |
| Measure: | 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) |
| Safety Issue: | |
| Description: |
| Measure: | Percentage of Participants Positive for 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 33 months) |
| Safety Issue: | |
| Description: | Presence of ADAs against atezolizumab during the study relative to the presence of ADAs at baseline |
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Hoffmann-La Roche |
November 19, 2020
