DESCRIPTION OF THE STUDY
Study CO39262 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 previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma.
Approximately 500 previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma will be randomized in a 1:1 ratio after run-in Period to receive treatment with one of the following regimens:
Arm A (control arm):
· Run-in Period (Days 1 - 21): All enrolled patients will receive targeted therapy with vemurafenib (960 mg twice daily [BID] by mouth [PO]) on Days 1-21, plus cobimetinib (60 mg PO once daily [QD]) on Days 1 - 21.
· Run-in Period (Days 22 - 28) Following Randomization: All enrolled patients will receive targeted therapy with vemurafenib (960 mg BID PO) on Days 22-28.
· Cycle 1 and Subsequent 28-day Treatment Cycles: Atezolizumab placebo will be administered intravenously (IV) on Cycle 1 Day 1 and then every two weeks (Q2W) + cobimetinib 60 mg QD on Days 1 - 21 of each 28-day treatment cycle + vemurafenib 960 mg BID on Days 1- 28.
Atezolizumab, Cobimetinib, Vemurafenib—F. Hoffmann-La Roche Ltd
8/Protocol Summary CO39262
· Cycle 1 & Subsequent 28 day Treatment Cycles: Patients in the active arm (blue arrow) will receive atezolizumab administered IV on Cycle 1 Day 1 and then Q2W with cobimetinib 60 mg QD 21/7 on Days 1 - 21 of each 28-day treatment cycle + vemurafenib 720 mg BID + vemurafenib placebo BID.
Arm B (active arm):
· Run-in Period (Days 1 - 21): All enrolled patients will receive targeted therapy with vemurafenib (960 mg BID PO on Days 1-21, plus cobimetinib (60 mg PO QD on Days 1 - 21).
· Run-in Period (Days 22 - 28) Following Randomization: All enrolled patients will receive targeted therapy with vemurafenib 720 mg (three 240 mg tablets)+ one vemurafenib placebo tablet BID PO on Days 22-28.
· Cycle 1 and Subsequent 28-day Treatment Cycles: Atezolizumab will be administered IV at 840 mg on Cycle 1 Day 1 and then Q2W+cobimetinib 60 mg QD on Days 1 - 21+vemurafenib 720 mg BID (three 240 mg tablets)+ one vemurafenib placebo tablet BID on Days 1 - 28 of each 28-day treatment cycle.
A stratified, permuted-block randomization scheme will be used for treatment allocation based on the following stratification factors:
· Geographic region (North America versus Europe versus and Australia/New Zealand/others)
· Metastatic classification (unresectable Stage IIIc, M1a, and M1b, versus M1c)
After signing informed consent, eligible patients will undergo screening procedures that include testing for the BRAF V600 mutation, laboratory tests (hematology, chemistry panel, and liver function tests), 12-lead electrocardiogram (ECG), left ventricular function evaluation (echocardiogram or multigated acquisition [MUGA] scan), contrast-enhanced brain computed tomography (CT) or magnetic resonance imaging (MRI), contrast-enhanced CT or MRI of the chest, abdomen, and pelvis, and ophthalmologic and dermatologic assessments.
NCI CTCAE v4.0 will be used to characterize the toxicity profile of the study treatments on all patients. A dedicated risk management plan will be included in the full protocol and designed to monitor and manage molecule specific and potential combination toxicities.
Tumor response and progression will be evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Any evaluable and measurable disease must be documented at screening and re-assessed at each subsequent tumor evaluation. Response will be assessed by the investigator at 8 week intervals. At the investigator’s discretion, CT/MRI scans may be repeated at any time if progressive disease is suspected. Objective response must be confirmed by repeat assessments ³4 weeks after initial documentation. In the case of stable disease (SD), tumor measurements must have met the SD criteria at least once after study entry at a minimum interval of not fewer than 6 weeks.
At run-in Day 21, all eligible patients will be randomized to treatment in either Arm A (atezolizumab placebo + cobimetinib +vemurafenib) or Arm B (atezolizumab + cobimetinib + vemurafenib +vemurafenib placebo).
Study treatment will continue until confirmed disease progression (as assessed by the investigator according to RECIST Version 1.1), death, unacceptable toxicity, or withdrawal of consent, whichever occurs first. Patients in the control arm are not eligible to crossover to the treatment arm at disease progression and will be followed for survival.
An independent data safety monitoring board (iDSMB) will be used. Key responsibilities will include review of efficacy and safety data on an ongoing basis. Specific methodological and operational details will be specified in the iDSMB charter.