Most patients with locally advanced or metastatic tumors succumb to their disease. Thus, there is a substantial need for novel therapeutic strategies to improve the outcome for patients with advanced or metastatic melanoma. Targeting the the Ras/Raf signalling pathway by BRAF and MEK inhibition as well as targeting immunologic checkpoint control with an antiPD-L1 antibody have emerged as treatment option. In this study the best timing for sequential use of both treatment options (BRAF/MEK inhibition and antiPD-L1 antibody) in patients with unresectable or metastatic BRAFV600 mutant melanoma will be assessed.
At this time there is no experience concerning the sequencing strategy when using the two effective therapeutical approaches as targeting the Ras/Raf signalling pathway by BRAF and MEK inhibition or targeting immunologic checkpoint control with an antiPD-L1 antibody. This is a prospective, open, multicenter, randomized phase II study in patients with unresectable or metastatic BRAFV600 mutant melanoma. In this study the scheduling of the treatment with a combined BRAF/MEK inhibition and the treatment with an anti-PD-L1 antibody will be assessed. After a 3 months run-in period with vemurafenib and cobimetinib, all patients who did not show disease progression or treatment interruption for more than 28 days during run-in phase will be randomized in a 1:1 ratio: * either to proceed vemurafenib and cobimetinib until disease progression and subsequently cross-over to atezolizumab treatment until disease progression (Arm A). * or to receive the anti-PD-L1 antibody atezolizumab until disease progression and subsequently cross-back to vemurafenib and cobimetinib until disease progression (Arm B). In a translational research program tumor tissue, blood plasma and peripheral blood mononuclear cell will be analyzed to evaluate the biologic effects of treatment sequence on the molecular profile and biomarker expression in tissue and plasma.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
186
960 mg vemurafenib BID until progression or unacceptable toxicity develops
60 mg cobimetinib QD, 21/7 until progression or unacceptable toxicity develops
1200 mg atezolizumab administered intravenously on day 1 of each 21 day-cycle. Will be given until progression or unacceptable toxicity develops
Hôpital Ambroise-Paré
Boulogne-Billancourt, France
Hospital Claude Huriez
Lille, France
Hôpital de la Timone
Marseille, France
CHU de Nantes
Nantes, France
Centre Hospitalier Lyon Sud
Pierre-Bénite, France
National Centre for Tumour Diseases (NCT)
Heidelberg, Baden-Wurttemberg, Germany
SLK-Kliniken Heilbronn GmbH
Heilbronn, Baden-Wurttemberg, Germany
University Hospital Mannheim, Clinic for Dermatology
Mannheim, Baden-Wurttemberg, Germany
University Hospital Essen, Department of Dermatology, Skin Cancer Center
Essen, North Rhine-Westphalia, Germany
HELIOS Klinikum Erfurt
Erfurt, Thuringia, Germany
...and 17 more locations
Time to First Documented Disease Progression
Time to first documented disease progression (PFS1) defined as time from start of run-in phase (date of first intake of study drug) to first documented disease progression date according to RECIST v. 1.1. (PD1) or death by any cause, whichever occurs first.
Time frame: 4 years
Time to Second Objective Disease Progression (PFS2)
Time to second objective disease progression (PFS2) defined as time from start of run-in phase (date of first intake of study drug) to second documented disease progression according to RECIST v. 1.1. (PD2) following randomization or death by any cause.
Time frame: 4 years
Adverse events according to CTCAE Version 4.03 criteria (Safety / Toxicity)
All adverse events according to CTCAE Version 4.03 criteria, and all serious adverse events regardless of causal relationship to the administration of the investigational agents will be assessed
Time frame: Until 90 days of discontinuation of dosing of the investigational product
Overall survival
Overall Survival (OS) of a patient defined as the time from start of run-in phase (date of first intake of study drug) until documented date of death
Time frame: 4 years
Overall survival 12 months
Overall survival rate at 12 months defined as the rate of patients alive 12 months after start of run-in phase (date of first intake of study drug)
Time frame: 1 year
Overall survival 24 months
Overall survival rate at 24 months defined as the rate of patients alive 24 months after start of run-in phase (date of first intake of study drug)
Time frame: 2 years
Overall survival 36 months
Overall survival rate at 36 months defined as the rate of patients alive 36 months after start of run-in phase (date of first intake of study drug)
Time frame: 3 years
Overall survival 48 months
Overall survival rate at 48 months defined as the rate of patients alive 48 months after start of run-in phase (date of first intake of study drug)
Time frame: 4 years
12-months disease control rate (DCR)
DCR is defined as the rate of patients showing complete response (CR) or partial response (PR) or stable disease (SD) at 12 months after start of run-in phase (date of first intake of study drug).
Time frame: 1 year
24-months disease control rate (DCR).
DCR is defined as the rate of patients showing complete response (CR) or partial response (PR) or stable disease (SD) at 24 months after start of run-in phase (date of first intake of study drug).
Time frame: 2 years
Rate of patients with progressive disease who could not cross-over to subsequent line of therapy due to deterioration of ECOG status or multiple and/or symptomatic brain metastases and/or leptomengial disease
* From vemurafenib + cobimetinib to atezolizumab (Arm A) * From atezolizumab to vemurafenib + cobimetinib (Arm B)
Time frame: 4 years
Time from first documented tumor progression until second documented tumor progression
PFS3 definded as time from first documented tumor progression (PD1) until second documented tumor progression (PD2) after randomization or death by any cause, whichever occurs first.
Time frame: 4 years
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