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Evaluating the Efficacy and Safety of a Sequencing Schedule of Cobimetinib Plus Vemurafenib Followed by Immunotherapy With an Anti- PD-L1 Antibody in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

NCT02902029

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Evaluating the Efficacy and Safety of a Sequencing Schedule of Cobimetinib Plus Vemurafenib Followed by Immunotherapy With an Anti- PD-L1 Antibody in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma
  • Official Title: A Phase II, Open-label, Randomized-controlled Trial Evaluating the Efficacy and Safety of a Sequencing Schedule of Cobimetinib Plus Vemurafenib Followed by Immunotherapy With an Anti- PD-L1 Antibody Atezolizumab for the Treatment in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

Clinical Trial IDs

  • ORG STUDY ID: ImmunoCobiVem_2015
  • NCT ID: NCT02902029

Conditions

  • Malignant Melanoma

Interventions

DrugSynonymsArms
VemurafenibArm A
CobimetinibArm A
AtezolizumabArm A

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalAfter a 3 months run-in period with vemurafenib and cobimetinib [960 mg vemurafenib twice daily (BID), 28/0; 60 mg cobimetinib daily (QD), 21/7], all patients who do not show disease progression or definite treatment interruption (e.g. due to unacceptable toxicity) for more than 28 days will be randomized. Further treatment with vemurafenib and cobimetinib (960 mg vemurafenib BID, 28/0; 60 mg cobimetinib QD, 21/7). After progression of disease patients in Arm A will subsequently receive atezolizumab treatment (1200 mg/ q3w).
  • Vemurafenib
  • Cobimetinib
  • Atezolizumab
Arm BExperimentalAfter a 3 months run-in period with vemurafenib and cobimetinib (960 mg vemurafenib BID, 28/0; 60 mg cobimetinib QD, 21/7), all patients who do not show disease progression or definite treatment interruption (e.g. due to unacceptable toxicity) for more than 28 days will be randomized. Further treatment with atezolizumab. Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on day 1 of each 21 day-cycle. After progression of disease patients in Arm B will cross back to vemurafenib and cobimetinib treatment (960 mg vemurafenib BID, 28/0; 60 mg cobimetinib QD, 21/7).
  • Vemurafenib
  • Cobimetinib
  • Atezolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent for the trial.

          -  Male or female patient being ≥18 years of age on day of signing informed consent.

          -  Histologically confirmed diagnosis of locally advanced, unresectable or metastatic
             melanoma AJCC (unresectable stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c) without active
             or untreated brain metastases; all known CNS lesions must have been treated with
             stereotactic therapy or surgery at least 4 weeks prior to the first dose of trial
             treatment AND the patient must be without evidence of clinical or radiographic disease
             progression in the CNS for at least 4 weeks prior to the first dose of trial treatment
             and any neurologic symptoms must have returned to baseline, the patient must have no
             evidence of new or enlarging brain metastases, and the patient must not have used
             steroids for at least 3 weeks prior to trial treatment.

          -  No previous therapy for the advanced or metastatic stage. Prior adjuvant therapy is
             permitted (e.g. Interferon, Interleukin-2-therapy, chemo- or radiotherapy). Prior
             adjuvant therapy has to be terminated (last dose) at least 28 days before enrolment.
             Patients who are in follow-up period of a clinical trial in adjuvant setting and
             progressing may be enrolled / randomized.

          -  Measurable disease, i.e., present with at least one measurable lesion per RECIST,
             version 1.1, for the definition of a measureable lesion.

          -  Presence of BRAF mutation (V600) in tumor tissue.

          -  Performance status of 0 or 1 on the ECOG Performance Scale.

          -  Adequate organ function.

          -  Adequate cardiac function.

          -  Able to take oral medications.

          -  Female subject of childbearing potential should have a negative pregnancy test within
             72 hours prior to receiving the first dose of study medication.

          -  Female patients of childbearing potential and male patients with partners of
             childbearing potential must agree to always use a highly effective form of
             contraception according to CTFG during the course of this study and for at least 6
             months after completion of study therapy.

        Exclusion Criteria:

          -  Use of any investigational or non-registered product within the 30 days before
             registration.

          -  Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form
             of immunosuppressive therapy within 7 days prior to study Day 1.

          -  Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic
             T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other
             antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).

          -  Prior therapy with a BRAF inhibitor (including but not limited to vemurafenib,
             dabrafenib, encorafenib and / or MEK inhibitor

          -  Prior major surgery.

          -  Known additional malignancy that is progressing or requires active treatment within 5
             years prior to the study.

          -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

          -  History of leptomeningeal metastases.

          -  History or current evidence of central serous retinopathy (CSR) or retinal vein
             occlusion (RVO) or predisposing factors to RVO or CSR.

          -  History of retinal degenerative disease.

          -  History of allogenic bone marrow transplantation or organ transplantation.

          -  History of Gilbert's syndrome.

          -  Impaired cardiovascular function or clinically significant cardiovascular diseases.

          -  Uncontrolled arterial hypertension despite medical treatment.

          -  Impairment of gastrointestinal function or gastrointestinal disease.

          -  Evidence of interstitial lung disease or active, non-infectious pneumonitis.

          -  Active infection requiring systemic therapy.

          -  Positive test for Human Immunodeficiency Virus (HIV).

          -  Positive test for Hepatitis B or Hepatitis C.

          -  Known hypersensitivity reaction to any of the components of study treatment.

          -  Medical, psychiatric, cognitive or other conditions, including known alcohol or drug
             abuse.

          -  Patients having received a live, attenuated vaccine within 4 weeks prior to the first
             dose of trial treatment.

          -  Legal incapacity or limited legal capacity.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Time to Second Objective Disease Progression
Time Frame:4 years
Safety Issue:
Description: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 objective disease progression according to RECIST v. 1.1. (PD2) following randomization or death from any cause

Secondary Outcome Measures

Measure:Adverse events according to CTCAE Version 4.0 criteria (Safety / Toxicity)
Time Frame:Until 90 days of discontinuation of dosing of the investigational product
Safety Issue:
Description:All adverse events according to CTCAE Version 4.0 criteria, that are related to the administration of the investigational agents will be assessed
Measure:Overall survival
Time Frame:4 years
Safety Issue:
Description: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
Measure:Overall survival 12 months
Time Frame:1 year
Safety Issue:
Description: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)
Measure:Overall survival 24 months
Time Frame:2 years
Safety Issue:
Description: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)
Measure:12-months disease control rate (DCR)
Time Frame:1 year
Safety Issue:
Description: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).
Measure:24-months disease control rate (DCR).
Time Frame:2 years
Safety Issue:
Description: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).
Measure:Rate of patients with progressive disease who could not cross-over to subsequent line of therapy due to deterioration of ECOG status and/or brain metastases
Time Frame:4 years
Safety Issue:
Description:From run-in phase (vemurafenib + cobimetinib) to study treatment in Arm A or Arm B From vemurafenib + cobimetinib to atezolizumab (Arm A) From atezolizumab to vemurafenib + cobimetinib (Arm B)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Hospital, Essen

Trial Keywords

  • unresectable stage IIIB, IIIC, IV melanoma

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