Clinical Trials /

Vemurafenib and Cobimetinib Combination in BRAF Mutated Melanoma With Brain Metastasis

NCT02537600

Description:

The purpose of this study is to determine wether cobimetinib + vemurafenib combination treatment is effective in the treatment of BRAFV600-mutated melanoma patients with brain metastasis

Related Conditions:
  • Cutaneous Melanoma
  • Melanoma of Unknown Primary
  • Mucosal Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Vemurafenib and Cobimetinib Combination in BRAF Mutated Melanoma With Brain Metastasis
  • Official Title: Evaluation of Cobimetinib + Vemurafenib Combination Treatment in Patients With Brain Metastasis BRAFV600 Mutated Cutaneous Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 2013-TL-MEL-Th
  • SECONDARY ID: 2014-001671-30
  • NCT ID: NCT02537600

Conditions

  • Malignant Melanoma

Interventions

DrugSynonymsArms
Cobimetinib + Vemurafenib combination treatmentVemurafenib = Zelboraf (commercial name), Cobimetinib = code number RO5514041/F04Cobimetinib + Vemurafenib combination

Purpose

The purpose of this study is to determine wether cobimetinib + vemurafenib combination treatment is effective in the treatment of BRAFV600-mutated melanoma patients with brain metastasis

Detailed Description

      Patients will be enrolled into 3 cohorts:

        -  Cohort A : Neurologically asymptomatic patients who have not received prior local
           treatment ;

        -  Cohort B. Neurologically asymptomatic patients who have received prior local treatment;

        -  Cohort C. Neurologically symptomatic patients who have or have not received prior local
           treatment Every patients will be treated with Vemurafenib 960 mg PO, twice daily from D1
           to D28, continuously

      Cobimetinib 60 mg PO, once daily, from D1 to D21 - 1 cycle = 28 days

      Treatment will be administered until progression (intracranial or extracranial), unacceptable
      toxicity, withdrawal of consent, death or decision of the treating investigator.

      Patients who develop intracranial or extracranial progression and who, in the opinion of the
      treating investigator, could benefit from continuing treatment may continue treatment with
      vemurafenib and cobimetinib after approval from the principal investigator.

      Patients who discontinue the study treatment will undergo an end-of-treatment visit 30 days
      after the last dose of vemurafenib and/or cobimetinib.

      Patients who discontinue the study treatment for any reason other than progression (e.g.
      toxicity) must be followed up every 8 weeks unless they withdraw their consent.
    

Trial Arms

NameTypeDescriptionInterventions
Cobimetinib + Vemurafenib combinationExperimentalEvery patients will be treated with : Vemurafenib 1920 mg / day from day 1 to day 28 continuously Cobimetinib 60 mg / day from day 1 to day 21 One cycle = 28 days Intervention = Cobimetinib + Vemurafenib combination treatment. Only one arm.
  • Cobimetinib + Vemurafenib combination treatment

Eligibility Criteria

        Inclusion Criteria:

          1. Men and women ≥ 18 years of age.

          2. Histologically confirmed metastatic cutaneous melanoma, mucous melanoma, or melanoma
             of unknown primary origin (stage IV).

          3. Documented BRAFV600 mutation determined in a hospital center specializing in the
             molecular genetics of cancer that is certified by the French national cancer institute
             (INCa).

          4. Presence of Brain Metastases (BM) for which surgical resection is not a reasonable
             treatment option but that may be amenable to treatment with targeted therapy, to be
             decided in the onco-dermatology and/or neuro-oncology multidisciplinary team meeting
             (MDTM).

          5. At least one measurable BM in at least one dimension between 5 and 40 mm on magnetic
             resonance imaging (MRI) with gadolinium (modified RECIST 1.1).

          6. Patients having previously received a maximum of two systemic therapies during the
             metastatic phase, except BRAF, Map ERK Kinase (MEK) or Extracellular signal Regulated
             Kinase (ERK) inhibitors or tyrosine kinase pan-inhibitors (TKIs); prior ipilimumab
             therapy is allowed if patients have documented cerebral progression 12 weeks after the
             last injection of treatment and if MRI confirms progression at least 4 weeks later. A
             period of at least 6 weeks must be observed between the last dose of ipilimumab and
             the first administration of the study treatments. Prior treatment with anti-programmed
             cell death (PD)-1 or anti-PD ligand 1 (PD-L1) is allowed.

          7. For patients who have received prior whole brain radiotherapy or radiosurgery and/or
             surgery for BM (cohorts B and C) demonstration of a significant progression of at
             least one lesion according to RECIST 1.1 criteria, . after at least 4 weeks have
             elapsed since this treatment has ended, and MRI at inclusion must demonstrate a
             significant progression of at least one lesion according to RECIST 1.1 criteria.

          8. Patients with symptomatic or asymptomatic BM.

          9. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

         10. Patients must have recovered from all the side effects (grade ≤ 1 according to the
             National Cancer Institute Common Terminology Criteria for Adverse Events, NCI-Common
             Toxicity Criteria for Adverse Event (CTCAE), version 4.03) of their most recent
             systemic or local treatment (except alopecia).

         11. Signed and dated informed consent before carrying out any procedures that are specific
             to the trial and are not procedures (examinations) conducted as part of normal patient
             care.

         12. Patients willing and able to comply with scheduled visits, treatment schedule,
             laboratory testing and other trial procedures.

         13. Negative serum pregnancy test within 10 days of the first dose of the study treatment
             for women of childbearing age. Women of non-childbearing potential may be included if
             they are surgically sterile or postmenopausal for ≥ 1 year.

         14. Fertile men and women must use an effective method of contraception during treatment
             and for at least 6 months after the last administration of the study treatment.
             Effective methods of contraception are defined as those that have a low failure rate
             (i.e. less than 1% per year) when used consistently and correctly, such as injectable
             implants combined with oral contraception or intra-uterine devices, or as total
             abstinence in cases where the lifestyle of the patient ensures compliance.

         15. Adequate hematologic, renal and hepatic function within 14 days of the administration
             of treatment:

        Hematologic Leucocytes > 2.0 x 109/L Neutrophils > 1.0 x 109/L Hemoglobin (transfusion
        allowed) > 9 g/dL Platelets > 100 x 109/L Liver Total bilirubin < 1.5 x upper limit of
        normal (ULN) (< 3.0 mg/dL for patients with Gilbert syndrome) Aspartate aminotransferase
        (AST) and alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN if there is liver metastasis)
        Alkaline phosphatase (ALP) < 3 x ULN (< 5 x ULN if there is liver or bone metastasis)
        Kidney Creatinine Or creatinine clearance < 1.5 x ULN ≥ 40 mL/min (Cockcroft-Gault formula)

        Exclusion Criteria:

          1. Uveal melanoma. Patients with mucous melanoma or melanoma of unknown primary origin
             are eligible if BRAFV600 mutation is confirmed.

          2. Symptomatic or diffuse leptomeningeal involvement.

          3. Symptoms of uncontrolled intracranial pressure. Increasing corticosteroid dose during
             the 7 days prior to the first dose of the study treatment is an exclusion criterion.
             Patients receiving corticosteroids and patients presenting intermittent seizures may
             be enrolled if the dose of corticosteroids and anti-epileptic treatments has been
             stable for at least 2 weeks before inclusion.

          4. Indication for urgent neurosurgery or radiotherapy.

          5. Prior malignancy active within the previous 3 years except for locally curable cancers
             that have been treated to complete remission or untreated stage I chronic lymphoid
             leukemia.

          6. Known human immunodeficiency virus (HIV) infection.

          7. Prior treatment with BRAF, MEK, or ERK inhibitors or pan-TKIs.

          8. Concurrent administration of any anticancer therapies other than those administered in
             this study.

          9. Treatment with any cytotoxic and/or investigational drug or targeted therapy within 4
             weeks of the first dose of the study treatment, or ipilimumab, anti-PD-1 or anti-PD-L1
             immunotherapy within 8 weeks of the study treatment and/or radiation therapy within 2
             weeks of the study treatment.

         10. Pregnant or breastfeeding women.

         11. Refractory nausea and vomiting, intestinal malabsorption, or significant bowel
             resection that would preclude adequate absorption or cause an inability to swallow
             tablets.

         12. Ulcerative colitis, erosive esophagitis or gastritis, infectious or inflammatory bowel
             disease, diverticula or other gastrointestinal condition increasing the risk of
             perforation.

         13. Any of the following within the 6 months prior to the first dose of study treatment:

               -  myocardial infarction,

               -  severe/unstable angina,

               -  symptomatic congestive heart failure (New York Heart Association grade ≥2),

               -  cerebrovascular accident or transient ischemic attack,

               -  pulmonary embolism,

               -  grade > 2 hypertension not controlled by medications.

         14. History or presence of clinically significant ventricular or atrial arrhythmia ≥ grade
             2 (NCI-CTCAE Version 4.03).

         15. Corrected QT (cQT) interval ≥ 450 ms and left ventricular ejection fraction (LVEF)
             below the lower limit of normal (LLN) or < 50% (scintigraphy or ultrasound).

         16. History, risk factor or retinal pathology that increases the risk of retinal vein
             occlusion (RVO) or central serous retinopathy (CSR): evidence of retinal pathology
             that is considered a risk factor for RVO or CSR, or a history of retinal detachment,
             central serous chorioretinopathy or retinal vein thrombosis. The risk factors for RVO
             are listed below:

               -  Uncontrolled glaucoma with intraocular pressures > 21 mm Hg,

               -  Serum cholesterol ≥ Grade 2 (≥ 7.75 mmol/L),

               -  Hypertriglyceridemia ≥ Grade 2 (≥ 3.42 mmol/L),

               -  Hyperglycemia (fasting) ≥ Grade 2 (≥ 8.9 mmol/L).

         17. Serious or uncontrolled medical disorders that, in the opinion of the investigator,
             may increase the risk associated with study participation or study drug
             administration, impair the ability of the patient to follow the protocol, or interfere
             with the interpretation of study results.

         18. Patients Under guardianship or curators, maintenance of justice, non-informed about
             diagnosis, unable to follow study medical requirement for geographical, social or
             psychic reasons.

         19. Patients with abnormal blood electrolyte test (Ca, Mg, K and Na) that could not be
             corrected.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete or partial intracranial response rate in cohort A on the evaluation of each patient's best tumor response by the centralized review committee according to modified Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria.
Time Frame:From baseline up to 36 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Complete or partial intracranial response rates in cohorts B and C based on the evaluation of each patient's best tumor response by the centralized review committee according to modified RECIST 1.1 criteria.
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Intracranial duration of response (DR) in cohorts A, B and C.
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Overall response rate of cohorts A, B and C
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Overall survival in cohorts A, B and C
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Frequency of Adverse events
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Overall duration of response (DR) in cohorts A, B and C.
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Patient free survival in cohorts A, B and C
Time Frame:Up to 36 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Center Eugene Marquis

Trial Keywords

  • BRAF mutation
  • Brain metastasis
  • Cobimetinib + Vemurafenib combination treatment

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