Clinical Trials /

Study of Neo-adjuvant Use of Vemurafenib Plus Cobimetinib for BRAF Mutant Melanoma With Palpable Lymph Node Metastases

NCT02036086

Description:

This study will evaluate the clinical and pathological response to vemurafenib and cobimetinib in the neoadjuvant treatment of patients with histologically confirmed, BRAF V600 mutation-positive Stage IIIB and C melanoma. 20 patients will be treated with vemurafenib and cobimetinib for 2 months. Then they will be assessed for surgery. Patients will undergo surgery and subsequently resume taking vemurafenib and cobimetinib after recovery from surgery. Patients will undergo radiation therapy if appropriate then continue vemurafenib and cobimetinib. The maximum treatment period is 12 months. After 12 months of treatment, patients will be followed for disease recurrence and survival during for a total of 5 years.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Neo-adjuvant Use of Vemurafenib Plus Cobimetinib for BRAF Mutant Melanoma With Palpable Lymph Node Metastases
  • Official Title: A Pilot Study of the Neo-adjuvant Use of Vemurafenib Plus Cobimetinib (GDC-0973) in Patients With BRAF Mutant Melanoma With Palpable Lymph Node Metastases.

Clinical Trial IDs

  • ORG STUDY ID: ML28606
  • NCT ID: NCT02036086

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
VemurafenibZelborafVemurafenib, pill, twice daily
CobimetinibGDC-0973Vemurafenib, pill, twice daily

Purpose

This study will evaluate the clinical and pathological response to vemurafenib and cobimetinib in the neoadjuvant treatment of patients with histologically confirmed, BRAF V600 mutation-positive Stage IIIB and C melanoma. 20 patients will be treated with vemurafenib and cobimetinib for 2 months. Then they will be assessed for surgery. Patients will undergo surgery and subsequently resume taking vemurafenib and cobimetinib after recovery from surgery. Patients will undergo radiation therapy if appropriate then continue vemurafenib and cobimetinib. The maximum treatment period is 12 months. After 12 months of treatment, patients will be followed for disease recurrence and survival during for a total of 5 years.

Detailed Description

      At Screening: Assessments will include CT or MRI of the brain, CT of chest, abdomen and
      pelvis, dermatology assessment, head and neck exam, pelvic and anal exam, ophthalmology exam,
      electrocardiogram (ECG), echocardiogram (ECHO) or multigated acquisition (MUGA) scan, a
      history and physical exam. A core biopsy will be performed within 14 days of study entry.

      During Treatment: The maximum treatment period is 12 months. Patients will be assessed
      monthly while on treatment. Assessments performed will include vital signs assessment and
      physical exam, dermatology exam, ophthalmology exam, echocardiogram (ECHO) or multigated
      acquisition (MUGA) scan, electrocardiogram (ECG), safety blood tests, pelvic and anal exam.

      Follow-up after treatment: Patients will be followed for 5 years. Radiology exams will be
      done to assess for disease. Other assessments performed include vital signs assessment and
      physical exam, dermatology exam, include echogram (ECHO) or multigated acquisition (MUGA)
      scans.
    

Trial Arms

NameTypeDescriptionInterventions
Vemurafenib, pill, twice dailyExperimentalVemurafenib, 960 mg, oral, twice daily plus Cobimetinib, 60 mg, oral, four times daily
  • Vemurafenib
  • Cobimetinib

Eligibility Criteria

        Inclusion Criteria:

          1. Naïve to treatment for locally advanced unresectable disease (Stage IIIB and C). Prior
             adjuvant therapy (including immunotherapy, e.g., Ipilimumab) is allowed if prior to
             nodal recurrence.

          2. Biopsy proven unresected melanoma with palpable regional lymph node metastases, stage
             IIIB or C or with recurrent regional lymphadenopathy that are not suitable or not
             preferred for surgical intervention.

          3. BRAFV600 mutation positive

          4. Eastern Cooperative Oncology Group performance status of 0 or 1

          5. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

          6. Adequate hematologic, renal and liver function within 7 days prior to the first dose
             of vemurafenib.

          7. Agree to always use an effective form(s) of contraception beginning from the informed
             consent signature date until at least 6 months after completion of study therapy

          8. Negative serum pregnancy test within 14 days prior to start of treatment in women of
             childbearing potential only.

        Exclusion Criteria:

          1. Cannot have received any prior therapy. Previous adjuvant immunotherapy is allowed if
             more than 3 months have elapsed prior to nodal recurrence.

          2. History of prior RAF or MEK pathway inhibitor treatment.

          3. Active malignancy (other than BRAF−mutated melanoma) or a previous malignancy within
             the past 3 years are excluded; except for patients with resected melanoma, resected
             basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected
             melanoma in situ, resected carcinoma in-situ of the cervix, and resected carcinoma
             in-situ of the breast.

          4. Evidence of distant metastatic disease.

          5. History of clinically significant liver disease (including cirrhosis), current alcohol
             abuse, or known infection with Human Immunodeficiency Virus (HIV), hepatitis B virus,
             or hepatitis C virus.

          6. Active infection or chronic infection requiring chronic suppressive antibiotics

          7. Pregnant or breastfeeding

          8. Active autoimmune disease

          9. Acromegaly

         10. History of malabsorption or other clinically significant metabolic dysfunction

         11. Requires a concomitant medication or dietary supplement that is prohibited during the
             study

         12. Current, recent (within 28 days of enrolment) or planned use of any investigational
             product outside of this study

         13. The following foods or supplements are prohibited at least 7 days prior to initiation
             of and during study treatment:

               1. St. John's wort or hyperforin

               2. Grapefruit juice

         14. History of or evidence of retinal pathology on ophthalmologic examination that is
             considered a risk factor for neurosensory retinal detachment / central serous
             chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular
             degeneration.

         15. Risk factors for retinal vein occlusion (RVO) based on the following:

               1. Uncontrolled glaucoma with intra-ocular pressures

               2. Serum cholesterol ≥Grade 2

               3. Hypertriglyceridemia ≥Grade 2

               4. Hyperglycemia (fasting) ≥Grade 2

         16. Clinically significant cardiac dysfunction, including the following:

               1. Current unstable angina

               2. Current symptomatic congestive heart failure of New York Heart Association class
                  2 or higher

               3. History of congenital long QT syndrome or or corrected QT interval greater than
                  450 msec at baseline or uncorrectable abnormalities in serum electrolytes
                  (sodium, potassium, calcium, magnesium, phosphorus).

               4. Current uncontrolled hypertension ≥Grade 2 (patients with a history of
                  hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible).

               5. Left ventricular ejection fraction (LVEF) below institutional lower limit of
                  normal (LLN) or below 50%, whichever is lower

         17. Palliative radiotherapy or major surgery within 14 days prior to first dose of study
             treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The feasibility of treating patients with unresectable melanoma and palpable lymph node metastases that harbor the BRAF mutation with neoadjuvant vemurafenib.
Time Frame:24 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Resectability rates post vemurafenib therapy
Time Frame:5 years
Safety Issue:
Description:
Measure:Local-regional recurrence rates after treatment with neo-adjuvant vemurafenib.
Time Frame:5 years
Safety Issue:
Description:
Measure:Time to distant metastases and Distant Metastatic Free Survival (DMFS).
Time Frame:5 years
Safety Issue:
Description:
Measure:Disease Free Survival (DFS) and Overall Survival (OS).
Time Frame:5 years
Safety Issue:
Description:
Measure:Immunohistochemical correlates of tumor response.
Time Frame:5 years
Safety Issue:
Description:
Measure:Safety and tolerability of vemurafenib in the neoadjuvant setting
Time Frame:5 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sunnybrook Health Sciences Centre

Trial Keywords

  • Melanoma stage IIIB or C with BRAF mutation
  • Recurrent regional lymphadenopathy not suitable for surgery
  • Eligible for neoadjuvant vemurafenib and cobimetinib

Last Updated