Patient case: 64-year-old male with cholangiocarcinoma; genetic feature: BRAF (V600E)

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

Summary: 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.

Eligibility: 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

Relevance to patient case: possibly relevant