Patient case: 80-year-old male with melanoma; genetic feature: BRAF (V600R)

Clinical trial: Neoadjuvant Vemurafenib + Cobimetinib in Melanoma: NEO-VC

Summary: Evaluation of the efficacy, safety and biologic effects of neo-adjuvant treatment with vemurafenib + cobimetinib in patients with limited metastasis of melanoma in stage IIIC/IV melanoma.

Detailed description: Patients with hardly resectable/unresectable limited metastasis in malignant melanoma stages IIIC/IV (AJCC 2010) carrying the BRAF V600 mutation, in order to achieve operability are enrolled in the NEO-VC-study. The main aim of this study is to achieve operability in a higher percentage of patients by neoadjuvant treatment through shrinkage of the tumors. Patients with operable stage IV disease show an impressive survival benefit with long term (5 y.) survival rates around 30 %. Only a percentage of up to 20 % can presently be treated by complete metastasectomy. This percentage may be enlarged by pre-treatment with an efficacious antitumor drug.

Eligibility: Inclusion Criteria:
  -  Adult patients, ≥ 18 years of age
  -  Willing and able to give informed consent
  -  Metastatic melanoma, stage IIIC or IV (American Joint Committee on Cancer 2010)
  -  ECOG (Eastern Cooperative Oncology Group ): 0-1
  -  MAP-kinase pathway inhibitor treatment-naïve
  -  Positive for BRAF V600 mutation, preferentially to be shown from metastatic tumor tissue
  -  Decision of eligibility for neoadjuvant combined vemurafenib and cobimetinib treatment by interdisciplinary tumor board. Patient with limited numbers of metastases and few organ systems involved should be selected, making surgical resection after neoadjuvant treatment probable.
  -  Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST V1.1) criteria
  -  Adequate hematologic and organ function as defined by:
  -  ANC (absolute neutrophil count ) ≥ 1.5 × 109/L
  -  Platelets ≥ 100 × 109/L
  -  Hemoglobin ≥ 9 g/dL
  -  Albumin ≥ 2.5 g/dL
  -  Bilirubin ≤ 1.5 × the upper limit of normal (ULN)
  -  AST (aspartate aminotransferase), ALT (alanine aminotransferase), and alkaline phosphatase ≤ 3 × ULN, except patients with documented liver metastases:
  AST and/or ALT ≤ 5 × ULN
  -  Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 × ULN
  -  Serum creatinine ≤ 1.5 × ULN
  -  For fertile men: effective contraception during treat-ment and for 6 months after completion in such a manner that the risk of pregnancy is minimized
  -  For women of childbearing potential, negative pregnancy test performed within 28 days prior study enrolment
  Exclusion Criteria:
  -  Candidates for direct surgery: patients with single site easily resectable metastasis
  -  Major surgical procedure or significant traumatic injury within 2 weeks prior to first dose of study drug treatment
  -  Active central nervous system metastases ex-cept metastases after complete resection or stereotactic irradiation and stable status for at least 3 months
  -  History of carcinomatous meningitis
  -  Severe cardiovascular disease within 6 months prior to study drug administration
  -  History or evidence of cardiovascular risk including any of the following
  -  LVEF (left ventricular ejection fraction ) < 50% or < LLN (lower limit of normal), whichever is lower
  -  a QTc (corrected QT interval ) interval > 450 ms
  -  evidence of clinically significant uncontrolled arrhythmias
  -  History or evidence of retinal vein occlusion
  -  Previous malignancy within 5 years prior to study, except for basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix
  -  Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol
  -  Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
  -  Legal incapacity or limited legal capacity
  -  Subjects housed in an institution on official or le-gal orders
  -  Participation in another clinical study with experimental therapy within the 30 days before start of treatment
  -  Pregnancy or lactation period
  -  Concomitant use of study therapy and drugs with a potential for QT prolongation (see database www.qtdrugs.org)
  -  Known immediate or delayed hypersensitivity re-action or idiosyncrasy to cobimetinib and/or vemurafenib and/or to any of its excipients
  -  Patients with diseases that affect liver function, such as viral hepatitis
  -  Patients receiving medications known to increase the risk of peripheral edema

Relevance to patient case: definitely relevant