ML29255 Neoadjuvant Vemurafenib and Cobimetinib Melanoma

Patients will be included in the study based on the following criteria:

* Signed informed consent
* Histologically confirmed, palpable, regional lymph node metastatic melanoma ≥ 1.5cm (stage IIIB-C; N1b-3) either at initial presentation or at regional lymph node recurrence considered surgically resectable at baseline by the treating medical oncologist and surgical oncologist
* Patients with intransit or satellite metastases with lymph node involvement are allowed if considered surgically resectable at baseline
* Measurable disease per RECIST 1.1
* Melanoma must be documented to contain a BRAFV600 mutation by a CLIA approved laboratory
* No evidence of distant metastasis
* Age ≥ 18 years
* ECOG performance status ≤1
* Adequate bone marrow function as indicated by the following:

  * ANC greater than 1500/µL
  * Platelets ≥ 100,000/µL
  * Hemoglobin greater than 9 g/dL
* Adequate renal function, as indicated by creatinine ≤1.5 x the upper limit of normal (ULN)
* Adequate liver function, as indicated by bilirubin ≤1.5 x ULN
* AST or ALT less than 3 x ULN (patients with documented liver metastases: AST and/or ALT ≤5 x ULN)
* Able to swallow pills
* Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year.
* Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the Investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.)
* Willing and able to undergo biopsy for research purposes
* Willing and able to sign informed consent

Exclusion Criteria:

* Had prior radiotherapy at lymph node basin
* Prior treatment with BRAF inhibitor or MEK inhibitor
* Active infection
* Pregnant, lactating or breast feeding women
* Concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
* History of malabsorption or other condition that would interfere with absorption of vemurafenib or cobimetinib
* Any underlying medical or psychiatric condition, which in the opinion of the Investigator will make the administration of vemurafenib and cobimetinib hazardous
* Unwillingness or inability to comply with study and follow-up procedures.
* The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:

  * St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer)
  * Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor)