Dose Escalation Study of ARQ 736 in Adult Subjects With Advanced Solid Tumors Harboring BRAF and/or NRAS Mutations

Inclusion Criteria:

• Signed written informed consent granted prior to initiation of any study-specific procedures
• Male or female subjects of ≥ 18 years of age
• All subjects must be positive for a BRAF and/or NRAS mutation
• Histologically or cytologically confirmed locally advanced, inoperable or metastatic solid tumors
• Failure to respond to at least one prior systemic therapy (including previous treatment with BRAF inhibitors) or to whom standard or curative therapy does not exist
• Life expectancy of greater than three months
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors
• Hemoglobin (Hgb) ≥10 g/dl
• Absolute neutrophil count (ANC) ≥1.5 x 10^9/L
• Platelet count ≥100 x 10^9/L
• Total bilirubin ≤1.5 × upper limit of normal (ULN)
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 × ULN (≤5 x ULN for subjects with liver metastases)
• Serum creatinine ≤1.5 × ULN or creatinine clearance >60 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal
• Left Ventricular Ejection Fraction (LVEF) ≥ the institutional lower limit normal (ILLN)
• Male or female subjects of child-producing potential must agree to use double-barrier contraceptive measures, oral contraception or avoidance of intercourse during the study and for 30 days after the last dose of ARQ 736
• Females of childbearing potential must have a negative serum pregnancy test within seven days prior to the first dose of ARQ 736
• Must agree to have tumor and/or skin (nevi) biopsy at baseline and on Day 15 or Day 22 of Cycle 1. Tumor biopsy will be done if the subject has a lesion for which in the Investigator's opinion a non- or minimally invasive tumor biopsy may be performed. If tumor biopsy is not available, skin (nevi) biopsy should be performed.

Exclusion Criteria:

• Anti-cancer chemotherapy, immunotherapy, or investigational agents within four weeks of the first dose of ARQ 736
• Major surgery or radiotherapy within two weeks of the first dose of ARQ 736
• Brain metastases that are progressing or have been documented to be stable for less than six weeks, or for which systemic corticosteroids are required
• History of allergic reactions attributed to compounds of similar chemical or biologic composition as ARQ 736
• Unable or unwilling to swallow the complete daily dose of ARQ 736
• Significant gastrointestinal disorder(s), in the opinion of the Investigator, (e.g., Crohn's disease, ulcerative colitis, extensive gastric resection)
• History of myocardial infarction (MI) within 6 months of the administration of the first dose of ARQ 736 (MI occurring > 6 months of the first dose of ARQ 736 will be permitted)
• History of congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification within 6 months of the administration of the first dose of ARQ 736
• Previous malignancy within 2 years of the first dose of ARQ 736, except carcinoma in-situ of the cervix
• Concurrent uncontrolled illness, including but not limited to:
• Ongoing or active infection, including human immunodeficiency virus (HIV) infection or bleeding
• Psychiatric illness/substance abuse/social situation that would limit compliance with study requirements
• Blood transfusion within five days prior to blood draw being used to confirm eligibility