Dose Escalation Study of ARQ 197 in Combination With Sorafenib in Adult Patients With Advanced Solid Tumors

Inclusion Criteria:

• Written informed consent granted prior to initiation of any study-specific screening procedures
• 18 year of age or older

• Histologically or cytologically confirmed locally advanced, inoperable or metastatic solid tumors. In the two expansion cohorts, only patients with histologically or cytologically confirmed HCC, RCC, breast cancer, NSCLC and melanoma are eligible. An exception for this criterion is that patients with HCC may be enrolled without histological confirmation of disease so long as they meet the following criteria for diagnosis of HCC (and all other protocol eligibility criteria):

  1. Lesion > 2cm in diameter
  2. α-fetoprotein (AFP) > 200 ng/mL
  3. Radiological appearance of mass is suggestive of HCC
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1
• Adequate bone marrow, liver, and renal functions, defined as:
• Platelet count ≥ 100 × 10^9/L (≥ 60 × 10^9/L for HCC patients enrolled in the expanded cohort)
• Hemoglobin ≥ 10 g/dL
• Absolute neutrophil count (ANC) ≥1.5 × 10^9/L
• Total bilirubin ≤ 1.5 mg/dL or ≤ 3 mg/dL with HCC or metastatic liver disease
• Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN with HCC or metastatic liver disease
• Serum creatinine ≤1.5 × ULN
• International normalized ratio (INR) 0.8 to 1.2 or 2 to 3 for patients receiving anticoagulant such as coumadin or heparin. Patients who are therapeutically anticoagulated are allowed to participate provided that no prior evidence of underlying abnormality exists in these parameters
• Women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of study drug
• Male and female subjects of child-bearing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last investigational drug dose received

Exclusion Criteria:

• Previous anti-cancer chemotherapy, radiotherapy, immunotherapy or investigational agents within 4 weeks prior to the first day of study defined treatment with the following exceptions: 1) a prostate cancer patient on androgen deprivation with gonadotropin-releasing hormone (GnRH) agonists can be enrolled while he remains on the immunotherapy; 2) a patient received palliative radiotherapy previous can be enrolled if the therapy was completed 1 week (7 days) prior to the first day of study defined treatment and the patient has recovered from any radiotherapy-related adverse event(s); and 3) patients are currently on sorafenib can be enrolled
• History of cardiac disease: congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification; active coronary artery disease (CAD); previously diagnosed clinically significant bradycardia, other uncontrolled cardiac arrhythmia defined as ≥ Grade 2 according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) (version 3.0), or uncontrolled hypertension; myocardial infarction occurred within 6 months prior to study entry (myocardial infarction occurred > 6 months prior to study entry is permitted)
• Active clinically serious infections defined as ≥ Grade 2 according to NCI CTCAE, version 3.0
• Substance abuse, medical, psychological or social conditions that may, in the opinion of the Investigator, interfere with the patient's participation in the study or evaluation of the study results
• Any condition that is unstable or which could jeopardize the safety of the patient and his/her protocol compliance
• Known human immunodeficiency virus (HIV) infection
• Pregnancy or breast-feeding
• Inability to swallow oral medications
• Significant gastrointestinal disorder, in the opinion of the Investigator, could interfere with the absorption of ARQ 197 and/or sorafenib (e.g. significant, uncontrolled inflammatory bowel disease or extensive small bowel resection).