RDEA119 and Sorafenib Combination Dose Escalation Study

Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
- Histological or cytological confirmed diagnosis of a solid tumor. In the dose escalation
phase, the tumor must be unresectable and locally advanced, or metastatic, and either no
proven effective therapy exists or the patient cannot tolerate such therapy. Patients
enrolled in the expanded MTD phase of the study must have either HCC or another select
tumor type (melanoma, head and neck, colorectal, breast, or thyroid). For HCC patients in
the expanded MTD phase: - Documentation of original biopsy for diagnosis is acceptable if
tumor tissue is unavailable. Histological confirmation is mandatory for patients without
cirrhosis. - Patients with cirrhosis may have a clinical diagnosis of HCC by the American
Association for the Study of Liver Diseases (AASLD) criteria.-cytotoxic chemotherapy; a
targeted agent, including sorafenib; or other experimental treatment) are eligible. For
non-HCC patients in the expanded MTD phase: - The tumor must be amenable to biopsy and the
patient must be willing to consent to biopsy. - Life expectancy of > 3 months. - Evidence
of measurable disease by RECIST criteria on computer assisted tomography (CT) or magnetic
resonance imaging (MRI). - Normal/adequate swallowing capability, functional small bowel
intact, and no malabsorption problems (in order to maximally quantify PK absorption
characteristics). - Amylase and lipase < or equal to 2 x upper limit of normal (ULN). -
Hemoglobin > or equal to 8.5 g/L. - ANC > or equal to 1,500/mm3. - Platelet count > or
equal to 75,000/mm3. - Total bilirubin < or equal to 1.5 x ULN (For patients with HCC,
refer to criterion number 14). - Aspartate aminotransferase (AST)/alanine aminotransferase
(ALT) < or equal to 2.5 x ULN (< or equal to 5 x ULN for patients with liver involvement).
- PT-INR/PTT < or equal to 1.5 x ULN (Patients who are being prophylactically
anti-coagulated with an agent such as coumadin or low molecular weight heparin (LMWH) or
therapeutically anti-coagulated with LMWH will be allowed to participate provided that
they meet these criteria; in addition, these patients must be monitored at appropriate
intervals throughout the study). - Patients with HCC should have a Child-Pugh score of 5-6
(Class A). - Creatinine < or equal to 1.5 x ULN. - Patients must not be pregnant or
breast-feeding, as chemotherapy is thought to present substantial risk to the
fetus/infant. Men and women of reproductive potential may not participate in this study
unless they have agreed to use an effective contraceptive method while on study. - No
severe or uncontrolled intercurrent illness that in the opinion of the investigator would
adversely impact the safety or efficacy of the treatment. - Ability to understand and
willingness to sign a written informed consent form. - Patients must be within normal
range cardiac function as measured by echocardiogram or multiple-gated acquisition (MUGA)
scan. Exclusion Criteria: - Previous treatment with sorafenib that required a dose
reduction due to toxicity. - Previous treatment with RDEA119. - Patients who have had
cytotoxic chemotherapy or radiotherapy within 4 weeks prior to entering the study, those
who have not recovered from adverse events due to agents administered more than 4 weeks
earlier, those who have concurrent use of cytotoxic chemotherapy not indicated in the
study protocol, or those with use of any other investigational agents < 4 weeks from the
first dose of the study drug. - Previous or concurrent cancer that is distinct in primary
site or histology from the cancer being evaluated in the study except cervical carcinoma
in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any
cancer curatively treated > 3 years prior to study entry. - Swallowing dysfunction and/or
malabsorption syndrome that would impair sorafenib and RDEA119 treatment. - Cardiac
disease: Congestive heart failure > New York Heart Association (NYHA) Class 2. Patients
must not have unstable angina or new onset angina (within the last 3 months) or myocardial
infarction (MI) within the past 6 months. - Cardiac ventricular arrhythmias requiring
anti-arrhythmic therapy. - Uncontrolled hypertension - Known human immunodeficiency virus
(HIV) infection. - Thrombotic or embolic events such as cerebrovascular accident including
transient ischemic attacks within the past 6 months. - Evidence or history of bleeding
diathesis or coagulopathy. - Major surgery, open biopsy or significant traumatic injury
within 4 weeks of first dose of study drug. - The use of inhibitors or inducers of CYP3A4
and CYP2C19 enzymes, as well as the concurrent treatment with any of the agents listed in
Section 3.7 of the protocol. These and other medications that are inhibitors and inducers
of CYP3A4 and CYP2C19 should be discussed with the sponsor. - Patients with known
hypersensitivity to any of the drugs or components given in this protocol. - Patients with
abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess, or small
bowel resection, any of which is within 6 months of study entry. - Patients with abdominal
radiation resulting in chronic diarrhea. - Patients with documented central nervous system
(CNS) metastasis who are not off steroids and other CNS therapies. - Evidence of
uncontrolled active infections except HCV and HBV. - Other serious medical or psychiatric
illness that would not permit the patient to be managed according to the protocol.