A Phase 1/2 Study of the Combination of RDEA119 and Sorafenib in Patients With Advanced Cancer
- 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
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
- 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
- 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
- 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.
- 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
- 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
- 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.