Study of Botanical PHY906 Plus Capecitabine for Advanced Unresectable Hepatocellular Carcinoma

Inclusion Criteria:

• Men or women 18 to 80 years of age with a histologic or cytologic diagnosis of HCC orwho meet all of the following criteria: (a) a-fetoprotein levels > 600 ng/mL; and (b)presence of cirrhosis or chronic hepatitis B or C; and (c) characteristic enhancementpattern of liver tumors on triphasic CT scan or MRI.

• All patients previously exposed to any prior anticancer treatments must have clearevidence of progressive disease after the most recent treatment regimen (see ExclusionCriteria).

• In the phase I (dose finding) and phase II (efficacy) portions of the study, patientsmay either have had no prior chemotherapy (chemotherapy naive), no prior capecitabinechemotherapy, or have been refractory to--or relapsed from--no more than two priorsystemically administered treatment regimens. (Chemoembolization is not regarded inthis context as a systemically administered treatment regimen.)

• All patients in both the phase I and phase II portions of this study must have atleast one previously unirradiated, bidimensionally measurable lesion by computerizedtomography (CT) or magnetic resonance imaging (MRI) scan of > 20 mm (if conventionalCT scan) or more than or equal to 10 mm (if spiral CT scan). Triphasic spiral CT orMRI scans are preferred when such equipment is available. All CT scans should employ a “hepatoma protocol” image capture technique.

• Patients with central nervous system (CNS) involvement will have had appropriatetreatment and will be free of progressive neurological deficits in the 28 days priorto enrollment.

• Patients with cirrhosis must have a Child-Pugh cirrhosis severity classification nogreater than B.

• Baseline performance status must be Eastern Cooperative Oncology Group (ECOG) 0, 1, or

• Life expectancy must be reasonably estimated to be > 12 weeks.

• Women patients who are known to be capable of conception should have a negative serumpregnancy test (beta-human chorionic gonadotropin [b-hCG]) within 2 weeks of startingthe study; all patients should agree to use adequate non-estrogenic birth controlmethods, consistent with the institute’s standard form of contraception if conceptionis possible during the study.

• Provide written informed consent prior to screening.

Exclusion Criteria:

• Patients with an estimated (Cockroft and Gault equation) to the power of 40 orcalculated baseline creatinine clearance of 30-50 mL/min should have the starting doseof capecitabine reduced to 750 mg/m2 BID X 14 days; the dose of PHY906 remainsunchanged. Patients with a baseline creatinine clearance of less than 30 mL/min shouldnot be enrolled in this trial.

• Patients with Child-Pugh cirrhosis severity classification of C.

• Baseline abnormalities in hepatic tests (AST > 5.0 X study center upper limit ofnormal (ULN); ALT > 5.0 X study center ULN; albumin < 2.8 g/dL; internationalnormalized ratio for prothrombin time (INR) > 1.5 X study center ULN; total bilirubin > 3.0 x study center ULN).

• Baseline hemoglobin < 10.0 g/dL; total WBC < 2.0 X 10 to the power of 9/L; absoluteneutrophil count (ANC) < 1.0 X 10 to the power of 9/L; or platelet count < 50.0 X 10to the power of 9/L.

• Patients who are pregnant or breastfeeding.

• Any prior radiation therapy (other than small portals used for the palliation ofisolated, symptomatic, osseous metastases) must have been completed more than 21 daysbefore entry into the study and evaluable lesions must not have been included in theradiation portal.

• Patients may be either treatment naive or have had previous anticancer treatment; ifpreviously treated they may not have been exposed to capecitabine and no more than twoprior systemically administered treatment regimens are allowed. It is required thatall treatment be completed no less than 21 days prior to the patient being treated inthis study. Chemoembolization or hepatic resection are not regarded as systemicallyadministered treatment regimens.

• Any treatment-related toxicity must have resolved within the 21 days prior to studyentry.

• Patients with previous or concurrent malignancy except for inactive non-melanoma skincancer and/or in situ carcinoma of the cervix, or other solid tumor treated curativelyand without evidence of recurrence within the last 3 years prior to study entry.

• Patients with known, untreated brain metastases are ineligible for this trial.Patients with treated (irradiated) brain metastases are eligible if treatment wascompleted more than 28 days prior to study entry and if clinical neurologic functionis stable. No patient, however, may enroll in this trial if they are taking phenytoin (Dilantin). Patients with carcinomatous meningitis, treated or untreated, are excludedfrom the study.

• Patients with uncontrolled metabolic disorders or other nonmalignant organ or systemicdiseases or secondary effects of cancer that induce a high medical risk.

• Patients receiving warfarin (Coumadin), or any of the coumarin-type anticoagulants atany dose, even “mini-dose,” are excluded from this study because of a possibleinterference in their metabolism by capecitabine.

• Known allergy or hypersensitivity to PHY906 or any of the components used in thePHY906 formulations, or to capecitabine.