A Phase I/II 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 or
who 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 enhancement
pattern of liver tumors on triphasic CT scan or MRI.

- All patients previously exposed to any prior anticancer treatments must have clear
evidence of progressive disease after the most recent treatment regimen (see
Exclusion Criteria).

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

- All patients in both the phase I and phase II portions of this study must have at
least one previously unirradiated, bidimensionally measurable lesion by computerized
tomography (CT) or magnetic resonance imaging (MRI) scan of > 20 mm (if conventional
CT scan) or more than or equal to 10 mm (if spiral CT scan). Triphasic spiral CT or
MRI 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 appropriate
treatment and will be free of progressive neurological deficits in the 28 days prior
to enrollment.

- Patients with cirrhosis must have a Child-Pugh cirrhosis severity classification no
greater than B.

- Baseline performance status must be Eastern Cooperative Oncology Group (ECOG) 0, 1,
or 2.

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

- Women patients who are known to be capable of conception should have a negative serum
pregnancy test (beta-human chorionic gonadotropin [b-hCG]) within 2 weeks of starting
the study; all patients should agree to use adequate non-estrogenic birth control
methods, consistent with the institute’s standard form of contraception if conception
is 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 or
calculated baseline creatinine clearance of 30-50 mL/min should have the starting
dose of capecitabine reduced to 750 mg/m2 BID X 14 days; the dose of PHY906 remains
unchanged. Patients with a baseline creatinine clearance of less than 30 mL/min
should not 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 of
normal (ULN); ALT > 5.0 X study center ULN; albumin < 2.8 g/dL; international
normalized 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; absolute
neutrophil count (ANC) < 1.0 X 10 to the power of 9/L; or platelet count < 50.0 X 10
to the power of 9/L.

- Patients who are pregnant or breastfeeding.

- Any prior radiation therapy (other than small portals used for the palliation of
isolated, symptomatic, osseous metastases) must have been completed more than 21 days
before entry into the study and evaluable lesions must not have been included in the
radiation portal.

- Patients may be either treatment naive or have had previous anticancer treatment; if
previously treated they may not have been exposed to capecitabine and no more than
two prior systemically administered treatment regimens are allowed. It is required
that all treatment be completed no less than 21 days prior to the patient being
treated in this study. Chemoembolization or hepatic resection are not regarded as
systemically administered treatment regimens.

- Any treatment-related toxicity must have resolved within the 21 days prior to study
entry.

- Patients with previous or concurrent malignancy except for inactive non-melanoma skin
cancer and/or in situ carcinoma of the cervix, or other solid tumor treated
curatively and 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 was
completed more than 28 days prior to study entry and if clinical neurologic function
is stable. No patient, however, may enroll in this trial if they are taking
phenytoin (Dilantin). Patients with carcinomatous meningitis, treated or untreated,
are excluded from the study.

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

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

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