A Phase II Trial of OSI-774 in Patients With Hepatocellular or Biliary Carcinoma

Inclusion Criteria:

- Histologically or cytologically confirmed hepatocellular carcinoma (HCC) or biliary
carcinoma that is surgically unresectable; exception: for surgically unresectable
HCC, a hypervascular mass on CT and an AFP > 100ng/mL will suffice as noninvasive
diagnostic criteria

- Measurable disease defined as at least one lesion whose longest diameter can be
accurately measured as ≥ 2.0 cm

- Absolute neutrophil count (ANC) ≥ 1500/mm3

- PLT ≥ 75,000/mm3

- Total bilirubin ≤ 2 x upper normal limits (UNL)

- Serum AST ≤ 3 x UNL

- Serum ALT ≤ 3 x UNL

- Serum creatinine ≤ 2 mg/dL

- Serum albumin ≥ 2.5 g/dL

- Patients not receiving anticoagulation: INR ≤ 1.5

- ECOG performance status (PS) 0, 1, or 2

- Estimated life expectancy ≥ 3 months

- Capable of understanding the investigational nature, potential risks and benefits of
the study and able to provide written informed consent

- HCC Patients Only: Child-Pugh classification of A or B

- For patients having prior cryotherapy, radiofrequency ablation, ethanol injection, or
photodynamic therapy, the following criteria must be met:

- > 6 weeks has elapsed since that therapy

- Indicator lesion(s) is/are outside the area of prior treatment or, if the only
indicator lesion is inside the prior treatment area, there must be clear
evidence of disease progression associated with that lesion

- Edges of the indicator lesion are clearly distinct on CT scanning

Exclusion Criteria:

- Ampulla of Vater tumors

- Any of the following as this regimen may be harmful to a developing fetus or nursing
child:

- Pregnant women

- Breastfeeding women

- Men or women of childbearing potential or their sexual partners who are
unwilling to employ adequate contraception (condoms, diaphragm, birth control
pills, injections, intrauterine device [IUD], surgical sterilization,
subcutaneous implants, or abstinence, etc.)

- NOTE: The effects of OSI-774 on the developing human fetus at the recommended
therapeutic dose are unknown

- Any of the following:

- > 1 prior systemic anticancer therapy; Note: Chemoembolization will be
considered as one prior chemotherapeutic regimen.

- Prior EGFR targeting therapy

- Nitrosoureas or mitomycin C ≤6 weeks prior to study entry

- Other chemotherapy ≤4 weeks prior to study entry

• Immunotherapy ≤ 4 weeks prior to study entry

- Biologic therapy ≤ 4 weeks prior to study entry

- Radiation therapy ≤ 4 weeks prior to study entry

- Prior cryotherapy, radiofrequency ablation, ethanol injection or photodynamic
therapy ≤6 weeks prior to study entry

- Failure to fully recover from adverse effects of prior therapies regardless of
interval since last treatment

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any other therapy
or supportive care considered investigational

- Major surgery, or significant traumatic injury occurring ≤ 3 weeks prior to
planned treatment start date

- Any of the following:

- Gastrointestinal tract disease resulting in an inability to take oral medication

- Requirement for IV alimentation

- Prior procedures affecting absorption

- Active peptic ulcer disease

- History of other malignancy other than hepatocellular or biliary carcinoma within the
previous 3 years, except for adequately treated basal cell or squamous cell skin
cancer, or carcinoma of the cervix

- Known abnormalities of the cornea such as:

- History of dry eye syndrome or Sjorgen's syndrome

- Congenital abnormality (e.g., Fuch's dystrophy)

- Abnormal slit-lamp examination using a vital dye (e.g., fluorescein,
Bengal-Rose)

- Abnormal corneal sensitivity test (Schirmer test or similar tear production
test)

- Known CNS metastases; NOTE: These patients are excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events

- Uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris, cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study
requirements

- HIV-positive patients receiving combination anti-retroviral therapy; NOTE: Patients
with immune deficiency are at increased risk of lethal infections when treated with
marrow-suppressive therapy; these patients are excluded from the study because of
possible pharmacokinetic interactions with OSI-774; appropriate studies will be
undertaken in patients receiving combination antiretroviral therapy when indicated