A Phase II Study of ZD1839 (Iressa, Gefitinib, NSC 715055) in Advanced Unresectable Hepatocellular Carcinoma
A Phase II Study of ZD1839 (Iressa, Gefitinib, NSC 715055) in Advanced Unresectable Hepatocellular Carcinoma
Phase II trial to study the effectiveness of gefitinib in treating patients who have advanced unresectable hepatocellular carcinoma (liver cancer). Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth
PRIMARY OBJECTIVES:
I. Evaluate the ability of ZD1839 to improve progression free survival in patients with advanced unresectable hepatocellular carcinoma.
II. Evaluate response rate of ZD1839 in advanced unresectable hepatocellular carcinoma.
III. Evaluate the effect of ZD1839 on measurable disease in patients with unresectable hepatocellular carcinoma.
IV. Evaluate the effect of ZD1839 on serum alpha-fetoprotein levels in patients with abnormal pretreatment serum levels.
V. Evaluate toxicity of ZD1839 in advanced unresectable hepatocellular carcinoma.
VI. Investigate biologic markers for outcome in patients with unresectable hepatocellular carcinoma treated with ZD1839.
OUTLINE: This is a multicenter study.
Patients receive oral gefitinib daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Patients are followed for 3 years from study entry.
Inclusion Criteria:
Patients must have advanced unresectable hepatocellular carcinoma based on the following criteria:
Histologically or cytologically confirmed, OR
Alpha-fetoprotein > 400 ng if patient is not hepatitis surface antigen positive, OR
Alpha-fetoprotein > 4000 ng if patient is hepatitis surface antigen positive
Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan, assessed within 4 weeks prior to randomization/registration
Prior use of liver-directed therapy (radio-frequency ablation, cryoablation, percutaneous ethanol injection, chemo-embolization, hepatic artery embolization and hepatic artery infused FUDR) is allowed, provided the patient has either progressive hepatic disease or measurable extrahepatic disease
ECOG performance status of 0, 1 or 2
Leukocytes >= 2,000/uL OR
Absolute neutrophil count >= 1,000/uL
Platelets >= 50,000/uL
Patients may not have Child Pugh Scale's class C cirrhosis
AST (SGOT) =< 5 x institutional upper limit of normal
Total bilirubin =< 2 x institutional upper limit of normal
Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min for patients with creatinine levels above institutional normal
PT =< 6 seconds over control
INR =< 2.3
Albumin >= 2.8 g/dL
Pregnant women are excluded from this study; sexually active women of child bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) for the duration of their participation in the study; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
Women who are breastfeeding a child are not eligible, unless they discontinue the breastfeeding
Patients must not have had prior systemic chemotherapy, biologic therapy or antiangiogenesis therapy; prior therapy with interferon alpha or interferon beta for treatment of hepatitis B or C is allowed provided
Prior palliative radiotherapy is permissible provided it has been completed 2 weeks from registration and the patient has measurable disease outside the radiation field
Patients may not be receiving any other investigational agents
Patients must not have a history of other malignancies that are active and require therapy (other than local therapies for non melanoma skin cancers)
Patients must not have known brain metastases; their poor prognosis would present challenges and their tendency to develop progressive neurologic dysfunction would confound the evaluation of neurologic and other adverse events
Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ZD1839
Patients must not have had prior treatment with an EGFR inhibitor
Patients must not have a history of an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Patients must not be HIV-positive and receiving combination anti-retroviral therapy; this therapy might have possible pharmacokinetic interactions with ZD1839; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated
Patients must not use the following known inducers of CYP3A4: carbamazepine, dexamethasone, ethosuxamide, glucocorticoids, griseofulvin, nafcillin, nelfinavir nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, phenytoin, primidone, progesterone, rifabutin, rifampin, rofecoxib, St John's Wort, sulfadimidine, sulfinpyrazone, troglitazone, efavirenz, modafinil, and rifapentine; drugs that induce CYP3A4 enzymes can cause reductions in ZD1839 plasma concentrations below levels thought to be biologically active
Patients must not be candidates for surgical resection or liver transplantation
Patients must not have grade 3 or grade 4 encephalopathy