Erlotinib in Treating Patients With Unresectable Liver Cancer and Liver Dysfunction

PRIMARY OBJECTIVES:

I. Establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of OSI-774 in patients with unresectable hepatocellular carcinoma (HCC) with moderate liver dysfunction.

II. Establish the pharmacokinetic and pharmacodynamic profile of OSI-774 in HCC patients with moderate liver dysfunction.

SECONDARY OBJECTIVES:

I. Assess possible anti-tumor effects of OSI-774 in patients with advanced hepatocellular carcinoma in terms of partial response (PR) and complete response (CR) as assessed by tumor shrinkage by RECIST criteria.

OUTLINE: This is a dose-escalation study.

Patients receive oral erlotinib once daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Inclusion criteria

• Histologically or cytologically confirmed unresectable hepatocellular carcinoma (HCC) with or without extrahepatic metastasis

• No fibrolamellar HCC
• No more than 2 prior therapies for HCC, including systemic chemotherapy, chemoembolization, hepatic arterial infusion of chemotherapeutic agents, and other novel agents
• Measurable disease

• At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR at least 10 mm by spiral CT scan
• Moderate hepatic dysfunction with any of the following:

• Bilirubin 2-4 g/dL
• Albumin < 2.5 g/dL
• Ascites
• PT 2-4 seconds > upper limit of normal (ULN)
• AST/ALT 2.6-10 times > ULN
• No known brain metastases
• No ascites that are refractory to conservative management (e.g., sodium restriction to 50 mEq/day dietary sodium and fluid restrictions and/or diuretics)
• Performance status - ECOG 0-2
• At least 16 weeks
• Granulocyte count ≥ 1,500/mm^3
• Platelet count ≥ 60,000/mm^3
• Hemoglobin ≥ 10 g/dL
• No decompensated liver disease
• No jaundice
• No portosystemic encephalopathy (evidenced by confusion, asterixis, significant sleep disturbance, or hypothermia less than 36º Celsius)
• No hyponatremia < 130 mEq/L
• No portal hypertension with bleeding esophageal or gastric varices within the past 3 months
• Creatinine ≤ 2 mg/dL
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No gastrointestinal tract disease resulting in an inability to take oral medication or requirement for IV alimentation
• No active peptic ulcer disease
• No abnormalities of the cornea (e.g., dry eye syndrome or Sjögren's syndrome)
• No congenital abnormality (e.g., Fuch's dystrophy)
• No significant traumatic injury within the past 21 days
• No other uncontrolled concurrent illness that would preclude study participation
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• At least 4 weeks since prior radiotherapy and recovered
• No prior surgical therapy affecting absorption
• At least 21 days since prior major surgery
• At least 4 weeks since any other prior agents and recovered
• No prior epidermal growth factor-receptor targeting therapies
• No other concurrent investigational agents
• No concurrent combination antiretroviral therapy for HIV-positive patients