A Dose-Finding, Safety, And Pharmacokinetic Study Of The Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor OSI-774 (NSC 718781) In Patients With Unresectable Hepatocellular Carcinoma And Moderate Hepatic Dysfunction
A Dose-Finding, Safety, And Pharmacokinetic Study Of The Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor OSI-774 (NSC 718781) In Patients With Unresectable Hepatocellular Carcinoma And Moderate Hepatic Dysfunction
Phase I trial to study the effectiveness of erlotinib in treating patients who have unresectable liver cancer and liver dysfunction. Biological therapies such as erlotinib may interfere with the growth of tumor cells and slow the growth of the tumor
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 more than 2 prior therapies for HCC, including systemic chemotherapy, chemoembolization, hepatic arterial infusion of chemotherapeutic agents, and other novel agents
Measurable disease
Moderate hepatic dysfunction with any of the following:
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