Erlotinib in Treating Patients With Unresectable Liver Cancer and Liver Dysfunction

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

Intervention / Treatment
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* Drug: erlotinib hydrochloride
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (erlotinib hydrochloride)<br>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. | Drug: erlotinib hydrochloride<br>* Given PO<br>* Other names: OSI-774;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity and maximum tolerated dose as measured by NCI CTCAE v3.0 continuously |  | 28 days | 
| Pharmacokinetic (PK) and pharmacodynamic profile, as measured by Cmax, Tmax, AUC0-24, AUC0-infinity, Cl/F, T1/2, accumulation ratio, and Cssmin | PK parameters characterized by use of descriptive statistics. Nonparametric statistical test for several unrelated (Kruskal-Wallis ANOVA) or related (Wilcoxon matched-pairs signed-rank test) parameters used. Relationships between drug dose and indices that reflect drug exposure (Cmax, AUC, Cssmin) evaluated with Kruskal-Wallis one-way ANOVA test. Extent of drug exposure (Cmax, AUC, Cssmin) compared among patients with various grades of toxicity using nonparametric statistical tests for two (Mann-Whitney U test) or several (Kruskal-Wallis one-way ANOVA) independent samples. | Days 8-28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rates (partial, complete, stable disease), as measured by CT scans using RECIST criteria | Response rates will be calculated as a proportion of the number of patients who are evaluable using 95% confidence intervals. | Up to 3 years |