Erlotinib in Treating Patients With Unresectable Liver Cancer and Liver 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

Study Overview

• Status: Completed
• Conditions: Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Adult Primary Hepatocellular Carcinoma
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Drug: erlotinib hydrochloride

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (erlotinib hydrochloride); 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.

Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: erlotinib hydrochloride; Given PO; Other Names: OSI-774; erlotinib; CP-358,774

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Melanie Thomas, M.D. Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start: August 1, 2002
• Primary Completion (Actual): December 1, 2005

Study Registration Dates

• First Submitted: October 3, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): January 23, 2013
• Last Update Submitted That Met QC Criteria: January 22, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride
• Other Study ID Numbers: NCI-2012-02499; U01CA062461 (U.S. NIH Grant/Contract); ID01-510; CDR0000257666 (Registry Identifier: PDQ (Physician Data Query))