RATIONALE: Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial is studying how well lapatinib works in treating patients with locally advanced or metastatic biliary tract or liver cancer that cannot be removed by surgery.

Condition	Treatment or Intervention	Phase
adult primary liver cancer extrahepatic bile duct cancer Gallbladder Cancer unresectable extrahepatic bile duct cancer unresectable gallbladder cancer	Drug: lapatinib  Procedure: enzyme inhibitor therapy  Procedure: protein tyrosine kinase inhibitor therapy	Phase II

Further Study Details: 

OBJECTIVES: Primary

• Determine the objective response rate in patients with locally advanced or metastatic unresectable biliary tract or hepatocellular cancer treated with lapatinib.

Secondary

• Determine the overall survival of patients treated with this drug.
• Determine the quantitative and qualitative toxic effects of this drug in these patients.
• Determine the progression-free survival of patients treated with this drug.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor site (biliary tree cancer [includes ampullary, bile duct, and gall bladder cancer] vs hepatocellular cancer).

Patients receive oral lapatinib once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 34-74 patients (17-37 per stratum) will be accrued for this study within 4.8-24.7 months.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed diagnosis of 1 of the following:
• Biliary cancer (gallbladder, ampullary, or intrahepatic or extrahepatic bile duct cancer)
• Hepatocellular cancer
• Ineligible for percutaneous ethanol injection or radiofrequency ablation (RFA)
• Locally advanced or metastatic disease
• Surgically unresectable disease
• Measurable disease
• At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan
• If patient has undergone prior transarterial chemoembolization (TACE), ethanol injection, or RFA, new lesions must be present in the liver if there is no other site of disease
• Measurable disease outside prior irradiation field OR disease progression within an irradiated field OR new lesion present
• No known brain metastasis

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• More than 12 weeks

Hematopoietic

• WBC ≥ 3,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 75,000/mm^3

Hepatic

• Bilirubin < 2.0 mg/dL
• AST and ALT ≤ 5.0 times upper limit of normal (ULN)
• PT < 4 seconds above ULN (unless taking warfarin)
• No Childs-Pugh class B or C liver disease

Renal

• Creatinine normal OR
• Creatinine clearance ≥ 50 mL/min

Cardiovascular

• Cardiac ejection fraction normal by echocardiogram or MUGA
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Gastrointestinal

• No GI tract disease resulting in an inability to take oral medication
• No malabsorption syndrome
• No requirement for IV alimentation
• No uncontrolled inflammatory GI tract disease (e.g., Crohn’s disease or ulcerative colitis)
• Able to swallow and retain oral medication

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective double barrier or hormonal contraception for at least 1 week before, during, and for at least 2 weeks after study treatment
• No prior allergic reaction to compounds of similar chemical or biologic composition to lapatinib
• No ongoing or active infection
• No other uncontrolled illness
• No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY: Biologic therapy

• No concurrent biologic therapy

Chemotherapy

• See Disease Characteristics
• No more than 1 prior chemotherapy regimen for metastatic or recurrent disease
• TACE is considered 1 regimen
• Prior chemotherapy for earlier stage disease allowed (neoadjuvant, adjuvant, or concurrent with radiotherapy)
• At least 3 weeks since prior chemotherapy and recovered

Endocrine therapy

• At least 14 days since prior and no concurrent dexamethasone or dexamethasone equivalent dose > 1.5 mg/day
• No concurrent hormonal therapy

Radiotherapy

• See Disease Characteristics
• See Chemotherapy
• At least 3 weeks since prior radiotherapy and recovered
• No concurrent radiotherapy to measurable lesions

Surgery

• No prior surgery affecting gastrointestinal (GI) absorption

Other

• No prior epidermal growth factor receptor-targeting therapy
• At least 7 days since prior and no concurrent use of any of the following CYP3A4 inhibitors:
• Clarithromycin
• Erythromycin
• Troleandomycin
• Delaviridine
• Ritonavir
• Indinavir
• Saquinavir
• Nelfinavir
• Amprenavir
• Lopinavir
• Itraconazole*
• Ketoconazole*
• Voriconazole*
• Fluconazole*
• Nefazodone
• Fluvoxamine
• Verapamil
• Diltiazem
• Cimetidine
• Aprepitant
• Grapefruit or grapefruit juice
• Bitter orange NOTE: *Doses ≤ 150 mg/day are allowed
• At least 14 days since prior and no concurrent use of any of the following CYP3A4 inducers:
• Phenytoin
• Carbamazepine
• Phenobarbital
• Efavirenz
• Nevirapine
• Rifampin
• Rifabutin
• Rifapentene
• Hypericum perforatum (St. John’s wort)
• Modafinil
• At least 6 months since prior and no concurrent amiodarone
• Concurrent oral anticoagulants (e.g., warfarin) allowed
• No concurrent antacids 1 hour before or after study drug administration
• No other concurrent gastric pH modifying drugs
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No other concurrent anticancer therapy

California
      City of Hope Comprehensive Cancer Center, Duarte,  California,  91010-3000,  United States; Recruiting
      University of California Davis Cancer Center, Sacramento,  California,  95817,  United States; Recruiting
      USC/Norris Comprehensive Cancer Center and Hospital, Los Angeles,  California,  90033,  United States; Recruiting
Illinois
      University of Chicago Cancer Research Center, Chicago,  Illinois,  60637-1470,  United States; Recruiting
Ohio
      Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University, Cleveland,  Ohio,  44106-5065,  United States; Recruiting
Pennsylvania
      Hillman Cancer Center at University of Pittsburgh Cancer Institute, Pittsburgh,  Pennsylvania,  15232,  United States; Recruiting

Study chairs or principal investigators

Ramesh K. Ramanathan, MD,  Study Chair,  University of Pittsburgh Cancer Institute   

Study ID Numbers:  CDR0000406604; CCC-PHII-53; NCI-6674; PCI-04091; NCT00101036
Record last reviewed:  January 2005
Last Updated:  April 4, 2005
Record first received:  January 7, 2005
ClinicalTrials.gov Identifier:  NCT00101036
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08