Lapatinib in Treating Patients With Unresectable Liver or Biliary Tract Cancer

• Progression-free survival after completion of study treatment [ Designated as safety issue: No ]
• Median overall survival after complection of study treatment [ Designated as safety issue: No ]
• Survival at 6 and 12 months after completion of study treatment [ Designated as safety issue: No ]
• Toxicity every month [ Designated as safety issue: Yes ]

• Progression-free survival after completion of study treatment
• Median overall survival after complection of study treatment
• Survival at 6 and 12 months after completion of study treatment
• Toxicity every month

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 unresectable liver or biliary tract cancer.

OBJECTIVES:

Primary

• Determine the objective response rate (complete response and partial response) in patients with unresectable hepatocellular carcinoma or biliary tract carcinoma treated with lapatinib.

Secondary

• Determine 6-month disease-free survival in patients treated with this drug.
• Determine the toxicity profile of this drug in these patients.
• Determine median overall survival and 6- and 12-month survival rates in patients treated with this drug.
• Correlate target epidermal growth factor receptor gene and protein expression and the genes that regulate cell cycle and apoptosis with clinical outcome in patients treated with this drug.

OUTLINE: This is a multicenter study.

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

PROJECTED ACCRUAL: A total of 70 patients will be accrued for this study within 1 year.

• Extrahepatic Bile Duct Cancer
• Gallbladder Cancer
• Liver Cancer

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:

  • Hepatocellular carcinoma (hepatoma)

    • Child-Pugh classification score ≤ 7
  • Biliary tract carcinoma
• Surgically unresectable disease

• Measurable disease

  • At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan
• Fresh tissue or paraffin embedded tissue from tumor blocks available
• No ampulla of Vater tumors
• No known brain metastases

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1 OR
• Karnofsky 60-100%

Life expectancy

• More than 12 weeks

Hematopoietic

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

Hepatic

• Bilirubin ≤ 2 times upper limit of normal (ULN)
• AST and ALT ≤ 3 times ULN
• Albumin ≥ 2.5 mg/dL
• INR ≤ 1.5 (for patients not receiving an anticoagulant)
• Live metastases or stable chronic liver disease allowed
• No current active hepatic or biliary disease except for Gilbert's syndrome or asymptomatic gallstone

Renal

• Creatinine ≤ 2 mg/dL

Cardiovascular

• Ejection fraction normal by echocardiogram or MUGA
• No unstable angina pectoris
• No cardiac arrhythmia

Gastrointestinal

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

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No significant traumatic injury within the past 3 weeks
• No active or ongoing infection
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to lapatinib
• No psychiatric illness or social situation that would preclude study compliance
• No other uncontrolled illness
• No other malignancy within the past 3 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 4 weeks since prior biologic therapy
• More than 4 weeks since prior immunotherapy

Chemotherapy

• See Radiotherapy
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• No prior cumulative doxorubicin dose > 450 mg/m^2

Endocrine therapy

• At least 14 days since prior and no concurrent glucocorticoids (e.g., dexamethasone or equivalent [dose > 1.5 mg/day])

Radiotherapy

• More than 4 weeks since prior radiotherapy
• More than 12 weeks since prior radiotherapy with or without a fluoropyrimidine as a radiosensitizer (for patients with biliary carcinoma only)

Surgery

• No prior surgical procedure affecting absorption
• More than 3 weeks since prior major surgery

Other

• Recovered from all prior therapy
• No more than 1 prior systemic anticancer therapy, including chemoembolization
• No prior epidermal growth factor receptor-targeting therapy

• More than 6 weeks since prior cryotherapy, radiofrequency ablation, ethanol injection, transarterial chemoembolization, or photodynamic therapy AND meets both of the following criteria:

  • Indicator lesion is outside the area of prior treatment OR there is clear evidence of disease progression associated with the sole indicator lesion
  • Edges of indicator lesion are clearly distinct by CT scan

• At least 7 days since prior and no concurrent H2 inhibitors or proton pump inhibitors

  • Concurrent antacids allowed provided they are administered > 1 hour before and > 1 hour after study drug administration

• At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the following:

  • Clarithromycin
  • Erythromycin
  • Troleandomycin
  • Delaviridine
  • Ritonavir
  • Indinavir
  • Saquinavir
  • Nelfinavir
  • Amprenavir
  • Lopinavir
  • Itraconazole
  • Ketoconazole
  • Voriconazole
  • Fluconazole (doses ≤ 150 mg/day are allowed)
  • Nefazodone
  • Fluvoxamine
  • Verapamil
  • Diltiazem
  • Cimetidine
  • Aprepitant
  • Grapefruit and grapefruit juice
  • Bitter orange
• At least 6 months since prior and no concurrent amiodarone

• At least 14 days since prior and no concurrent CYP3A4 inducers, including any of the following:

  • Phenytoin
  • Carbamazepine
  • Phenobarbital
  • Oxcarbazepine
  • Efavirenz
  • Nevirapine
  • Rifampin
  • Rifabutin
  • Rifapentine
  • Roxithromycin
  • Telithromycin
  • Hypericum perforatum (St. John's wort)
  • Modafinil
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No other concurrent anticancer therapy
• Concurrent oral anticoagulants (e.g., coumadin or warfarin) allowed provided there is increased vigilance in monitoring INR