Lapatinib Ditosylate in Treating Patients With Unresectable Liver or Biliary Tract Cancer

PRIMARY OBJECTIVES:

I. To evaluate the objective response rate (complete response [CR] + partial response [PR]) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria in each group of patients.

SECONDARY OBJECTIVES:

I. To evaluate the progression free survival at 6 months. II. To evaluate the toxicity profile of this treatment in each group of patients.

III. To evaluate median overall survival, 6 and 12 months survival rates. IV. To assess target-epidermal growth factor receptor (EGFR)/EGFR-P protein expression and the genes that regulate the cell cycle and apoptosis, which are either downstream of or cross-talk with the EGFR signaling pathway, to explore their association with clinical outcome.

V. To measure expression profile and mutations of genes critical for EGFR and (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2 signaling pathways with particular relevance to GW572016, and to explore new gene-drug relationships as relating to hepatocellular and biliary carcinomas.

OUTLINE: This is a multicenter study.

Patients receive oral lapatinib ditosylate 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.

Inclusion criteria

• 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
• Performance status - ECOG 0-1
• Performance status - Karnofsky 60-100%
• More than 12 weeks
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 75,000/mm^3
• 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
• Creatinine ≤ 2 mg/dL
• Ejection fraction normal by echocardiogram or MUGA
• No unstable angina pectoris
• No cardiac arrhythmia
• 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)
• 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
• More than 4 weeks since prior biologic therapy
• More than 4 weeks since prior immunotherapy
• See Radiotherapy
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• No prior cumulative doxorubicin dose > 450 mg/m^2
• At least 14 days since prior and no concurrent glucocorticoids (e.g., dexamethasone or equivalent [dose > 1.5 mg/day])
• 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)
• No prior surgical procedure affecting absorption
• More than 3 weeks since prior major surgery
• 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