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

Study Overview
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Brief Summary
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Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase II trial is studying how well lapatinib ditosylate works in treating patients with unresectable liver or biliary tract cancer

Detailed Description
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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.

Official Title
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A Phase II Study of Efficacy and Tolerability of GW572016 in Patients With Advanced Hepatocellular and Biliary Carcinomas

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, Recurrent Extrahepatic Bile Duct Cancer, Recurrent Gallbladder Cancer, Unresectable Extrahepatic Bile Duct Cancer, Unresectable Gallbladder Cancer

Intervention / Treatment
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* Drug: lapatinib ditosylate
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

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: Arm I<br>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. | Drug: lapatinib ditosylate<br> <br> * Other names: Tykerb;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 |
| --- | --- | --- |
| Proportion of Patients Demonstrating Objective Response (PR+CR) as Defined by RECIST | PR (Partial Response) definded as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. CR (Complete Response) is defined as the disappearance of all target lesions. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival |  | up to 6 months | 
| Toxicity Profile Assessed Using NCI CTCAE Version 3.0 | Percentage of patients with Adverse events accordng to NCI CTCAE version 3.0 | Up to 3 years | 
| Median Overall Survival |  | Up to 3 years | 
| Overall Survival |  | up to 12.6 months | 
| Target-EGFR/EGFR-P Protein Expression | EGFR (exons 18-21) | Up to 3 years | 
| Expression Profile and Mutations of Genes Critical for EGFR and ERBB2 Signaling Pathways |  | Up to 3 years |