Dasatinib in Treating Patients With Advanced Liver Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This phase II trial is studying how well dasatinib works in treating patients with advanced liver cancer that cannot be removed by surgery. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the progression-free survival (PFS) rate and response rate (complete and partial response) at 4 months in patients with unresectable advanced hepatocellular carcinoma treated with dasatinib. SECONDARY OBJECTIVES: I. Determine the median PFS and overall survival of patients treated with this drug. II. Assess the toxicity and tolerability of this drug in these patients. OUTLINE: This is a multicenter study. Patients receive oral dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 4 weeks and then every 3-6 months thereafter.

Official Title
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A Phase II Trial of Dasatinib (BMS-354825) in Advanced Hepatocellular Carcinoma

Conditions
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Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

Intervention / Treatment
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* Drug: dasatinib


Participation Criteria
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Eligibility Criteria
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Criteria: WBC >= 3,000/mm^3 LVEF normal Histologically or cytologically confirmed hepatocellular carcinoma; Advanced disease, unresectable disease, no Childs C criteria Measurable disease, defined as >= 1 unidimensionally measurable lesion >= 20 mm by conventional techniques or >= 10 mm by spiral CT scan Not a candidate for percutaneous ethanol injection or radiofrequency ablation (RFA) Prior transarterial chemoembolization, ethanol, and RFA allowed if new lesions are present in the liver and there are no other sites of disease No pleural effusion or ascites requiring paracentesis within the past 4 weeks No known brain metastases ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100% Life expectancy > 3 months Absolute neutrophil count >= 1,500/mm^3 Platelet count >= 75,000/mm^3 Bilirubin =< 2 times upper limit of normal (ULN) AST and ALT =<2.5 times ULN (5 times ULN if liver involvement by tumor) Creatinine =< 2 times ULN PT =< 1.5 times ULN (no anticoagulation) Albumin >= 2.5 mg/dL No history of allergic reactions attributed to compounds of similar chemical or biological composition to dasatinib No evidence of encephalopathy No condition that would preclude ability to swallow and retain dasatinib tablets, including any of the following: Gastrointestinal tract disease resulting in an inability to take oral medication; Requirement for IV alimentation; Prior surgical procedures affecting absorption: Active peptic ulcer disease No clinically significant ECG abnormalities No clinically significant cardiovascular disease, including any of the following: Myocardial infarction or ventricular tachyarrhythmia within the past 6 months; Prolonged QTc >= 480 msec (Fridericia correction); Major conduction abnormality (unless cardiac pacemaker is present) No other uncontrolled illness, including, but not limited to, any of the following: Ongoing or active infection; History of significant bleeding disorder, including congenital (von Willebrand's disease) or acquired disorders (antifactor VIII antibodies); Psychiatric illness or social situation that would preclude study compliance Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Recovered from all prior therapy One prior systemic chemotherapy regimen allowed Prior cryosurgery allowed More than 4 weeks since prior transarterial chemoembolization More than 4 weeks since prior radiotherapy Prior or concurrent localized palliative radiotherapy (i.e., bony metastasis) allowed provided it was administered for =< 3 days At least 7 days since prior and no concurrent antithrombotic and/or antiplatelet agents (e.g., warfarin, heparin, low molecular weight heparin, acetylsalicylic acid, and/or ibuprofen) At least 7 days since prior and no concurrent agents with proarrhythmic potential At least 7 days since prior and no concurrent medications or substances that are potent inhibitors or inducers of CYP3A4 No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent embolization or chemoembolization No concurrent systemic antacids (H2 receptor antagonists or proton pump inhibitors) Locally active antacids allowed provided they are held for 2 hours before and 2 hours after dasatinib dose No other concurrent investigational agents No other concurrent anticancer agents or therapies

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: Oral Dasatinib<br>Patients receive oral dasatinib at 70 mg twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: dasatinib<br>* Given orally<br>* Other names: Sprycel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Complete and Partial Response) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Response = CR + PR | 4 months | 
| Four Month Progression-free Survival (PFS) | Progression-free survival calculated using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival | Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Until disease progression or death, up to 4 years | 
| Overall Survival | Estimated using the product-limit method of Kaplan and Meier. | Up to 4 years | 
| Safety and Tolerability | Summarize observed grade 3 and higher toxicities related to dasatanib. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 were used for reporting. | Up to 4 years |