Belinostat in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial is studying the side effects and best dose of belinostat and to see how well it works in treating patients with liver cancer that cannot be removed by surgery. Belinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine the dose-limiting toxicity (DLT) and establish the maximum tolerated dose (MTD) of PXD101 (belinostat) in patients with unresectable hepatocellular carcinoma (HCC). (Phase I) II. Assess the pharmacokinetic profiles of PXD101 in these patients. (Phase I) III. Assess tumor response in patients treated with this drug. (Phase II) OUTLINE: This is a multicenter, dose-escalation phase I study followed by a phase II study. PHASE I: Patients receive belinostat intravenously (IV) over 30 minutes on days 1-5. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of belinostat until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. PHASE II: Patients receive belinostat (as in phase I) at the MTD determined in phase I. After completion of study therapy, patients are followed for up to 8 weeks.

Official Title
-----------------
A Phase I/II Study of PXD101 in Patients With Unresectable Hepatocellular Carcinoma With Pharmacokinetic and Pharmacodynamic Evaluation

Conditions
-----------------
Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

Intervention / Treatment
-----------------
* Drug: belinostat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed hepatocellular carcinoma that is not amenable to curative resection Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques OR as ≥ 10 mm with MRI or spiral CT scan No known brain metastases No clinical ascites or encephalopathy Life expectancy > 12 weeks ECOG performance status (PS) 0-2 or Karnofsky PS 60-100% WBC ≥ 3,000/mm³ Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ 1.7 mg/dL Albumin ≥ 2.8 mg/dL ALT ≤ 5.0 times upper limit of normal (ULN) Alkaline phosphatase ≤ 6 times ULN Prothrombin time ≤ 4 sec above ULN Creatinine ≤ 1.6 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients use effective contraception No Child's-Pugh's grading Class C hepatic impairment No history of allergic reaction attributed to compounds of similar chemical or biologic composition to PXD101 No marked baseline prolongation of QT/QTc interval, including the following: Repeated demonstration of a QTc interval > 500 msec Long QT Syndrome No ongoing or active infection No significant cardiovascular disease, including any of the following: Unstable angina pectoris Uncontrolled hypertension Congestive heart failure related to primary cardiac disease Condition requiring anti-arrhythmic therapy Ischemic or severe valvular heart disease Myocardial infarction within the past 6 months No psychiatric illness or social situation that would preclude study compliance No other uncontrolled illness More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered More than 4 weeks since prior radiotherapy and recovered At least 2 weeks since prior valproic acid No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent participation in another investigational study No other concurrent investigational agents No other concurrent anticancer therapy No concurrent use of any of the following: Disopyramide Dofetilide Ibutilide Procainamide Quinidine Sotalol Bepridil Amiodarone Arsenic trioxide Cisapride Calcium channel blockers (e.g., lidoflazine) Clarithromycin Erythromycin Halofantrine Pentamidine Sparfloxacin Domperidone Droperidol Chlorpromazine Haloperidol Mesoridazine Thioridazine Pimozide Methadone

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor therapy)<br>Patients receive belinostat IV over 30 minutes on days 1-5. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. | Drug: belinostat<br>* Given IV<br>* Other names: PXD101;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicities (DLT) and Maximum Tolerated Dose (MTD) of Belinostat in Patients With Inoperable HCC (Phase I) | DLT is defined as any grade 4 hematological toxicity and any grade 3 or 4 non hematological toxicity during cycle 1, excluding alopecia. Specifically, grade 3 nausea, vomiting, or diarrhea that does not respond to therapy is considered dose-limiting. Also, delays in treatment greater than 2 weeks are also dose-limiting. MTD is defined as the dose below which >= 2 of 3 or >= 2 of 6 patients experience DLT. Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. | Course 1 | 
| Tumor Response in Patients With Inoperable HCC Using Belinostat (Phase II) | Evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. The 95% confidence intervals should be provided. | Every 2 courses (approximately 6 weeks) |