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

Phase 1

Completed

Conditions: Adult Primary Hepatocellular Carcinoma
Advanced Adult Primary Liver Cancer
Localized Unresectable Adult Primary Liver Cancer
Recurrent Adult Primary Liver Cancer

Interventions: Drug: belinostat

Registration Number: NCT00321594

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (enzyme inhibitor therapy)	belinostat	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.

Primary Outcome Measures

Name	Time	Method
Dose-limiting Toxicities (DLT) and Maximum Tolerated Dose (MTD) of Belinostat in Patients With Inoperable HCC (Phase I)	Course 1	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.
Tumor Response in Patients With Inoperable HCC Using Belinostat (Phase II)	Every 2 courses (approximately 6 weeks)	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.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (2): Cancer Therapeutics Research Group
🇸🇬
Singapore, Singapore
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States