A Phase I/II Study of PXD101 in Patients With Unresectable Hepatocellular Carcinoma With Pharmacokinetic and Pharmacodynamic Evaluation
18 Years
N/A
Both
Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer
Trial Information
A Phase I/II Study of PXD101 in Patients With Unresectable Hepatocellular Carcinoma With Pharmacokinetic and Pharmacodynamic Evaluation
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.
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
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of belinostat in patients with inoperable HCC (Phase I)
Outcome Description:
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.
Outcome Time Frame:
Course 1
Safety Issue:
Yes
Principal Investigator
Winnie Yeo
Investigator Role:
Principal Investigator
Investigator Affiliation:
Chinese University of Hong Kong-Prince of Wales Hospital
Authority:
United States: Food and Drug Administration
Study ID:
NCI-2009-00141
NCT ID:
NCT00321594
Start Date:
May 2006
Completion Date:
Related Keywords:
- Adult Primary Hepatocellular Carcinoma
- Advanced Adult Primary Liver Cancer
- Localized Unresectable Adult Primary Liver Cancer
- Recurrent Adult Primary Liver Cancer
- Carcinoma
- Liver Neoplasms
- Carcinoma, Hepatocellular
Name | Location |
|---|---|
| University of Wisconsin Hospital and Clinics | Madison, Wisconsin 53792-0001 |
