A Phase I/II Study of PXD101 in Patients With Unresectable Hepatocellular Carcinoma With Pharmacokinetic and Pharmacodynamic Evaluation
A Phase I/II Study of PXD101 in Patients With Unresectable Hepatocellular Carcinoma With Pharmacokinetic and Pharmacodynamic Evaluation
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
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:
No ongoing or active infection
No significant cardiovascular disease, including any of the following:
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: