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

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

Study Overview

• Status: Completed
• Conditions: Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Adult Primary Hepatocellular Carcinoma
• Intervention / Treatment: Drug: belinostat

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.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 119074
    • Cancer Therapeutics Research Group
• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (enzyme inhibitor therapy); 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; Given IV; 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)

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Winnie Yeo, Chinese University of Hong Kong-Prince of Wales Hospital

Publications and helpful links

General Publications

• Yeo W, Chan SL, Mo FK, Chu CM, Hui JW, Tong JH, Chan AW, Koh J, Hui EP, Loong H, Lee K, Li L, Ma B, To KF, Yu SC. Phase I/II study of temsirolimus for patients with unresectable Hepatocellular Carcinoma (HCC)- a correlative study to explore potential biomarkers for response. BMC Cancer. 2015 May 12;15:395. doi: 10.1186/s12885-015-1334-6.
• Wang LZ, Ramirez J, Yeo W, Chan MY, Thuya WL, Lau JY, Wan SC, Wong AL, Zee YK, Lim R, Lee SC, Ho PC, Lee HS, Chan A, Ansher S, Ratain MJ, Goh BC. Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients. PLoS One. 2013;8(1):e54522. doi: 10.1371/journal.pone.0054522. Epub 2013 Jan 30. Erratum In: PLoS One. 2014;9(1). doi:10.1371/annotation/df796504-a2ea-4807-a412-85985bb2550b.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: May 2, 2006
• First Submitted That Met QC Criteria: May 2, 2006
• First Posted (Estimate): May 4, 2006

Study Record Updates

• Last Update Posted (Actual): November 6, 2017
• Last Update Submitted That Met QC Criteria: October 3, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Belinostat
• Other Study ID Numbers: NCI-2009-00141; N01CM62205 (U.S. NIH Grant/Contract); CTRG-HC06/21/05; CDR0000463519 (Registry Identifier: PDQ (Physician Data Query))