Clinical trial NCT00321594: Belinostat in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery
Official title: A Phase I/II Study of PXD101 in Patients With Unresectable Hepatocellular Carcinoma With Pharmacokinetic and Pharmacodynamic Evaluation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Adult Primary Hepatocellular Carcinoma
Advanced Adult Primary Liver Cancer
Localized Unresectable Adult Primary Liver Cancer
Recurrent Adult Primary Liver Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-05-04
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Dose-limiting Toxicities (DLT) and Maximum Tolerated Dose (MTD) of Belinostat in Patients With Inoperable HCC (Phase I)
timeFrame: Course 1
measure: Tumor Response in Patients With Inoperable HCC Using Belinostat (Phase II)
timeFrame: Every 2 courses (approximately 6 weeks)
Secondary outcomes:
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Singapore
country: Singapore
facility: Cancer Therapeutics Research Group
Study officials:
affiliation: Chinese University of Hong Kong-Prince of Wales Hospital
name: Winnie Yeo
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.