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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00321594
• Collaborator: (none)
• Enrollment: 54
• Locations: 2
• Arm: 1
• Duration (Months): 77
• Patients Per Site: 27
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer	Drug: belinostat	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the dose-limiting toxicity (DLT) and establish the maximum tolerated dose (MTD) of PXD101 (belinostat) in patients with unresectable hepatocellular carcinoma (HCC). (Phase

1. 1. 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 Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of PXD101 in Patients With Unresectable Hepatocellular Carcinoma With Pharmacokinetic and Pharmacodynamic Evaluation
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
2	Cancer Therapeutics Research Group	Singapore		Singapore	119074

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Winnie Yeo, Chinese University of Hong Kong-Prince of Wales Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00321594
• Other Study ID Numbers: NCI-2009-00141; CTRG-HC06/21/05; N01CM62205; CDR0000463519; NCT01251445
• First Posted: May 4, 2006
• Last Update Posted: Nov 6, 2017
• Last Verified: Oct 1, 2017

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Belinostat

Study Results

Participant Flow

Arm/Group Title	Phase I, Level 1	Phase I, Level 2	Phase I, Level 3	Phase I, Level 4	Phase II, MTD Dose
Arm/Group Description	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. belinostat: Given IV Dose level: 600 mg/m2/day	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. belinostat: Given IV Dose level: 900 mg/m2/day	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. belinostat: Given IV Dose level: 1200 mg/m2/day	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. belinostat: Given IV Dose level: 1400 mg/m2/day	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. belinostat: Given IV Dose level: 1400 mg/m2/day
Period Title: Phase I, Level 1-4
STARTED	3	3	6	6	0
COMPLETED	3	3	6	6	0
NOT COMPLETED	0	0	0	0	0
Period Title: Phase I, Level 1-4
STARTED	0	0	0	6	36
COMPLETED	0	0	0	6	36
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Phase I	Treatment (Enzyme Inhibitor Therapy)	Total
Arm/Group Description	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. belinostat: Given IV Level 1: Dose: 600mg/m2/day Level 2: Dose: 900mg/m2/day Level 3: Dose: 1200mg/m2/day	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. belinostat: Given IV Dose: 1400mg/m2/day	Total of all reporting groups
Overall Participants	12	42	54
Age (year) [Median (Full Range) ]
Median (Full Range) [year]	54	57.5	56.5
Sex: Female, Male (Count of Participants)
Female	2 16.7%	4 9.5%	6 11.1%
Male	10 83.3%	38 90.5%	48 88.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	12 100%	42 100%	54 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Singapore	2 16.7%	1 2.4%	3 5.6%
United States	0 0%	1 2.4%	1 1.9%
Hong Kong	10 83.3%	34 81%	44 81.5%
South Korea	0 0%	5 11.9%	5 9.3%
Australia	0 0%	1 2.4%	1 1.9%

Outcome Measures

1. Primary Outcome

Title	Dose-limiting Toxicities (DLT) and Maximum Tolerated Dose (MTD) of Belinostat in Patients With Inoperable HCC (Phase I)
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.
Time Frame	Course 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I, Level 1	Phase I, Level 2	Phase I, Level 3	Phase I, Level 4
Arm/Group Description	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. belinostat: Given IV Dose: 600 mg/m2/day	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. belinostat: Given IV Dose: 900 mg/m2/day	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. belinostat: Given IV Dose: 1200mg/m2/day	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. belinostat: Given IV Dose: 1400mg/m2/day
Measure Participants	3	3	6	6
Count of Participants [Participants]	0 0%	0 0%	0 0%	1 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I, Level 1, Phase I, Level 2, Phase I, Level 3, Phase I, Level 4
	Comments	MTD is defined as the dose below which >=2 of 3 or >= 2 of 6 patients experience DLT
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Maximum Tolerated Dose
	Estimated Value	1400
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	MTD was not reached and the maximum dose of 1400 mg/m2 is used in Phase II portion

2. Primary Outcome

Title	Tumor Response in Patients With Inoperable HCC Using Belinostat (Phase II)
Description	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.
Time Frame	Every 2 courses (approximately 6 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase II, MTD
Arm/Group Description	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. belinostat: Given IV Dose: 1400mg/m2/day
Measure Participants	42
Partial Response	1 8.3%
Stable disease	19 158.3%
Progressive disease	22 183.3%

Adverse Events

Time Frame	The adverse event data was assessed during treatment.
Adverse Event Reporting Description	the definition of adverse event and/or serious adverse event is same as clinicaltrials.gov definition The AE were only monitored for participants in Phase II portion.
Arm/Group Title	Phase I, Level 1		Phase 1, Level 2		Phase I, Level 3		Phase I, Level 4		Phase II, MTD
Arm/Group Description	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. belinostat: Given IV Dose: 600 mg/m2/day		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. belinostat: Given IV Dose: 900mg/m2/day		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. belinostat: Given IV Dose: 1200mg/m2/day		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. belinostat: Given IV Dose: 600 to 1400mg/m2/day		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. belinostat: Given IV Dose: 1400mg/m2/day
All Cause Mortality
	Phase I, Level 1		Phase 1, Level 2		Phase I, Level 3		Phase I, Level 4		Phase II, MTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		1/42 (2.4%)
Serious Adverse Events
	Phase I, Level 1		Phase 1, Level 2		Phase I, Level 3		Phase I, Level 4		Phase II, MTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/42 (0%)
Other (Not Including Serious) Adverse Events
	Phase I, Level 1		Phase 1, Level 2		Phase I, Level 3		Phase I, Level 4		Phase II, MTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/42 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.