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A Phase 1 Trial of PXD101 in Combination With 13-cis-Retinoic Acid in Advanced Solid Tumor Malignancies

Phase 1
18 Years
Open (Enrolling)
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase 1 Trial of PXD101 in Combination With 13-cis-Retinoic Acid in Advanced Solid Tumor Malignancies


I. To assess the safety and feasibility of combining PXD101 (belinostat) with
13-cis-retinoic acid [13-cRA] (isotretinoin) in patients with advanced solid tumor

II. To define the maximum tolerated dose (MTD) of PXD101 when administered in combination
with 13-cRA and to describe the toxicities at each dose studied.

III. To evaluate the pharmacokinetics of PXD101 and 13-cRA when given in combination.


I. To demonstrate upregulation of retinoic acid receptor-beta (RARĪ²) and retinoic X-receptor
(RXR) expression in tumor tissues after treatment with PXD101 and 13-cRA.

II. To measure apoptosis in tumor biopsies after treatment. III. To assess the change in
gene expression after exposure to PXD101 and 13-cRA.

IV. To document any clinical activity of the combination of PXD101 and 13-cRA.

OUTLINE: This is a multicenter, dose-escalation study of belinostat.

Patients receive belinostat intravenously (IV) over 30 minutes on days 1-5 and isotretinoin
orally (PO) once daily (QD) on days 1-14. Courses repeat every 21 days in the absence of
disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of PXD101 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 during the first course of therapy.

Once the MTD is determined, an expanded cohort of 10 patients are enrolled and treated at
the MTD. These patients also undergo blood collection periodically during treatment for
pharmacokinetic studies.

All patients undergo blood collection, buccal scrapings, and tumor biopsies periodically for
biomarker, pharmacodynamic, gene expression, and laboratory studies.

After completion of study treatment, patients are followed for >= 8 weeks.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed metastatic or
unresectable solid tumor for which standard curative or palliative measures do not
exist or are no longer effective

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)

- Life expectancy of greater than 3 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min
for patients with creatinine levels above institutional normal

- Eligibility of patients receiving any medications or substances known to affect or
with the potential to affect the activity or pharmacokinetics of belinostat will be
determined following review of their case by the Principal Investigator

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation should a woman become pregnant or suspect she
is pregnant while participating in this study, she should inform her treating
physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to belinostat or other agents used in study

- Patients should not have taken valproic acid, another histone deacetylase inhibitor,
for at least 2 weeks prior to enrollment

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, or psychiatric illness/social situations that would limit compliance with
study requirements

- A marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a
QTc interval > 500 msec; Long QT Syndrome; the required use of concomitant medication
on belinostat infusion days that may cause Torsade de Pointes

- Significant cardiovascular disease including unstable angina pectoris, uncontrolled
hypertension, congestive heart failure related to primary cardiac disease, a
condition requiring anti-arrhythmic therapy, ischemic or severe valvular heart
disease, or a myocardial infarction within 6 months prior to the trial entry

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with belinostat

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of belinostat in combination with isotretinoin determined by dose limiting toxicities graded according to NCI CTCAE 4.0

Outcome Description:

Tables will be created to summarize these toxicities and side effects by dose and by cycle. Tabular and graphical summaries will be used to explore the relationship of type and grade of toxicity to dose, cycle, and pharmacokinetics.

Outcome Time Frame:

21 days

Safety Issue:


Principal Investigator

Thehang Luu

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beckman Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

June 2006

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • Neoplasms



University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania  15213
City of Hope Medical Center Duarte, California  91010
City of Hope Duarte, California  91010
University of Pittsburgh Pittsburgh, Pennsylvania  15261
UC Davis Comprehensive Cancer Center Sacramento, California  95817
University of Southern California Los Angeles, California  90033