Study of the Safety and Tolerability of PCI-24781 in Patients With Lymphoma

Lymphoma Clinical Trial

— PCYC-0403  

Official title:

Phase I/II Dose-Escalation Study of the Pan-Histone Deacetylase (HDAC) Inhibitor PCI-24781 in Lymphoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00724984
• Other study ID #: PCYC-0403
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: July 28, 2008
• Last updated: February 27, 2014
• Start date: July 2008

Study information

• Verified date: February 2014
• Source: Pharmacyclics
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The first part of the study will determine the highest dose of study drug that can be taken without causing serious side effects in patients with lymphoma. The appropriate dose determined from the first part of the study will be used in the second part of the study to assess disease response in 2 different types of lymphoma patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• • age = 18 years

• Phase I: Any measurable, histologically confirmed, and previously treated lymphoma

• Phase II: Measurable, histologically confirmed, and previously treated lymphoma in one of the following categories:

1. Follicular non-Hodgkin's Lymphoma

2. Mantle cell lymphoma

• Ability to swallow oral capsules without difficulty

• Estimated life expectancy > 12 weeks

• ECOG performance status = 1

• Willing and able to sign a written informed consent

Exclusion Criteria:

• • More than four prior systemic treatment regimens (not counting maintenance rituximab; salvage therapy/conditioning regimen preceding autologous bone marrow transplantation [ABMT] and ABMT count as one regimen)

• Allogeneic bone marrow transplant

• Immunotherapy, chemotherapy, radiotherapy or experimental therapy within 4 weeks before first day of study drug dosing

• Major surgery within 4 weeks before first day of study drug dosing

• CNS lymphoma or a history of meningeal carcinomatosis

• Prior treatment with an HDAC inhibitor (unless for treatment of Mycosis fungoides or Sézary syndrome)

• Creatinine > 1.5 x institutional upper limit of normal (ULN) or creatinine clearance = 50 mL/min

• Total bilirubin > 1.5 x institutional ULN (unless elevated from documented Gilbert's syndrome)

• AST and ALT > 2.5 x institutional ULN

• Platelet count < 75,000/µL for Phase I and <100,000>µL for Phase II

• Absolute neutrophil count (ANC) < 1500/µL

• Malabsorption

• Corticosteroids > 20 mg prednisone equivalent per day (topical, inhaled, or nasal corticosteroids are permitted)

• Concurrent therapeutic anticoagulation (Phase I only)

• Uncontrolled illness including but not limited to: ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV heart failure), unstable angina pectoris, cardiac arrhythmia, and psychiatric illness that would limit compliance with study requirements

• Risk factors for, or use of drugs known to prolong QTc interval or that may be associated

• QTc prolongation (defined as a QTc = 450 msecs) or other significant ECG abnormalities including 2nd degree AV block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min). If the screening ECG has a QTc = 450 msecs, the ECG can be submitted for a centralized, cardiologic evaluation.

• History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty and/or stenting within the past 6 months.

• For patients with history of myocardial infarction, congestive heart failure, abnormal left ventricular ejection fraction (LVEF), and/or prior anthracycline exposure, LVEF < 50%, as assessed by ventriculography (nuclear or heart catheterization) or echocardiogram, when performed within 28 days of first dose of study drug.

• For patients with history of coronary artery disease, a cardiac stress test (either exercise or pharmacologic) that demonstrates clinically significant abnormalities when performed within 28 days of first dose of study drug.

• Known HIV infection.

• Other medical or psychiatric illness or organ dysfunction which, in the opinion of the investigator, would either compromise the patient's safety or interfere with the evaluation of the safety of the study agent.

• Pregnant or lactating women (female patients of child-bearing potential must have a negative serum pregnancy test within 14 days of first day of drug dosing, or, if positive, a pregnancy ruled out by ultrasound).

• Women of child-bearing potential, or sexually active men, unwilling to use adequate contraceptive protection during the course of the study.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hodgkin Disease
• Lymphoma
• Lymphoma, Non-Hodgkin

Intervention

Drug:
• PCI-24781
Phase I Dose Escalation: Up to 5 cohorts will receive PCI-24781 orally at doses starting at 30mg/m2 two times a day approximately 4-6 hours apart ("BID"), up to 90mg/m2 administered 5 days/week during the first 21 days of each 28 day cycle until the maximum tolerated dose (MTD) is reached. If a dose limiting toxicity (DLT) occurs, then the next cohort will receive PCI-24781 BID for 7 days every other week (2 times in a 28 day cycle). Phase II Efficacy Evaluation: All patients will receive PCI-24781 orally at the dosage and regimen determined in Phase I.

Locations

Country	Name	City	State
United States	University of Vermont and Fletcher Allen Health Care	Burlington	Vermont
United States	Northwestern University Medical School	Chicago	Illinois
United States	Horizon Oncology Center	Lafayette	Indiana
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of California, San Francisco	San Francisco	California
United States	Washington University School of Medicine	St. Louis	Missouri
United States	University of Massachusetts Medical School	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Pharmacyclics

Country where clinical trial is conducted

United States, 

References & Publications (1)

Buggy JJ, Cao ZA, Bass KE, Verner E, Balasubramanian S, Liu L, Schultz BE, Young PR, Dalrymple SA. CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo. Mol Cancer Ther. 2006 May;5(5):1309-17. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase I (Dose Escalation Phase): MTD and DLTs of PCI-24781 Administered Twice Daily (BID) Measure: Disease Response	Number of patients experienced DLT in each cohort	From the Date of PCI-24781 first administration to Cycle 2 Day 1	Yes
Primary	Phase II: Overall Response Rate (CR+PR)		From first response assessment (day 22 to 28 of Cycle 2) to last response assessment on day 22-28 in even-numbered cycles	No

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