Clinical trial NCT00724984: Study of the Safety and Tolerability of PCI-24781 in Patients With Lymphoma
Official title: Phase I/II Dose-Escalation Study of the Pan-Histone Deacetylase (HDAC) Inhibitor PCI-24781 in Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Lymphoma
Hodgkin Disease
Lymphoma, Non-Hodgkin
Keywords: PCI-24781
Lymphoma
Hodgkin Disease
Lymphoma, Non-Hodgkin
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Follicular
Lymphoma, B-Cell, Marginal Zone
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Mantle Cell
Lymphoma, T-Cell, Cutaneous
Lymphoma, T-Cell, Peripheral
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
First posted: 2008-07-30
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Phase I (Dose Escalation Phase): MTD and DLTs of PCI-24781 Administered Twice Daily (BID) Measure: Disease Response
timeFrame: From the Date of PCI-24781 first administration to Cycle 2 Day 1
measure: Phase II: Overall Response Rate (CR+PR)
timeFrame: From first response assessment (day 22 to 28 of Cycle 2) to last response assessment on day 22-28 in even-numbered cycles
Secondary outcomes:
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Chicago
country: United States
facility: Northwestern University Medical School
state: Illinois
city: Lafayette
country: United States
facility: Horizon Oncology Center
state: Indiana
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Burlington
country: United States
facility: University of Vermont and Fletcher Allen Health Care
state: Vermont
Study officials:
affiliation: Pharmacyclics LLC.
name: Thorsten Graef, MD
role: STUDY_DIRECTOR
References:
citation: 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. doi: 10.1158/1535-7163.MCT-05-0442.