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phII Study of an HDAC Inhibitor in Very High-risk Relapsed/Refractory Hodgkin's Lymphoma Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00496431
Recruitment Status : Terminated (ITF2357 (Givinostat) was well tollerated but had limited activity against refractory/relapsed HL)
First Posted : July 4, 2007
Last Update Posted : May 24, 2013
Information provided by (Responsible Party):

Tracking Information
First Submitted Date  ICMJE July 3, 2007
First Posted Date  ICMJE July 4, 2007
Last Update Posted Date May 24, 2013
Study Start Date  ICMJE May 2007
Actual Primary Completion Date March 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 3, 2007)
to evaluate the efficacy according to the International Working Group response criteria for Hodgkin's lymphomas [ Time Frame: every 28 days ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT00496431 on Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE phII Study of an HDAC Inhibitor in Very High-risk Relapsed/Refractory Hodgkin's Lymphoma Patients
Official Title  ICMJE Phase II Study of the Histone-deacetylase Inhibitor ITF2357 in Very High-risk Relapsed/Refractory Hodgkin's Lymphoma Patients
Brief Summary

This is a multi-center, open label, phase II study testing ITF2357 in a population of very high-risk relapsed/refractory Hodgkin's lymphoma patients.

The patients will receive 50 mg ITF2357 four times a day at 6-hour intervals in fed conditions for 28 consecutive days unless evidence of progressive disease, presence of unacceptable adverse events or patient's request to discontinue treatment occurs.

Decision regarding the continuation of ITF2357 will be made on:

  • the basis of tumor reassessment upon completion of cycle defined as above and not later than 7 days and
  • the occurred toxicity (if any). If complete response or partial response or stabilization of disease after first cycle, without concomitant relevant toxicities is observed, the treatment may continue as long as there is no evidence of progressive disease or appearance of unacceptable adverse events. In any case the treatment shall not exceed 84 days of drug intake overall (i.e. 12 weeks).

Treatment will be administered on an outpatient basis and patients will be followed regularly with physical and laboratory tests, as specified in the protocol; in case of hospitalization, the treatment will be continued or interrupted according to the Investigators' decision.

The study will accrue 23 patients evaluable for efficacy and the anticipated duration of the study is about 18 months.

Detailed Description

Histone deacetylases (HDACs) are enzymes involved in the remodeling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypoacetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies.

Hodgkin's lymphoma (HL) is a relatively uncommon lymphoma histotype, with an incidence in Italy of approximately 1700 new cases per year (approximately 12% of all lymphomas). Combination chemotherapy with or without radiotherapy cures approximately 70 percent of advanced-stage HL. Fifty percent of the failing patients can be salvaged by second line chemotherapy (mainly high-dose regimens), while the remaining patients eventually die by disease progression. The development of an effective salvage regimen for this refractory/resistant population represents a true unmet medical need.

The use in the latter patient subset of HDAC inhibitors, like ITF2357, is supported by several considerations. Namely: (1) a chemically related HDACi hydroxamate has shown activity in this clinical condition; (2) the drug markedly inhibits the production of several cytokines, and cytokine production in HL granuloma has a defined role in the pathogenesis of HL; (3) an effective treatment for refractory/relapsed HL is presently lacking; (4) ITF2357, up to 200 mg daily per os, has shown a favorable toxicity profile. All the above mentioned arguments represent a strong rationale prompting the use of ITF2357 in this patient population.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hodgkin's Lymphoma
Intervention  ICMJE Drug: histone deacetylase inhibitor (ITF2357)
50 mg b.i.d. (or every 8 hours or every 6 hours), every day
Study Arms  ICMJE Experimental: ITF2357
Intervention: Drug: histone deacetylase inhibitor (ITF2357)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: February 1, 2012)
Original Estimated Enrollment  ICMJE
 (submitted: July 3, 2007)
Actual Study Completion Date  ICMJE March 2009
Actual Primary Completion Date March 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Signed Informed Consent Form; Age ≥ 18 years; History of histologically confirmed Hodgkin's lymphoma Subjects are eligible for this trial if (1) they have failed at least 1 cycle of chemotherapy, with or without radiotherapy, and if (2) they are considered incurable by the referring physician, and would be treated with second-line or subsequent-line salvage regimens, mainly with palliative intent; Clinical laboratory values ANC > 1500/µL; Platelet count > 75000/µL Hemoglobin > 9 g/dL (may not be transfused or treated with erythropoietin to maintain or exceed this level) Total bilirubin < 1.6 mg/dL; AST or ALT < 2.5 times the upper limit of normal Serum creatinine < 2.0 mg/dL or creatinine clearance > 50 mL/min Serum Potassium and Magnesium within normal limits; Measurable disease (according to the International Working Group response criteria for HL); ECOG performance status of 0 or 1; Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential (use per institutional standard); Life expectancy of > 3 months;; At least 4 weeks since last treatment for HL Willingness and capability to comply with the requirements of the study;

Exclusion Criteria:

Active bacterial or mycotic infection requiring antimicrobial treatment on Day 1; Pregnancy or lactation; A marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval > 450 ms, according to Bazett's correction formula); The use of concomitant medications that prolong the QT/QTc interval;

Clinically significant cardiovascular disease e.g.:

Uncontrolled hypertension, myocardial infarction, unstable angina New York Heart Association (NYHA) Grade II or greater congestive heart failure History of any cardiac arrhythmia requiring medication (irrespective of its severity) Grade II or greater peripheral vascular disease A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome); Positive blood test for HIV, HBV and HCV; Identification of viral DNA by quantitative PCR for EBV (Ebstein Barr virus), JC virus, CMV (Cytomegalovirus) and Herpes Zoster; History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications;

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00496431
Other Study ID Numbers  ICMJE DSC/07/2357/26
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Italfarmaco
Study Sponsor  ICMJE Italfarmaco
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Alessandro Massimo Gianni, MD Istituto Nazionale per lo studio e la cura dei Tumori (Milan - Italy)
PRS Account Italfarmaco
Verification Date April 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP