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

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ClinicalTrials.gov 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):

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.

Condition or disease Intervention/treatment Phase
Hodgkin's Lymphoma Drug: histone deacetylase inhibitor (ITF2357) Phase 1 Phase 2

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 : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of the Histone-deacetylase Inhibitor ITF2357 in Very High-risk Relapsed/Refractory Hodgkin's Lymphoma Patients
Study Start Date : May 2007
Primary Completion Date : March 2009
Study Completion Date : March 2009

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: ITF2357 Drug: histone deacetylase inhibitor (ITF2357)
50 mg b.i.d. (or every 8 hours or every 6 hours), every day

Primary Outcome Measures :
  1. to evaluate the efficacy according to the International Working Group response criteria for Hodgkin's lymphomas [ Time Frame: every 28 days ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00496431

Istituto Nazionale per lo studio e la cura dei Tumori
Milan, Italy, 20133
Sponsors and Collaborators
Principal Investigator: Alessandro Massimo Gianni, MD Istituto Nazionale per lo studio e la cura dei Tumori (Milan - Italy)

Responsible Party: Italfarmaco
ClinicalTrials.gov Identifier: NCT00496431     History of Changes
Other Study ID Numbers: DSC/07/2357/26
First Posted: July 4, 2007    Key Record Dates
Last Update Posted: May 24, 2013
Last Verified: April 2009

Additional relevant MeSH terms:
Hodgkin Disease
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Histone Deacetylase Inhibitors
Givinostat hydrochloride
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action