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Phase II Trial of the Histone-Deacetylase Inhibitor ITF2357 Followed by Mechlorethamine in 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: NCT00792467
Recruitment Status : Completed
First Posted : November 18, 2008
Last Update Posted : February 2, 2012
Information provided by (Responsible Party):

Brief Summary:

This is a single-center, open label, phase II study aimed at testing the activity of multiple cycles of ITF2357 followed by Mechlorethamine administered to patients with relapsed/refractory Hodgkin's lymphoma.

Patients will receive a maximum of twelve 3-week cycles of ITF2357 followed by Mechlorethamine according to the following schema:

  • ITF2357, 50 mg every 6 hours, per os, days 1 - 3
  • Mechlorethamine, 6 mg/sqm, intravenously , day 4

Study therapy will be administered every 21 days as long as there is no evidence of progressive disease or unacceptable adverse events or patient's request to discontinue treatment occurs, but in any case for a maximum of 12 cycles.

Decision regarding the continuation of ITF2357/Mechlorethamine therapy will be made on (i)the basis of tumor reassessment following cycles 2, 6, 9, and 12 and (ii) the occurrence of toxicity. Tumor response will be evaluated according to the International Working Group response criteria HL.

Treatment will be administrated on an outpatient basis and patients will be followed regularly with physical and laboratory tests, as specified in the protocol; in case of hospitalisation, 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 24 months.

Condition or disease Intervention/treatment Phase
Hodgkin's Lymphoma Drug: 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 related hydroxamate, SAHA, 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of the Histone-Deacetylase Inhibitor ITF2357 Followed by Mechlorethamine in Relapsed/Refractory Hodgkin's Lymphoma Patients
Study Start Date : February 2008
Actual Primary Completion Date : July 2010
Actual Study Completion Date : September 2010

Arm Intervention/treatment
Experimental: ITF2357

Patients will receive the following therapy cycle

  • ITF2357, 50 mg every 6 hours, per os, days 1 - 3;
  • Mechlorethamine, 6 mg/sqm, intravenously , day 4. Therapy will be administered every 21 days as long as there is no evidence of progressive disease or unacceptable toxicity, but in any case for a maximum of 12 cycles.
Drug: ITF2357
ITF2357, supplied as hard gelatine capsules for oral administration at the strength of 50 mg each.

Primary Outcome Measures :
  1. To evaluate the anti-lymphoma efficacy of daily oral doses of ITF2357 followed by intravenous Mechlorethamine administered to patients with refractory/relapsed Hodgkin's lymphoma. [ Time Frame: Efficacy ]

Secondary Outcome Measures :
  1. To evaluate the safety and tolerability of multiple courses of ITF2357 followed by Mechlorethamine in a population of chemotherapy pretreated patients [ Time Frame: Safety and tollerability ]

Information from the National Library of Medicine

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

Inclusion Criteria:

  • Written Informed Consent;
  • Age ≥18 years;
  • Histologically confirmed diagnosis of Hodgkin's lymphoma;
  • Subjects who have failed second-line or subsequent-line salvage chemo- radiotherapy regimens for whom no other treatment options of proven efficacy can be given;
  • Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements;
  • 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;
  • Subjects with at least one bi-dimensional lesion measurable by CT-scan or MRI, according to the Revised Response Criteria for Malignant Lymphoma of the International Working Group (J Clin Oncol, 25:579-586, 2007);
  • 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;
  • Life expectancy of >3 months;
  • Subjects receiving intravenous Mechlorethamine (6 mg/sqm) as single agent at least 4 weeks before study entry;
  • Willingness and capability to comply with the requirements of the study.

Exclusion Criteria:

  • Active bacterial or mycotic infection requiring antimicrobial treatment
  • Pregnancy or lactation
  • Anticancer chemotherapy or radiotherapy during the study or within 4 weeks of study entry.
  • A marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval > 450 ms, according to Bazett's correction formula - see appendix I for the formula)
  • Use of concomitant medications that prolong the QT/QTc interval (see appendix H for full list)
  • Clinically significant cardiovascular disease including:
  • 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)
  • 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 and JC virus.
  • History of other diseases, metabolic dysfunctions, physical examination findings, or clinical laboratory findings 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 identifier (NCT number): NCT00792467

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Istituto Nazionale per la Cura e lo Studio dei Tumori
Milano, Italy, 20133
Sponsors and Collaborators
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Principal Investigator: Alessandro Massimo Gianni, MD Istituto Nazionale per la Cura e lo Studio dei Tumori, Milano, Italy

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Responsible Party: Italfarmaco Identifier: NCT00792467    
Other Study ID Numbers: DSC/07/2357/31
First Posted: November 18, 2008    Key Record Dates
Last Update Posted: February 2, 2012
Last Verified: January 2012
Additional relevant MeSH terms:
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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
Alkylating Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents