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Phase II Trial of the Histone-Deacetylase Inhibitor ITF2357 Followed by Mechlorethamine in Relapsed/Refractory Hodgkin's Lymphoma Patients

Phase 1/Phase 2
18 Years
Not Enrolling
Hodgkin's Lymphoma

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Trial Information

Phase II Trial of the Histone-Deacetylase Inhibitor ITF2357 Followed by Mechlorethamine in Relapsed/Refractory Hodgkin's Lymphoma Patients

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.

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

- 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

- 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

Type of Study:


Study Design:

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

Outcome Measure:

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.

Outcome Time Frame:


Safety Issue:


Principal Investigator

Alessandro Massimo Gianni, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Istituto Nazionale per la Cura e lo Studio dei Tumori, Milano, Italy


Italy: Ministry of Health

Study ID:




Start Date:

February 2008

Completion Date:

September 2010

Related Keywords:

  • Hodgkin's Lymphoma
  • Hodgkin Disease
  • Lymphoma