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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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.
Alessandro Massimo Gianni, MD
Istituto Nazionale per la Cura e lo Studio dei Tumori, Milano, Italy
Italy: Ministry of Health