Phase II Study of the Histone-deacetylase Inhibitor ITF2357 in Very High-risk 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 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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
to evaluate the efficacy according to the International Working Group response criteria for Hodgkin's lymphomas
every 28 days
Alessandro Massimo Gianni, MD
Istituto Nazionale per lo studio e la cura dei Tumori (Milan - Italy)
Italy: Ministry of Health