Conditions: Hodgkin's Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
This study has the following objectives:

Primary Objective

* 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.

Secondary Objective

\- To evaluate the safety and tolerability of multiple courses of ITF2357 followed by Mechlorethamine in a population of chemotherapy pretreated patients.

Detailed description:
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.

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.

Arms:
arm 1: Patients received the following therapy cycle

* ITF2357, 50 mg every 6 hours, per os, days 1 - 3;
* Mechlorethamine, 6 mg/sqm, intravenously , day 4. Therapy was administered every 21 days as long as there was no evidence of progressive disease or unacceptable toxicity, but in any case for a maximum of 12 cycles.

The mean number of complete treatment cycles received by patients was 5.25, with a minimum of 1 cycle and a maximum of 12 cycles.

Interventions: intervention 1: ITF2357
Intervention descriptions: intervention 1: ITF2357, supplied as hard gelatine capsules for oral administration at the strength of 50 mg each.

Protocol document: