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

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

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.

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.

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