A Phase II Multiple Dose Clinical Trial of Histone Deacetylase Inhibitor ITF2357 in Patients with Relapsed or Progressive Multiple Myeloma: Preliminary Results.

Multiple myeloma (MM) is an incurable disease due to the neoplastic proliferation of plasma cells. Histone deacetylase (HDAC) inhibitors are a novel class of agents that can induce tumour cell growth arrest, differentiation and/or apoptosis in vitro and inhibit tumour growth in animals. ITF2357, an orally effective member of the family of HDAC inhibitors, is a potent inducer of apoptosis and death of MM cells (Golay et al. Leukemia, 2007). It has also a potent inhibitory activity on secretion of pro-inflammatory cytokines by stromal and mesenchimal stem cells. For these properties, ITF2357 has been given safely to patients with Crohn’s disease and plaque psoriasis as an anti-inflammatory drug. We report the preliminary results of a phase II multiple dose clinical trial of oral ITF2357 in patients with relapsed or progressive MM, who had received at least two previous lines of treatment. Primary endpoint was to determine the maximum tolerated dose of ITF2357 administered every 12 hours for 4 consecutive days followed by 3 days of rest every week during the first cycle (i.e., first 4 weeks). Up to 12 weeks of treatment with ITF2357 were scheduled. Concomitant oral dexamethasone was given at a maximum dose of 20 mg every week. Fifteen patients (aged 52–77 years) have been enrolled so far. The first 6 patients received 150 mg ITF2357 every 12 hours for 4 consecutive days every week. Because 2 of them experienced a grade 3 gastro-intestinal toxicity (diarrhea) during the first cycle, the subsequent 9 patients received 100 mg ITF2357 every 12 hours with the same weekly schedule. None of them experienced a dose-limiting toxicity during the first cycle. The median duration of treatment was 7 weeks, range from 2 (1 patient) to 12 weeks (5 patients). Thrombocytopenia(≥ grade 2) was the most common side effect, which we observed in 11 cases: grade 4 thrombocytopenia occurred in 4 patients. Grade 3–4 gastro-intestinal toxicity was observed in 4 patients. No grade 4 neutropenia was registered. Three patients experienced 4 serious adverse events: pneumonia in one, severe deterioration of general conditions requiring hospitalization in another and both events in the last one. Two months after completing the 12 weeks of treatment one patient developed atrial fibrillation which required therapy. Two other patients had transient ECG abnormalities without need of hospitalization or therapy. We observed 1 partial remission, 4 stable diseases (SD) and 10 disease progressions. At last follow-up, 6 patients remain alive (3 in SD and 3 with disease progression) and 9 are dead (all for progressive MM). Although ITF2357 is tolerable when administered orally at the dose of 100 mg every 12 hours for 4 consecutive days every week, it is unlikely that it may play a significant therapeutic activity when used alone in advanced MM. However, we noted some evidence of anti-myeloma activity in a group of patients with deteriorated clinical conditions and advanced disease. Therefore, further clinical investigation is warranted to clarify how best to exploit this drug when given in combination with other active drugs to MM patients.