A Phase I Study of Oral Melphalan Combined with LBH589 for Patients with Relapsed or Refractory Multiple Myeloma (MM).
Authors: Berenson James R. , Yellin Ori , Boccia Ralph V. , Nassir Youram , Rothstein Shellie , Swift Regina A. 
Published: October 2019

Abstract
Abstract 1855
Poster Board I-881
We and others have shown that LBH589, a potent histone deacetylase inhibitor (HDACi), significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity triggered by chemotherapeutic agents. Using our SCID-hu models of MM, we have also shown a striking inhibition of MM cell growth in vivo when LBH589 was combined with low doses of melphalan compared to treatment with either drug alone. Thus, these preclinical studies provided the rationale for evaluating the combination of oral melphalan with oral LBH589 for the treatment of MM patients with relapsed or refractory disease. We present the results of an ongoing phase I, open-label, multicenter, dose-escalation study. The initial treatment schedule involved administering patients oral LBH589 every Monday, Wednesday and Friday (MWF) combined with oral melphalan on days 1–5 of a 28-day cycle. Patients were to be treated to maximum response plus 2 additional cycles or complete 8 cycles of therapy without disease progression. To date, 15 patients have been enrolled. At study entry, eleven patients (73%) had International Staging System II or III MM. Fourteen patients were previously treated with melphalan. Three subjects were enrolled into the first cohort (oral LBH589 10 mg; melphalan 0.05 mg/kg) and all experienced significant hematological adverse events. During cycle 1, 2 of 3 subjects had grade 3 thrombocytopenia and all 3 patients developed grade 3 neutropenia. As a result, the melphalan dosing schedule was changed from being administered on days 1-5 to only on days 1, 3 and 5. Three subjects were enrolled into this modified first cohort using the same doses of both drugs. One subject in this cohort experienced both a grade 3 neutropenia and thrombocytopenia. However, there were no DLTs in this cohort and so enrollment into the next cohort (LBH589 at 20 mg and melphalan at 0.05 mg/kg) was initiated. In this cohort, one subject experienced a DLT (grade 4 thrombocytopenia) while the other two developed grade 3 thrombocytopenia. One patient achieved a immunofixation (IF)+ CR but withdrew consent due to intolerable fatigue. As a result, three additional patients were evaluated at this dose level, and two patients have responded including one active patient who is now in PR and another one also achieved a PR but had to be taken off study due to persistent grade 3 neutropenia. Based on the ongoing significant fatigue among patients treated with LBH89 throughout the treatment cycle, the protocol was revised so that the HDACi was administered only during the first two weeks (days 1, 3, 5, 8, 10, and 12) of the 28-day schedule. To date, 3 patients have recently started treatment with this modified schedule of LBH589 at 20 mg and melphalan at 0.05 mg/kg again administered on days 1, 3 and 5 of each 28-day cycle but are not yet evaluable for response. Thus, 12 patients are currently evaluable for response and 4 (33 %) who had previously received melphalan at higher doses have achieved a response including 1 complete response (IF+ CR) and 3 partial responses. Another 4 patients showed stable disease so that disease control was achieved overall in 8 (67%) patients. Overall, the most common ≥ grade 3 adverse events included reversible neutropenia and thrombocytopenia. Specifically, there were 6 cases of grade 3 neutropenia, 6 with grade 3 thrombocytopenia and 1 with grade 4 thrombocytopenia. All of these cytopenias were reversible. Because of the encouraging response rate (33%) that has already been observed in this relapsed and refractory population of heavily pretreated MM patients previously treated with melphalan, an expanded Phase II trial will be conducted using this combination once the MTD has been determined and schedule of dosing has been optimized.

Disclosures:
Berenson: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding, Speakers Bureau. Off Label Use: LBH589 is a histone deacetylase inhibitor that is used for the treament of multiple myeloma. Rothstein:Novartis Pharmaceuticals Corporation: Employment.