"Aplidin is a a novel marine-derived compound with promising results."
Dr. Enrique M. Ocio

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Enrique M. Ocio, Constantine Mitsiades, M. Victoria Mateos, Patricia Maiso, Faustino Mollinedo, Mercedes Garayoa, Consuelo Gajate, Joan Blade, Felipe Prosper, Juan José Lahuerta, Nicholas Mitsiades, Ciaran J. McMullan, Nikhil C. Munshi, Teru Hideshima, Dharminder Chauhan, Carmen Cuevas, Pablo Avilés, Glynn Faircloth, Paul G. Richardson, Atanasio Pandiella, Kenneth C. Anderson, J.F. San Miguel Hospital Universitario de Salamanca, Spain; Centro de Investigacin del Cncer, Universidad de Salamanca, Spain; Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, USA; Hospital Clinic, Barcelona, Spain; Clinica Universitaria de Navarra, Spain; Hospital 12 de Octubre, Madrid, Spain; Pharmamar SA. Madrid, Spain Pharmamar Inc., Cambridge, MA, USA

Introduction Plitidepsin is a cyclic depsipeptide isolated from the marine tunicate, Aplidium albicans with promising antitumor activity. This work represents a comprehensive study (in vitro, in vivo and clinical) of its antimyeloma efficacy. Material Methods In vitro studies were performed in 23 multiple myeloma (MM) cell lines and in cells from 16 MM patients. For the in vivo analysis a human plasmocytoma model in CB17-SCID mouse was used. Mice were randomized to receive Aplidin 100 g/Kg ip x 7 days/week (n=9), Aplidin 140 g/Kg ip x 5 days/week (n=7) or vehicle alone (n=9). The clinical efficacy of Aplidin in relapsed/refractory patients was evaluated in a non-randomized two-stage Phase II, multicenter, clinical trial. Dosage of Aplidin was 5 mg/m2 every 2 weeks. Results Aplidin showed clear in vitro efficacy (IC50:1-10 nM) in the 23 cell lines tested including those resistant to dexamethasone, melphalan or doxorubicin. It was also active in the presence of microenvironment (IL-6, IGF-1 and BMSCs). Thirteen out of the 16 patient samples were sensitive to Aplidin with >80% cell death in 8 cases and 60-80% in the remaining ones without significant toxicity in non tumor cells. Combination of Aplidin with dexamethasone, bortezomib or lenalidomide showed clear potentiation. Aplidin acts by inducing apoptosis with caspase-3, -7, -8, -9 and PARP cleavage. It also involves the activation of p38 and JNK signalling, Fas/CD95 translocation to lipid rafts and downregulation of Mcl-1 and myc. In mice studies, both schedules of treatment reduced tumor growth and increased survival with statistical differences in the group receiving 140 g/Kg x 5d/week (p=0.04, Log Rank p=0.02). No significant toxicity was observed. These data provided the rationale for a clinical trial that has included 31 patients with relapsed/refractory MM. Median age was 65 years (47-82) and the median number of prior lines of therapy was 4 (range: 1-9) including autologous stem cell transplant (60%), thalidomide (58%) and bortezomib (48%). Out of the 26 evaluable patients, 2 (8%) achieved PR and 3 (12%) MR. Eight patients (31%) remained in stable disease (SD). Due to the synergism with dexamethasone observed in the in vitro studies, the protocol was amended to allow the addition of this agent in pts progressing after 3 cycles or with SD after 4 cycles. With a median follow-up of 14 months (range: 6.8-16.3), the time to progression in responding pts was 5.8 months (4.9-7.6). The most common G3-4 adverse events were fatigue (7%), serum creatine phosphokinase increase (7%), muscle toxicity (10%) and hepatic toxicity (10%). No significant hematologic toxicity or neuropathy was observed. Conclusion Aplidin is effective both as a single agent and in combination with dexamethasone in the in vitro and in vivo settings. Its activity in relapsed/refractory MM patients is promising with an acceptable toxicity profile.

Abstract #1178 appears in Blood, Volume 110, issue 11, November 16, 2007

Keywords: Targeted Therapy|Clinical Trial|Apoptosis

Disclosure: Employment: Carmen Cuevas, Pablo Avils and Glynn Faircloth are employees of Pharmamar.

Saturday, December 8, 2007 5:30 PM

Session Info: Poster Session: Myeloma: Experimental Therapies for Multiple Myeloma (5:30 p.m.-7:30 p.m.)