Phase II Optimization, Open-Label Clinical Trial of Zalypsis^® (PM00104) in Relapsed/Refractory Multiple Myeloma Patients

Abstract 4041

Several new agents have recently been incorporated to the treatment of Multiple Myeloma (MM), which have shown increased anti-tumor activity and remarkable improvements in clinical outcomes. However, novel agents and therapies are still needed for patients relapsing/refractory to these new agents. PM00104 is a novel marine-derived compound with marked in vitro and in vivo pre-clinical activity in MM cell lines and patient cells (Ocio et al., Blood, 2009). It promotes DNA double-strand breaks in malignant plasma cells, as well as over-expression of p53 in p53 wild–type cell lines. Moreover, PM00104 induces toxicity on mature normal hematopoietic cells, but not on immature hematopoietic stem cells. On the basis of the observed activity, we designed this multicenter, open label, single arm, non-comparative, phase II clinical trial in order to determine the recommended dose (RD) to be administered as 1-hour (h) intravenous (i.v) infusion on days 1, 8 and 15 every 4 weeks (q4wk) in relapsed/refractory MM patients. We report herein data from the optimization phase only of this study.

Only adult patients with relapsed/refractory disease having received at least 2 but no more than 5 prior therapeutic regimens were included in the study. The study was divided in two phases: an initial optimization phase, with the primary objective of finding the RD of PM00104 by using a classical dose escalation phase I scheme, followed by an expansion phase with the objective of analyzing the efficacy of PM00104 in the treatment of MM at the RD established in the previous phase. A total of 55 patients were expected to participate, 18 in the optimization and 37 in the expansion phase. Patients showing disease progression (PD) after 2 cycles or stable disease (SD) after 4 cycles could have dexamethasone (40 mg weekly) added to their treatment exclusively during the expansion phase. Only data from the optimization phase (i.e. without dexamethasone) are presented here. Secondary study objectives included the assessment of the safety, tolerability and efficacy of PM00104 in MM patients, as well as the collection of pharmacokinetic (PK) and pharmacogenomic (PGx) information.

Twenty two patients were treated in the optimization phase, median age was 61 years (range, 40–74), median number of prior therapy lines was 3 lines (range, 2–5) and prior treatment with bortezomib and lenalidomide was received by 96% and 68% patients, respectively. Seventy-seven percent (77%) of patients received prior autologous stem-cell transplantation (ASCT) and 13% of patients received an allogeneic transplantation. The median number of cycles at dose level (DL) 1 (2 mg/m²) was 2 cycles (range, 1–7), at DL 2 (2.5 mg/m²) was 3 cycles (range, 1–12) and at DL 3 (2.2 mg/m²) was 2 cycles (range, 1–5). Two patients out of 6 had DLTs at DL 2: one patient had grade 4 neutropenia lasting > 7 days, another patient had febrile neutropenia, grade 4 neutropenia lasting more than 7 days and grade 4 thrombocytopenia with pulmonary hemorrhage. Two patients out of 4 had DLTs at DL 3: febrile neutropenia and grade 4 thrombocytopenia. After dose escalation, DL 1 was declared as the RD.

The main toxicity at the RD was hematological: grade 3/4 thrombocytopenia and grade 3/4 neutropenia, observed in 66% and 67% of patients, respectively. Non-hematological toxicity was mostly mild/moderate and consisted of grade 1/2 nausea (41%), vomiting (36%), pyrexia (32%), anorexia (23%) and grade 1 transitory liver enzymes elevation (40%). Grade 3/4 creatinine elevation occurred in 14% of cases.

Table 1 shows overall response (OR): sixteen patients were evaluable for efficacy. One patient (6.0%) had a PR, 4 patients (25%) had MR and 9 patients (56%) achieved SD, 3 of which for longer than 4 months. The median duration of response (DR) was 4 months.

PM00104 is a novel agent with an interesting activity in patients relapsing/refractory to new anti-myeloma agents and shown here to be safe. The RD of PM00104 administered as a 1-h i.v. infusion on days 1, 8 and 15 q4wk has been established at 2 mg/m². The expansion phase of this study is currently ongoing, yet on the basis of the observed preliminary therapeutic efficacy, combination of PM00104 with other anti-myeloma agents is warranted.