Phase I/II study of weekly PM00104 (Zalypsis®) in patients with relapsed/refractory multiple myeloma

Despite improvements in the prognosis of multiple myeloma (MM) associated with the recent introduction of immunomodulatory drugs (IMIDs), such as thalidomide or lenalidomide, and proteasome inhibitors (PIs), such as bortezomib (Richardson et al, 2003; Dimopoulos et al, 2007), MM remains incurable and virtually all patients relapse. Moreover, patients with relapsed MM refractory to lenalidomide and bortezomib have a dismal prognosis (Kumar et al, 2012) and drugs with different mechanisms of action are currently under investigation (Ocio et al, 2014) for these patients. PM00104 (Zalypsis ) gives rise to double-strand DNA breaks, increases the G0–G1 phase and induces apoptosis (Ocio et al, 2009) in MM cells. It is effective on cell lines resistant to conventional anti-myeloma treatments and it has shown synergy with several anti-myeloma drugs (Ocio et al, 2009, 2010). A previous phase I trial of PM00104 administered as a 1-h intravenous (i.v.) infusion on Days 1, 8 and 15, every 4 weeks established 2 0 mg/m as the recommended dose (RD) in patients with solid tumours (Massard et al, 2013). The evaluation of this schedule, as well as the optimization of the dose of PM00104 in relapsed/refractory MM, was the main objective of the current trial. Patients ≥18 years old with measurable relapsed/refractory MM after at least two prior therapeutic lines, with adequate bone marrow (BM), renal, cardiac and hepatic function and Eastern Cooperative Oncology Group Performance Status ≤2 were enrolled in 10 medical centres in Spain. During the initial optimization phase, a conventional 3 + 3 dose-escalation design (PM00104 doses of 2 0, 2 2 and 2 5 mg/m, administered as 1-h intravenous infusion on Days 1, 8 and 15, every 4 weeks) was used to determine the maximum tolerated dose (MTD) and the RD based on the dose-limiting toxicities (DLTs) observed during the first treatment cycle. DLTs included any grade 4 event or grade 3 event taking >7 d to resolve to grade ≤1 or baseline values, two PM00104-related dose omissions during the first cycle, a dose delay >14 d in the first dose of Cycle 2, any grade ≥ 2 cardiac toxicity related to PM00104 with evidence of cardiac damage, grade ≥ 3 nausea or vomiting refractory to antiemetic therapy, grade ≥ 3 hepatic toxicity, grade 3/4 haematological toxicity (lasting >7 d or concomitant with grade 3/4 haemorrhage if extensive BM infiltration) and febrile neutropenia. Once the RD was established, the cohort was expanded (expansion phase) to obtain preliminary information on anti-tumour activity (overall response rate). Patients who showed disease progression (PD) after two cycles or stable disease (SD) after four cycles (i.e., non-optimal responses) had oral dexamethasone (DXM) added at a dose of 40 mg/week, taken 30 min before each PM00104 infusion. Twenty-one and 13 patients were treated in the optimization and expansion phase, respectively. The main patient characteristics are shown in Table I. The most commonly received previous antineoplastic agents in both phases were IMIDs (thalidomide or lenalidomide) and PIs (bortezomib). Thirteen patients were evaluable for DLT. No DLTs were observed at 2 0 mg/m, but following dose escalation to 2 5 mg/m, two patients had DLTs (grade 3 febrile neutropenia and grade 4 neutropenia). An intermediate dose level (2 2 mg/m) was explored; two patients had DLTs (grade 3 febrile neutropenia and grade 4 thrombocytopenia). Therefore, 2 2 mg/m was considered the MTD and 2 0 mg/m was declared the RD. A total of 18 patients were treated at the RD. The most common PM00104-related adverse events (AEs) consisted of mild to moderate fatigue, nausea, anorexia, vomiting and pyrexia (Table II). Only one case of tumour lysis syndrome reached grade 3. One patient discontinued treatment due to grade 2 nausea and dizziness. Grade 3–4 haematological abnormalities at the RD were frequent and one patient discontinued treatment as a result of anaemia, neutropenia (both grade 3) and grade 4 thrombocytopenia. The most common non-haematological laboratory abnormality was creatinine increase, although most cases were related to the underlying disease. Therefore, AEs were generally mild to moderate, transient, non-cumulative and had no relevant clinical consequences; myelosuppression was the most significant toxicity. No objective responses were observed in the 14 patients evaluable at the RD (2 0 mg/m). However, nine patients showed clinical benefit (i.e., SD was maintained). Of note, although no response improvement was observed in any of the seven patients who received DXM during the expansion phase, three refractory patients showed an improvement in progression-free survival after the addition of DXM: a patient who started DXM in Cycle 3 with PD achieved SD for 8 3 months (refractory to IMIDs and bortezomib) and two patients with SD who started DXM in Cycle 4 maintained SD for 7 6 months (refractory to bortezomib) and 12 0 months (relapse after autologous stem cell transplantation), correspondence