Elez ME1, Tabernero J, Geary DR, Macarulla T, Kang SP, Kahatt C, Soto-Matos Pita A, Fernandez-Teruel C, Siguero M, Cullell-Young M, Szyldergemajn S, Ratain MJ.
PURPOSE: Lurbinectedin (PM01183) binds covalently to DNA and has broad activity against tumor cell lines. This first-in-human phase I study evaluated dose-limiting toxicities (DLTs) and defined a phase II recommended dose (RD) for PM01183 as a 1-hour intravenous (i.v.) infusion every 3 weeks (q3wk). Experimental design: Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design.
RESULTS: PM01183 was safely escalated over 200-fold, from 0.02 mg/m2 to 5.0 mg/m2. Dose-doubling was utilized, requiring 15 patients and 9 dose levels to identify DLT. The RD was 4.0 mg/m2, with one of 15 patients having DLT (grade 4 thrombocytopenia). Clearance was independent of body surface area; thus, a flat dose (FD) of 7.0 mg was used during expansion. Myelosuppression, mostly grade 4 neutropenia, occurred in 40% of patients but was transient and manageable, and none was febrile. All other toxicity was mild, and fatigue, nausea and vomiting were the most common at the RD. Pharmacokinetic parameters showed high interindividual variation, though linearity was observed. At or above the RD, the myelosuppressive effect was significantly associated with the area under the concentration-time curve (white blood cells, p=0.0007; absolute neutrophil count, p=0.016). A partial response was observed in one pancreatic adenocarcinoma patient at the RD.
CONCLUSION: A FD of 7.0 mg is the RD for PM01183 as a 1-hour infusion q3wk. This dose is tolerated and active. Severe neutropenia occurred at this dose, although it was transient and with no clinical consequences in this study.