First-in-human phase i study of lurbinectedin (PM01183) in patients with advanced solid tumors

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 (DLT) and defined a phase II recommended dose for PM01183 as a 1-hour intravenous infusion every three weeks (q3wk). Experimental Design: Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design. Results:PM01183was safely escalated over 200-fold, from0.02 to 5.0mg/m2.Dose doublingwas utilized, requiring 15 patients and ninedose levels to identifyDLT.The recommended dosewas 4.0mg/m2,withoneof 15 patients having DLT (grade 4 thrombocytopenia). Clearance was independent of body surface area; thus, a flat dose 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 themost common at the recommended dose. Pharmacokinetic parameters showed high interindividual variation, though linearitywas observed. At or above the recommended dose, the myelosuppressive effect was significantly associated with the area under the concentration-time curve from time zero to infinity (white blood cells, P= 0.0007; absolute neutrophil count, P = 0.016). A partial response was observed in one patient with pancreatic adenocarcinoma at the recommended dose. Conclusion: A flat dose of 7.0mgis the recommended dose 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. © 2014 American Association for Cancer Research.