A Phase I/II Study for Dose-finding, and to Investigate the Safety, Pharmacokinetics and Preliminary Efficacy of NK012, an SN-38-Incorporating Macromolecular Polymeric Micelle, in Patients with Multiple Myeloma

OBJECTIVE: Multiple myeloma (MM) is the second most common hematological cancer. An attempt to treat MM using a topoisomerase I inhibitor was made based on our previous non-clinical studies suggesting the usefulness of an SN-38 derivative. Our aim was to conduct a phase I/II study of NK012, a micelle-forming SN-38 conjugate, in patients with relapsed/refractory multiple myeloma (RRMM). METHODS: NK012 was administered at doses of 12-24 mg/m(2) and the safety, pharmacokinetics and preliminary efficacy were evaluated. RESULTS: Neutropenia was the most common grade 3 or 4 adverse drug reaction. Grade 4 neutropenia accounted for the majority of dose-limiting toxicities and only appeared at a dose of 24 mg/m(2). The maximum concentrations and the area under the concentration-time curves from time zero to infinity for both NK012 and its active metabolite SN-38 increased in a dose-dependent manner. The best overall response was stable disease, which was achieved in 12 out of 16 patients. CONCLUSION: The recommended dose of NK012 monotherapy for RRMM patients was concluded to be 20 mg/m(2). However, this phase I/II study was terminated at the end of the phase I stage because no patients showed an objective response. Additional clinical studies of combination therapy with NK012 and other agents are warranted.