A phase I dose-escalation study of NK012

Abstract

2538 Background: NK012 is a micelle-forming macromolecular prodrug of EHC (7-ethyl-10-hydroxycamptothecin), also known as SN-38 the active metabolite of irinotecan, bound to an amphiphilic block copolymer. NK012 accumulates as nanoparticles in tumors where it gradually releases EHC by chemical hydrolysis under neutral conditions. Accumulation and sustained release of EHC could result in increased efficacy of the drug. Methods: Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-minute infusion every 21 days without premedications. UGT1A1 genotype screening was performed prior to enrollment, and UGT1A1*28/*28 homozygotes were treated at a reduced dose level with the potential for dose escalation based on toxicities. At least three patients were treated and evaluated for dose-limiting toxicities at each dose level prior to dose escalation. Pharmacokinetic samples were obtained during cycles 1 and 2 of treatment. Results: Eighteen patients have received 54 cycles of treatment across 5 dose levels ranging from 9 - 28 mg/m2. Four homozygous patients have also been enrolled at dose levels ranging from 4.5 - 10.5 mg/m2 and received a total of 16 cycles. Three of the 22 patients previously received irinotecan. No dose-limiting toxicities were reported at dose levels 1–4. One patient at dose level 5 (28 mg/m2) experienced uncomplicated grade 4 neutropenia lasting > 7 days, which was a dose-limiting toxicity per protocol. As a result, this level has been expanded to a total of 6 patients. Hematologic toxicities have consisted of transient grade 3 neutropenia (1 pt), grade 4 neutropenia (4 pts), and grade 3 thrombocytopenia (1 pt) with 3 patients requiring dose delays due to neutropenia. Nonhematologic toxicities have been minimal. Two partial responses have been reported in patients with previously treated breast cancer and small cell lung cancer, respectively. Ten patients have experienced stable disease as best response (range 3–10 cycles), four patients experienced disease progression, two were inevaluable, and 4 are too early to evaluate. Conclusions: NK012 is well tolerated and has demonstrated antitumor activity in patients with refractory tumors. Phase II trials are warranted in patients with tumor types demonstrating sensitivity to irinotecan. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Nippon Kayaku Co, Ltd Nippon Kayaku