A Phase I and pharmacokinetic study of HMN-214, a novel oral polo-like kinase inhibitor, in patients with advanced solid tumors

Abstract

3034 Background: HMN-176 is a stilbazole derivative with potent antitumor activity in preclinical models. HMN-176 interferes with localization of polo-like kinase 1(PLK-1). PLK-1 is upregulated in multiple malignancies including pancreatic cancer (Gray, et al. Proc. AACR, Vol 44, 2nd ed: 919, 2003). HMN-214 is a prodrug of HMN-176 with improved oral absorption. We performed a dose escalation trial of HMN-214 to establish its toxicity and pharmacokinetic (PK) profiles and maximum tolerated dose (MTD) when administered daily × 21 days every 28 days. Methods: Patients (pts) had advanced solid tumors, adequate organ function and performance status 0–2. HMN-214 was escalated in cohorts of 3, with expansion if 1/3 pts on a dose level had a dose-limiting toxicity. Results: 33 pts (median age 66; M:F 19:14) have received 71 cycles HMN-214. Pts were treated at 3, 6 and 9.9 mg/m2/d. At 9.9 mg/m2/d, 1 pt had grade 3 hyperglycemia, chest pain (non-cardiac) and myalgias and 1 pt had grade 3 bone pain. Pts were then stratified into Lightly Pretreated (LPT) and Heavily Pretreated (HPT) cohorts and treated at de-escalated levels of 3, 6 and 8 mg/m2/d. One of 6 LPT pts at 8 mg/m2/d had grade 3 bone pain; no HPT pts at 8 mg/m2/d had DLT. One pt had grade 3 anemia; no other gr 3 and no gr 4 hematologic toxicity was seen. PK studies on day 1 of dosing indicate the active compound (HMN-176) reaches maximum concentration 2.2 to 6.7 hours after oral dosing and t1/2varies from 11.8 to 15.8 hours. Cmax and AUC0–24 increased appropriately according to dose. Antitumor activity was noted in a colon cancer pt at 9.9 mg/m2/d with a transient decrease (40%) in CEA after cycle 1, a breast cancer pt at 9.9 mg/m2/d with stable disease for 6 months, and bronchial carcinoid pt at 8 mg/m2/d with stable disease at 2+ months. Conclusions: HMN-214 is a novel oral PLK-1 inhibitor with an excellent toxicity profile and dose-linear PKs when administered on a daily × 21 schedule. The MTD and the dose recommended for Phase II trials is 8 mg/m2/d, with no difference in tolerance in LPT and HPT pts. Given the early indications of antitumor activity, HMN-214 will be investigated as a novel therapy in Phase 2 trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NS Pharma