Phase I study of ON 01910.Na, a novel polo-like kinase 1 pathway modulator, administered as a weekly 24-hour continuous infusion in patients with advanced cancer

Abstract

2515 Background: ON 01910.Na induces G2/M cell cycle arrest, apoptosis, and cell death in a broad spectrum of cancer cells, but not in non-neoplastic cells. In vitro, cell killing is dependent on drug exposure time. Based on these preclinical findings, a weekly 24hr continuous infusion (CI) study to determine safety and MTD of ON 01910.Na was initiated. Methods: Patients with advanced cancers received ON 01910.Na as a weekly 24hr CI. Dose cohorts ranged from 250–2750 mg/m2 based on a modified Fibonacci escalation algorithm using the accelerated titration scheme (NCI). Intra-patient dose escalation was allowed. Intensive and comprehensive plasma sampling was performed at weeks 1 and 4 or 8 to determine drug pharmacokinetics. Results: 23 pts (7:16 M:F, 45–80 yrs) have received ON 01910.Na. At the max dose (2750 mg/m2), 3 pts have received 6, 3 and 2 wks of 24-hour CI therapy. The median (range) wks of CI delivered was 6 (2 - 36). Grade 2 toxicities (2-grade increase over baseline) included fatigue (3 pts) and anorexia (1 pt). Fatigue (11/23 pts) was the most common side effect, with no grade 3 or greater fatigue observed. Overall, three grade 3 events occurred, none of which were drug-related. The best response was a pt with advanced ovarian cancer who maintained stable disease for 36 wks of treatment. Plasma concentrations of ON 01910.Na reach a steady state within 3 hrs of starting infusion, and decline rapidly after the end of infusion. The drug has a half-life of about 2 hrs, with clearance decreasing and drug exposure (AUC) increasing non-linearly as dose increases. Mean steady state plasma concentration at the max assessed dose of 2,750 mg/m2 was 52.8 ± 7.3 μg/ml, well in excess of drug concentrations shown to be cytotoxic to several cancer cell-lines in vitro, including cell-lines widely resistant to chemotherapeutics. Conclusions: ON 01910.Na is well tolerated as a weekly 24h continuous infusion. In the dose range studied, the drug exhibited non-linear kinetics with rapid attainment of plasma concentrations that are cytotoxic to cancer cells in vitro, but have limited end-organ toxicity in vivo. Study data continues to accrue, and we expect to recommend a phase II dose shortly. Further analysis and combination phase I studies are planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Onconova Therapeutics, Inc. Onconova Therapeutics, Inc. Onconova Therapeutics, Inc.