Phase I dose-escalation study of ON 01910.Na in combination with oxaliplatin in patients with advanced solid tumors.

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e13133 Background: ON 01910.Na is a new multikinase inhibitor, which induces mitotic catastrophe and apoptosis in cancer but not in normal cells. Multiple pathways are involved including polo-like kinase. Cell killing effects are exposure time-dependent in vitro. In addition, a combination of ON 01910.Na with oxaliplatin produced significant synergy in effect, prompting phase I evaluation in humans. Methods: Patients with advanced cancer received a starting dose of ON 01910.Na 250mg/m2 as a 24hr continuous infusion (CI) repeated weekly. Oxaliplatin was administered biweekly as 85mg/m2, 2 hr infusion. The ON 01910.Na dose cohorts ranged from 250-1350 mg/m2 based on a modified Fibonacci escalation algorithm using the accelerated titration scheme (NCI). Intrapatient dose escalation was allowed. Pharmacokinetic (PK) sampling is to be performed at the maximum tolerated dose (MTD) level. Results: 13 patients (pts) (all females; ages: 38-71 yrs) have received combination therapy. At the highest dose (1350 mg/m2), 2 pts have received 6 weeks of continuous therapy. The overall mean (range) number of weeks of continuous therapy delivered was 11.1 (3-42). Grade 2 toxicities (2-grade increase in toxicity) include anorexia (1 pt), nausea (2 pt), fatigue (1 pt), peripheral sensory neuropathy (1 pt), abdominal cramps (1 pt), neutropenia (1 pt) and vomiting (2 pt). Partial response was observed in 1 pt with chemotherapy- refractory ovarian cancer (26 wk, prior progressions on paclitaxel+carboplatin [carbo], topotecan+docetaxel, carbo+gemcitabine, doxorubicin hydrochloride liposome, paclitaxel+bevacizumab, and etoposide). Stable disease was observed in a pt with colon cancer (42 wk, prior progressions on FOLFOX-4 and FOLFIRI+bevacizumab), and in a pt with ovarian cancer (19 wk, prior progressions on carbo+paclitaxel, doxorubicin hydrochloride liposome, gemcitabine+carbo, topotecan, vinorelbine, and bevacizumab+paclitaxel). Conclusions: It is feasible to administer ON 01910.Na as a 24hr infusion in combination with oxaliplatin. Tumor response was seen in chemotherapy-refractory ovarian cancer. The toxicities are tolerable and dose escalation continues. Further analysis of response and toxicity as well as PK at the MTD dose level is planned as this study continues to enroll patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onconova Therapeutics, Inc. Onconova Therapeutics, Inc. Onconova Therapeutics, Inc.