Phase I study of ON 01910.Na, a novel modulator of the Polo-like kinase 1 pathway, in adult patients with solid tumors

Abstract

Purpose: We conducted a first-in-man (to our knowledge) phase I study to determine the dose-limiting toxicities (DLTs), characterize the pharmacokinetic profile, and document any antitumor activity of ON 01910.Na, a new chemical entity that arrests cancer cells in G(2)/M by modulating mitotic regulatory pathways including polo-like kinase 1 (Plk1).

Patients and methods: Patients had solid tumors refractory to standard therapy. ON 01910.Na was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 in 28-day cycles. The starting dose was 80 mg, and an accelerated titration schedule (single-patient cohorts) was used for escalation. Pharmacokinetics were studied on days 1 and 15 of cycle 1.

Results: Twenty patients (11 women and nine men; age 46 to 73 years) were enrolled onto the study. Dose levels of 80, 160, 320, 480, 800, 1,280, 2,080, and 3,120 mg were evaluated in single-patient cohorts. A DLT and additional grade 2 toxicities made the 4,370-mg dose (n = 6) not tolerable, and the next lower dose cohort (3,120 mg) was expanded to six assessable patients. Toxicities were skeletal, abdominal, and tumor pain; nausea; urge to defecate; and fatigue. Hematologic toxicity was infrequent and mild. ON 01910.Na pharmacokinetics were characterized by a rapid distribution phase (distribution half-life, 1 hour) and a relatively slow elimination phase (elimination half-life, 27 hours). A refractory ovarian cancer patient had an objective response after four cycles and remained progression free for 24 months.

Conclusion: ON 01910.Na showed a distinct but moderate toxicity pattern. The recommended phase II dose of ON 01910.Na with this schedule of administration is 3,120 mg. Single-agent activity was documented in an ovarian cancer patient.

Figures

Fig 1.

Clinical course of a 73-year-old woman with relapsed, poor prognosis ovarian cancer. After initial diagnosis in October of 2004 (CA-125 of 66,000 U/mL), she underwent surgery followed by eight cycles of carboplatin and paclitaxel. She developed disease progression during the eighth cycle (CA-125 went up to 45 U/mL from a nadir of 24 U/mL, and new lesions appeared in the pelvis) and started second-line topotecan. After two cycles, progressive disease was again documented, with CA-125 increasing up to 200 U/mL while on treatment and peaking at 395 U/mL, together with increased tumor volume. She received four cycles of ON 01910.Na, evidencing a partial response by computed tomography (CT) and a significant decrease in CA-125. The lower panel shows the evolution of the CA-125, and the upper panel depicts images from CT scan imaging before protocol therapy, at the completion of treatment, and in her 18-month follow-up.

Fig 2.

(A) Representative ON 01910.Na plasma concentration-time profiles after 2-hour intravenous infusion at the dose of 4,370 mg in one patient. The symbols represent the observed concentration data, and the solid and dashed lines represent the predicted concentration-time curve by fitting the observed data with two-compartment model. (B) ON 01910.Na maximum plasma concentration (Cmax) and (C) area under the concentration-time curve (AUC0-∞) as a function of ON 01910.Na dose.