Abstract 3908: Norton-Simon modeling for the optimization of dose and schedule of palifosfamide in breast cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Palifosfamide (P), the stabilized active metabolite of ifosfamide, is a bifunctional DNA alkylating agent with broad anticancer activity, including against cells with ALDH over-expression resistant to cyclophosphamide. In contrast to other agents of its class, P's favorable safety profile, rapid onset of action, and comparable activity by IV and PO routes permits optimization of dose-schedule. To this end we used Norton-Simon Modeling to analyze the growth curves of the MX-1 breast cancer xenograft model, unperturbed and perturbed by various dose-schedules of P. This method fits an equation ΔN(t)/αt=F(N)·G(t) to experimental data on tumor size N as a function of time t to define the magnitude and shape of the curve of growth perturbation G as a function of time t before, during, and after the administration of anticancer therapy. In general (as in this case), growth perturbation “peaks” at a number of days after administration and declines thereafter. This is largely due to the induction of spontaneously reversible resistance (tachyphylaxis) as evidenced by the cancers’ reversion to drug sensitivity after a period of drug absence. Hence, repeated cycles of intermittent therapy allows for further growth perturbation, providing for sustained anticancer effect. The solution of the Norton-Massague equation ΔN(t)/αt=aN^b-cN^d fit unperturbed growth exactly (r^2=0.99973). 180 mg/kg as a single dose caused tumor volume regression with a peak growth perturbation at 7 days after administration. The effect of lower dose levels in (growth perturbation as a % of that of 180 mg/kg as a single dose; peak at days after start of administration) were 120 mg/kg (75%; 7), 80 mg/kg (34%; 5), and 53 mg/kg (16%; 3). When P was given in divided doses over 5 days, 180 mg/kg cumulative dose resulted in (94%; 10), 120 mg/kg (55%; 6), and 80 mg/kg (16%; 3). Hence, the administration of P over 5 days preserved almost full efficacy but delayed the time of emergence of drug resistance by 43% (from 7 days to 10 days). Moreover, analysis of the effects of P alone, docetaxel alone, and the simultaneous combination indicates that the shapes and magnitudes of the single-agent curves add to perfectly predict that of the combination, with minimal loss of single-agent activity. Hence, the daily x 5 schedule (9 days off) at highest tolerated dose level is proposed for clinical study, both as a single agent and in combination with other anticancer medications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3908. doi:1538-7445.AM2012-3908