Abstract 5266: Pediatric Preclinical Testing Program (PPTP) evaluation of the CDK inhibitor SCH 727965
Authors: Smith Malcolm A. , Maris John M. , Courtright Josh , Friedman Henry S. , Kier Stephen T. , Lock Richard B. , Carol Hernan , Gorlick Richard , Kolb E Anders , Kang Min , Reynolds Christopher Patrick , Morton Christopher L. , Houghton Peter J. 
Published: February 2011

Background: SCH 727965 is a potent inhibitor of CDK1, CDK2 and CDK9 activities in vitro and has been shown to be effective as a single agent against a wide-spectrum of adult tumor xenograft models including lung, prostate, breast, ovarian and multiple myeloma, with tumor growth inhibition from 12% to 150% (regression) noted. The activity of SCH 727965 was evaluated against the PPTP's in vitro and in vivo panels.

Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood acute lymphoblastic leukemia (ALL). SCH 727965 (provided by Schering-Plough) was tested in vitro at concentrations from 0.1 nM to 1.0 μM and was tested against the PPTP in vivo panel using a 40 mg/kg dose administered IP twice-weekly for 2 weeks, repeated at Day 21 with a total planned treatment and observation period of 6 weeks. Three measures of antitumor activity were used: 1) an objective response measure modeled after the clinical setting; 2) a treated to control (T/C) tumor volume measure; and 3) a time to event (4-fold increase in tumor volume) measure based on the median event-free survival (EFS) of treated and control animals for each xenograft.

Results: The median IC50 value for the PPTP cell lines was 7.5 nM, with a less than 4-fold range between the minimum (3.4 nM) and maximum (11.2 nM) IC50 values. SCH 727965 demonstrated an activity pattern consistent with cytotoxic activity for most of the PPTP cell lines with minimum (Ymin) T/C% values approaching 0% for most cell lines. SCH 727965 was well tolerated in vivo, with a toxicity rate &lt; 5%. All 43 (36 solid tumor and 7 ALL) xenograft models studied were evaluable for efficacy. SCH 727965 induced significant differences in EFS distribution compared to control in 23 of 36 (64%) evaluable solid tumor xenografts. Seven of 33 solid tumor xenografts evaluable for the EFS T/C activity measure showed a 2-fold or greater increase in time to event for the SCH 727965 treated group. SCH 727965 did not induce objective responses in the PPTP solid tumor panels. The best response in these panels was stable disease (SD) which was observed for the osteosarcoma xenograft OS-1. PD2 (progressive disease with growth delay) was observed in 15 of 36 xenografts, being most commonly observed in the rhabdomyosarcoma (4 of 6), rhabdoid tumor (2 of 2) and the Ewing sarcoma (3 of 5) tumor panels. In the ALL panel, the best response was a complete response (CR), which was observed in a single xenograft (ALL-17). A T-cell ALL xenograft (ALL-16) attained a partial response (PR). The remaining 5 ALL xenografts showed progressive disease.

Conclusions: SCH 727965 potently inhibits the cell lines of the PPTP in vitro panel and shows an interesting pattern of in vivo activity suggesting its potential applicability against selected childhood cancer subtypes. (Supported by NCI NO1CM42216)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5266.