Abstract 4746: Early clinical support for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as a radiosensitizer in cancers involving the CNS

Abstract

Abstract Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase I/II studies [AACR #CT129, 2016] in subjects with cancers involving the CNS. The current presentation reviews clinical and in vitro data that support radiosensitizing properties for DM-CHOC-PEN in cancers involving the CNS. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer involving the CNS. The dose schedule was 2-tiered: 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal livers. All subjects with resistant or new CNS lesions that did not respond to DM-CHOC-PEN were given the option of surgery, stereotaxic radio-surgery (SRS) or whole brain irradiation (WBRT). As preclinical support, human NSCLC adenocarcinoma cells (H-2086) growing in culture (106 cells/mL) were pretreated with DM-CHOC-PEN (0.1 -1.0 µg/mL) for 24 hrs, drug washed, re-fed fresh medium and then 48 h later irradiated (SRS with 6, 9 or 12 Gy). Results: Fifty-three (53) subjects with/without CNS involvement have been treated to date with DM-CHOC-PEN. Five (5) subjects (4-NSCLC & 1-sarcomas) in the Phase I/II trials required surgery for persistent CNS lesions following DM-CHOC-PEN therapy. DM-CHOC-PEN was identified in samples from all subjects - 90-212 ng/g tumor [subjects had been treated with 39-98.8 mg/m2 of drug]. Five subjects (1-sarcoma & 4-NSCLC) who had been treated with DM-CHOC-PEN for 6-wks - 8-mos had persistent NSCLC lesions involving the CNS were treated with SRS or WBRT. All five subjects had excellent objective results (OS 8+ - 29+ mos) with no CNS toxicity. Preclinical in vitro studies supported the clinical data: NSCLC cells treated with DM-CHOC-PEN (0.1 -1.0 µg/mL) demonstrated 50 & 100% cytotoxicity @ 0.4 & 1.0 µg/mL; for SRS alone (6, 9 &12 Gy) - cell kill was 20 & 65% @ 6 & 12 Gy [100% kill was not observed at this dose range]; for DM-CHOC-PEN (0.25 µg/mL) + SRS (6-12 Gy) - cell kill was 80 & 100% @ 6 & 12 Gy. Thus, in combination - less drug (0.25 µg/mL) and 12 Gy - produced a 100% cell kill, as compared to either SRS or drug, alone. Photon induced charge transfer reactions with DM-CHOC-PEN will be discussed. Conclusion: Preliminary data is presented that supports DM-CHOC-PEN’s cytotoxicity and radiosensitizing properties in cancers involving the CNS. Observations during clinical trials support the drug’s persistent presence in human tumors after systemic administration and notable positive effect on response to subsequent radiation. Complete data on patient responses and observed toxicities will be presented. Supported by - NCI/SBIR grants - R43/44CA132257 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: Lee Roy Morgan, R S. Weiner, T Mahmood, R. Kawauchi, K Devisetty, J Herman, M Bhandari, R Summe, E Benes, AH Rodgers, ML Ware, JS Hayman, J Weber, Jay J. Zou. Early clinical support for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as a radiosensitizer in cancers involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4746. doi:10.1158/1538-7445.AM2017-4746