Abstract CT119: Early phase I clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) plus radiation in cancers involving the CNS
Authors: Morgan LR , Mahmood T , Weiner R S. , Kawauchi R , Bhandari M , Devisitty K , Herman J , Summe R , Ware ML , Friedlander P , Rodgers AH 
Published: August 2018

Abstract
Purpose:4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a mechanism of action (MOA) via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase I/II studies [AACR, 58, #CT129, 2017] in subjects with cancers involving the CNS. Four (4) subjects in the Phase I/II trials required surgery for persistent CNS lesions following DM-CHOC-PEN therapy and DM-CHOC-PEN was identified in samples from all 4-subjects - 90-212 ng/g tumor [subjects had been treated with 39-98.8 mg/m2 of drug]. Thus, the drug penetrates the CNS and concentrates in tumors. It is available, therefore, to act as a radiosensitizer as demonstrated in in vitro studies [AACR, 58, #4746, 2017]. The current presentation reviews Phase I clinical data that supports the safety, dose-tolerance, and use of DM-CHOC-PEN with radiation in subjects with cancers involving the CNS - IND 68,876.
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. A single dose was administered prior to standard radiation therapy. The dose was escalated from 39 mg/m2 to 98.7 mg/m2 I.X1, then 3-weeks later the subject received stereotaxic radio-surgery (SRS) or whole brain irradiation (WBRT). Total radiation administered was 15-30 Gy depending on the size and number of lesions.
Results: Nine (9) subjects with cancer involving the CNS have been treated to date - (6-NSCLC, 1-breast, 1-melanoma & 1-sarcoma). Subjects received 39, 55, 70, 86.8 or 98.7 mg/m2 followed by 15-30 Gy of radiation. The drug/radiation combination was well tolerated. One (1) subject with NSCLC developed vasogenic edema and tumor necrosis which resolved; that subject is in complete remission 31+ mos. Six out of nine subjects have had objective responses (OS 4 - 42+ mos.) Bioavailability for DM-CHOC-PEN revealed a rebound phenomenon @ ~ 50 hours post-infusion with a T-release of 26.7 h. The same phenomenon was observed with RBCs (estimation using Monolix 3.2). DM-CHOC-PEN was detected bound to RBCs for 3-days (after 70 mg/m2); DM-CHOC-PEN was also detected in the urine (Cmax=17.5 µg/mL) until day 15. The AUC was linear for all doses. Pre-clinical 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 radiation 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) plus radiation (6-12 Gy) - cell kill was 80 & 100% @ 6 & 12 Gy. Photon induced charge transfer reactions with DM-CHOC-PEN will be discussed.
Conclusion: Preliminary data is presented that supports enhanced cytotoxicity and safety of DM-CHOC-PEN plus radiation as therapy for subjects with cancers involving the CNS. Observations during Phase I/II clinical trials with DM-CHOC-PEN alone support the drug's persistent presence in human tumors after systemic administration and possible positive effects on response to subsequent radiation. Complete data on subject responses and observed toxicities will be presented. Supported by - NCI/SBIR grants - R43 CA213545-01 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center.
Citation Format: LR Morgan, T Mahmood, R S. Weiner, R Kawauchi, M Bhandari, K Devisitty, J Herman, R Summe, ML Ware, P Friedlander, AH Rodgers. Early phase I clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) plus radiation in cancers involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT119.