Abstract CT119: Early phase I clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) plus radiation in cancers involving the CNS

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