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 and II trials (the latter on subjects with CNS involvement) [AACR #1185, 2013; AACR #CT 129]. The primary aim was to assess clinical response and secondary aims to monitor toxicities/safety and verify the MTDs for IV administered DM-CHOC-PEN that derived in Phase I study (IND 68,876). We report here the responses and toxicities seen in all the subjects treated.

Subjects & Methods: In Phase I, DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer; cohorts received escalating doses from 39 - 111 mg/m2. The Phase II dose schedule was 2-tiered: 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal livers.

Results: Fifty two (52) subjects have been treated to date - 25 in Phase I (cancer subjects with or without CNS involvement) and 27 in Phase II (with CNS involvement). The common tumor types treated were primary brain cancers and melanoma, breast, and lung cancers involving the CNS. The drug was well tolerated; the most common adverse effects were fatigue (17%), reversible liver dysfunction (9%) and nausea (11%). No neuro/psychological, hematological, cardiac or renal toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels (39-111 mg/m2). The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) were 3 and 24 hours, respectively. Both DM-CHOC-PEN and DM-PEN were detected 3 to 15 days after administration associated (up to 50%) with rbcs. Of interest, young adults (<40 y/o) demonstrated significant increases in Cmax and AUC vs. older subjects, supporting the need for trials in adolescents and young adults. DM-CHOC-PEN was also detected in CNS tumor tissue obtained surgically from five (5) subjects - in concentrations of 75-210 ng/g, 22 days to 9 mos. post treatments at doses of 39 or 98.7 mg/m2 of drug. To date, 16 subjects with lung cancer (11 with NSCLC involving the CNS) have been treated. Seven of the 11 subjects with NSCLC involving the CNS (incl. 6 with cerebellar disease) have responded with CR/PR (RECIST 1.1) and improved OS/QOL/PFS (Kaplan-Meier) lasting 8+ - 32+ mos. Conclusion: DM-CHOC-PEN is safe at these dose levels and has produced objective responses with manageable toxicities in subjects with cancer involving the CNS. Complete data on subject responses and observed toxicities will be presented. We propose a 3-stage mechanism for drug entry into the CNS and into NSCLC cells via reversible binding with RBCs and then associated with L-glutamine transport into cells. 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: Roy S. Weiner, Lee Roy Morgan, T Mahmood, R. Kawauchi, C. Gordon, ML Ware, M. Matrana, TM Cosgriff, AH Rodgers, G. Bastian, M. Bhandari, J-J Zou. Clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) 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 CT052. doi:10.1158/1538-7445.AM2017-CT052