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 including subjects with CNS involvement) [AACR #1185, 2013; AACR #CT 129, 2019]. The primary aims of the previously reported Phase I/II DM-CHOC-PEN trials were to assess clinical response and monitor toxicities/safety and verify the maximum tolerated doses (MTD) for IV administered DM-CHOC-PEN (IND 68,876) to subjects with cancer. We report here the responses and toxicities seen in subjects with NSCLC involving the CNS that lacked genetic rearrangements, tumor targets and/or had failed standard therapies. Subjects & Methods: DM-CHOC-PEN was administered to adults (> 18 y/o) as a 3-hr IV infusion once every 21 days employing a verified 2-tiered MTD schedule: 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal livers. Results: Fifty two (52) adult subjects with cancer have been treated to date, including16 subjects with lung cancer, of which 11 had NSCLC (adeno/large cell carcinomas) involving the CNS that lacked genetic rearrangements/no tumor targets and/or had failed standard therapies. Seven of the 11 subjects with NSCLC involving the CNS also possessed cerebellar metastases. 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, nor drug associated deaths. PK modeling revealed that AUCs were parallel for both the 85.8 and 98.7 mg/m2 doses employed. The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) at the MTD were 3 and 24 hours, respectively. Both DM-CHOC-PEN and DM-PEN were detected for up to 15 days post administration associated with rbc's. DM-CHOC-PEN was also detected in CNS tumor tissue obtained anatomically from five (5) subjects - in concentrations of 75-210 ng/g, 22 days to 9 mos. post-treatments. 8 subjects have responded with CR/PR (RECIST 1.1) and improved OS/QOL/PFS (Kaplan-Meier) lasting 8+ - 70+ mos. Conclusion: DM-CHOC-PEN is a bis-alkylator of DNA that is safe at the dose levels described and has produced long term objective responses with manageable toxicities in subjects with NSCLC involving the CNS lacking genetic rearrangements or tumor targets and/or had failed standard therapies. Complete data on subject responses and observed toxicities will be presented. A 3-stage mechanism is proposed for drug entry into the CNS and into NSCLC cells via reversible binding with RBC's 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 from the Louisiana Clinical and Translational Science Center, New Orleans, LA.

Citation Format: Roy S. Weiner, Lee Roy Morgan, Marcus Ware, Tallat Mahmood, Craig Gordon, Manish Bhandari, Andrew Rodgers, Marc Matrana, Thomas M. Cosgriff, Philip Friedlander, Jay J. Zou. Phase II clinical trial results for 4-demethyl-4-cholesteryloxycarbonyl-penclomedine (DM-CHOC-PEN) in advanced non-small cell lung cancer (NSCLC) involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT152.