Abstract CT158: Use of 4-demethyl-4-cholesteryloxycarbonyl-penclomedine (DM-CHOC-PEN) as therapy for advanced non-small cell lung cancer (NSCLC) involving the CNS
Authors: Morgan Lee Roy , Weiner Roy S. , Mahmood T. , Gordon C. , Bhandari M. , Rodgers AH , Ware ML , Matrana Marc , Cosgriff Thomas M. , Friedlander Philip , Zou J-J 
Published: June 2022

Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate that was designed to penetrate the blood brain barrier and be useful as therapy for brain tumors (IND 68,876). A 3-stage mechanism is proposed for drug entry into the CNS and into cancer cells via reversible binding with sialic acid on the surface of RBC’s; and transported into cancer cells with L-glutamine. DM-CHOC-PEN has a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine. DM-CHOC-PEN has completed clinical trials involving sixty-four (64) adults and nineteen (19) adolescent/young adult subjects with advanced cancers. Long term survival, good qualities of life and minimal toxicities [AACR #1185, 2013; AACR #CT 129, 2019; AACR #CT152, 2021] have been reported. This update provides affirmation that the drug, previously described as a treatment for non-small cell lung cancer (NSCLC) involving the CNS, is well tolerated with continued durations of responses, no new toxicities, good survival and good quality of life. Primary aims of the previously reported DM-CHOC-PEN clinical trials were to assess clinical response and monitor toxicities/safety and verify the maximum tolerated doses (MTD) for the drug administered IV to subjects with cancer. Here is an update on the long term responses, tolerance and quality of survival in subjects with NSCLC involving the CNS.

Subjects & Methods: DM-CHOC-PEN was administered to adults (&gt; 18 y/o) with NSCLC involving the CNS that lacked genetic rearrangements or tumor targets and/or had failed standard therapies 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: Sixteen (16) adult subjects with NSCLC have been treated to date, which 11 had NSCLC (adeno/large cell carcinomas) involving the CNS that lacked genetic rearrangements, had 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 with no Gr-3 toxicities. The most common Gr-2 adverse effects were reversible fatigue (17%), reversible vasogenic edema (9%) and nausea (9%). No drug associated neuro/psychological, hematological, cardiac or renal toxicities have been observed, nor have there been any drug associated deaths reported. The pK modelling and properties for the drug have been previously reported [AACR #1185, 2013] and continue to be confirmed. Eight (8) subjects with NSCLC involving the CNS responded to DM-CHOC-PEN with documented CR/PR (RECIST 1.1) and improved OS/QOL/PFS (Kaplan-Meier) lasting 8 - 82+ mos. with survivals of 25% at 34 mos., 50% at 10 mos. and 8% at 84+ 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 and improved quality of life 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. Supported by NCI/SBIR grants - R43/44CA132257 and NIH NIGMS 1 U54 GM104940 - the latter supports the Louisiana Clinical and Translational Science Center, New Orleans, LA

Citation Format: Lee Roy Morgan, Roy S. Weiner, T. Mahmood, C. Gordon, M. Bhandari, AH Rodgers, ML Ware, Marc Matrana, Thomas M. Cosgriff, Philip Friedlander, J-J Zou. Use of 4-demethyl-4-cholesteryloxycarbonyl-penclomedine (DM-CHOC-PEN) as therapy for advanced non-small cell lung cancer (NSCLC) involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT158.