Abstract CT181: Phase I/II clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as treatment for adolescents and young adults (AYA) with cancers involving the CNS
Authors: Morgan Lee Roy , Weiner Roy S. , Mahmood Tallat , Ware Marcus , Rodgers Andrew H. , Bhandari Manish , Friedlander Philip 
Published: September 2020

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 now in Phase II clinical trials in AYA subjects with cancer with CNS involvement. The aims were to assess clinical responses, monitor toxicities/safety and confirm MTDs for IV administered DM-CHOC-PEN in AYA individuals (IND 68,876). We report here responses, pharmacokinetics and toxicities seen in Phase I/II DM-CHOC-PEN trials with AYA subjects +/- CNS involvement. Subjects & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer in escalating doses from 50 to 98.7 mg/m2. The MTD identified was similar to that seen during the adult Phase I trial – 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal liver function. Results: Fifteen (15) AYA subjects have been treated to date (with or without CNS involvement). The common tumor types treated were oligoastrocytoma, astrocytoma, GBM; leukemia (ALL), lymphoma (NHL), melanoma, breast and lung cancers (NSCL). Most subjects (12) had CNS involvement. The drug was well tolerated; the most common adverse effects were fatigue (17%). No neuro/cognitive, liver dysfunction, hematological, cardiac, renal or GI toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels (50-98.7 mg/m2). The Cmax for DM-CHOC-PEN was 100 hours for the AYA subjects; very different to what has been observed for older adults (&gt;50 y/o). The drug was also cleared quicker, as compared to older adults (2o to less existing co-morbidities in the AYA subjects). However, the drug was detectable in plasma and rbcs for 15 days in the AYA (15 – 39 y/o). Differences in PK profiles between AYA and older adult subjects will be reviewed in depth. Three (3) of the AYA subjects (1 each with NSCLC, astrocytoma and breast cancers involving the CNS) have responded with CR/PR (RECIST 1.1), improved QOL/PFS (Kaplan-Meier) and OS from 12 to 58+ mos. All subjects will be reviewed. Conclusion: DM-CHOC-PEN is safe in doses of 39 – 98.7 mg/m2 and has produced objective responses with manageable toxicities in AYA 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 cancer cells via reversible binding with RBCs and then association with L-glutamine transport into cells. Supported by NCI/SBIR & LA state grants – R43/44CA132257, R43/44CA203351 and NIH NIGMS 1 U54 GM104940 – the latter funds the Louisiana Clinical and Translational Science Center.

Citation Format: Lee Roy Morgan, Roy S. Weiner, Tallat Mahmood, Marcus Ware, Andrew H. Rodgers, Manish Bhandari, Philip Friedlander. Phase I/II clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as treatment for adolescents and young adults (AYA) with cancers involving the CNS [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT181.