Abstract P038: Early phase II clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in adolescents and young adults (AYA) with brain cancers

• Published in: Molecular cancer therapeutics 2021-12, Vol.20 (12_Supplement), p.P038-P038
• Main Authors: Morgan, Lee Roy, Weiner, Roy S., Mahmood, Tallat, Ware, Marcus L., Rodgers, Andrew H., Bhandari, Manish, Friendlander, Philip
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-21-P038

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 is currently in Phase II trial in AYA subjects with cancer that have CNS involvement. The aims for the trials are to assess clinical responses, monitor toxicities, safety and confirm the MTDs for IV administered DM-CHOC-PEN (IND 68,876) to AYA subjects with cancer involving the CNS. We report here responses and toxicities observed to date in Phases I & II DM-CHOC-PEN clinical trials with AYA subjects that had cancer involving the CNS. Subjects & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to AYA subjects. The dosing schedule was 2-tiered: subjects with liver involvement received 85.8 mg/m2 and subjects with normal liver function received 98.7 mg/m2. Results: nineteen (19) AYA subjects with CNS involvement have been treated to date. The common tumor types treated were oligoastrocytoma, astrocytoma, GBM; leukemia (ALL), lymphoma (NHL), melanoma, breast and lung cancers (NSCL). Three (3) AYA patients are currently being followed with diagnoses of breast cancer, astrocytoma, and lung cancer and have had good qualities of life at 12, 59 and 72+ mos. All patients have been followed with lab tests, scans (RECIST 1.1) and virtual exams. The drug was well tolerated. The most common adverse effect was 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. The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) were 3 and 24 hours, respectively for the AYA subjects; similar to what was seen for older adults. The drug and metabolite were still detectable in plasma and rbcs for 21 to 50 days in the AYA (15 – 39 y/o) group vs. 3 to < 21 days (previously reported for adult subjects (>60 y/o) (AACR #1185, 2013). Differences in PK profiles between AYA and older adult subjects will also be reviewed in depth. Conclusion: DM-CHOC-PEN is safe for usage 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 cel