4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine carbonate with a MOA via bis-alkylation of DNA @ N 7-guanine and N 4-cytosine that has completed adult clinical Phase I and II trials in individuals with malignancies involving the CNS. We report here objective clinical observations seen in a clinical Phase I DM-CHOC-PEN trial with AYA subjects that have cancer (some of which had CNS involvement). Subjects & Methods: DM-CHOC-PEN was administered as a single 3-hr IV infusion once every 21 days in escalating doses from 50-98.7 mg/m 2 to individuals (aged 15-39 years of age) with advanced malignancies. Results: Twelve (12) AYA individuals have been treated to date (with or without CNS involvement). The drug was well tolerated with fatigue (17%) being the most common adverse effect. No neuro/cognitive, liver dysfunction, hematological, cardiac, renal or GI toxicities were observed. Pharmacokinetic profiling revealed higher AUCs for all dose levels (50-98.7 mg/m 2) than had been seen previously in adults. Three (3) AYA individuals treated (1 each with NSCLC, ALL, and astrocytoma involving the CNS) have responded with CR/PR (RECIST 1.1), improved QOL/PFS (Kaplan-Meier) and OS from 8 to 35+ mos. Conclusion: DM-CHOC-PEN is safe in doses of 50-98.7 mg/m 2 and produced objective responses with improved OS and manageable toxicities in AYA individuals with malignancies involving the CNS. Complete data on subject responses and observed toxicities will be presented. The data support a 3-stage mechanism for tumor cytotoxicity: entry into the CNS and into the tumor via reversible binding to RBC membranes; then transported into cancer cells with L-glutamine; and bis-alkylation as described above.