Abstract Purpose: 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 II studies [AACR, #CT129, 2017] in subjects with cancers involving the CNS. Four (4) subjects in the Phase I/II trials required surgery for persistent CNS lesions following DM-CHOC-PEN therapy with 39-98.8 mg/m2 of drug. DM-CHOC-PEN was identified in samples from all 4-subjects - 90-212 ng/g tumor. Thus, the drug penetrates the CNS and tumors and is available to act as a radiosensitizer; the latter has been supported with in vitro studies [AACR, #4746, 2017]. The current presentation reviews Phase I clinical data that supports the safety, dose-tolerance and use for DM-CHOC-PEN plus radiation in subjects with cancers involving the CNS - IND 68,876. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once to subjects with advanced cancer involving the CNS. A single dose (39 mg/m2 to 98.7 mg/m2 in escalating Phase I scheme) was administered once 3-weeks prior to receiving stereotaxic radio-surgery (SRS), gamma knife or whole brain irradiation (WBRT) therapy. Radiation was administered in doses of 15-30 Gy depending on the size and number of lesions. Results: Thirteen (13) subjects with cancer involving the CNS have been treated to date with DM-CHOC-PEN (6-NSCLC, 1-breast, 1-melanoma, 2-GBM & 3-sarcomas). Subjects received 39, 50, 70, 86.8 or 98.7 mg/m2 and 15-30 Gy of radiation. The drug/radiation combination was well tolerated. One (1) subject with NSCLC did develop vasogenic edema and tumor necrosis which resolved and the subject is in complete remission 42+ mos. A second subject with a recurrent GBM with confusion progressed - Gr-3. Ten (10) of the thirteen (13) subjects have had objective results (OS 8-54+ mos.) Bioavailability for DM-CHOC-PEN revealed a rebound phenomenon @ ~ 50 hours post-infusion with a T-release of 26.7 h. The same phenomenon was observed with RBCs (estimation using Monolix 3.2). DM-CHOC-PEN was detected bound to RBCs for 3-days (after 70 mg/m2) and was also detected in the urine (Cmax=17.5 µg/mL) until day 15. The AUC was linear for all doses. Pre-clinical radiosensitization in vitro studies [AACR #1917, 2017] support the present trial study result. Photon induced charge transfer reactions with DM-CHOC-PEN will be discussed as a MOA. Conclusion: Data is presented that documents effectiveness and safety of DM-CHOC-PEN plus radiation as therapy for subjects with cancers involving the CNS. Observations during Phase I/II clinical trials with DM-CHOC-PEN alone supported the drug’s persistent presence in human tumors after systemic administration and possible positive effects on response to subsequent radiation. Complete data on subject responses and observed toxicities will be presented. Supported by - NCI/SBIR grants - R43 CA213545-02 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: RS Weiner, T Mahmood, Lee Roy Morgan, K. Harris, A. Baghian, SJ DiBiase, P. Friedlander, ML Ware, R. Kawauchi, J. Herman, M. Bhandari. A Phase I clinical trial: Use of 4-demethyl-4-cholesteryl- oxycarbonyl-penclomedine (DM-CHOC-PEN) plus radiation as treatments for cancers involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT065.