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 I/II studies [AACR, #CT129, 2017] in adult 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 the long term Phase I clinical data that supports safety, dose-tolerance and use of 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 anywhere from 48 hours to 3-weeks prior to receiving stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT). Radiation was administered in doses of 15-30 Gy depending on the size and number of lesions. Results: Nineteen (19) subjects with cancer involving the CNS have been treated to date with DM-CHOC-PEN (6-NSCLC, 1-breast, 1-melanoma, 5-GBM, 3-sarcomas, 1-astrocytoma & 2-renal cell carcinomas). Subjects received 39, 50, 70, 86.8 or 98.7 mg/m2 of DM-CHOC-PEN. Five subjects received WBRT (30 Gy) and 14 subjects received SRS (15-24 Gy. One (1) subject with NSCLC did develop vasogenic edema and tumor necrosis which resolved and the subject is in complete remission 55+ mos. A second subject with a recurrent GBM developed Gr-3 confusion secondary to an enlarging lesion which was removed. Drug was present in ng/g of tumor conc.; confusion resolved. Ten (10) of the thirteen (13) subjects have had objective results (OS 8-58 mos.) Bioavailability for DM-CHOC-PEN revealed a rebound phenomenon @ ~ 50 hours post-infusion with a T-release of 26.7 h. and drug in the plasma (Cmax=17.5 µg/mL) until day 15 . The AUC was linear for all doses. Pre-clinical radiosensitization in vitro studies [AACR #1917, 2017] supported the present trial. 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 this trial supported the drug's ability to penetrate human tumors involving the CNS and acceptability as a method to improving responses to 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: Steven J. DiBiase, Roy S. Weiner, Tallat Mahmood, Kendra Harris, Ronald Kawauchi, Kiran Devisetty, James Herman, Manish Bhandari, Marcus Ware, Paul Friedlander, Lee R. Morgan, Ali Baghian. Phase I clinical trial: results from the use of 4-demethyl-4 cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) plus radiation as treatment for 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 CT101.