Abstract 4746: Early clinical support for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as a radiosensitizer in cancers involving the CNS

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/II studies [AACR #CT129, 2016] in subjects with cancers involving the CNS. The current presentation reviews clinical and in vitro data that support radiosensitizing properties for DM-CHOC-PEN in cancers involving the CNS. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer involving the CNS. The dose schedule was 2-tiered: 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal livers. All subjects with resistant or new CNS lesions that did not respond to DM-CHOC-PEN were given the option of surgery, stereotaxic radio-surgery (SRS) or whole brain irradiation (WBRT). As preclinical support, human NSCLC adenocarcinoma cells (H-2086) growing in culture (106 cells/mL) were pretreated with DM-CHOC-PEN (0.1 -1.0 µg/mL) for 24 hrs, drug washed, re-fed fresh medium and then 48 h later irradiated (SRS with 6, 9 or 12 Gy). Results: Fifty-three (53) subjects with/without CNS involvement have been treated to date with DM-CHOC-PEN. Five (5) subjects (4-NSCLC & 1-sarcomas) in the Phase I/II trials required surgery for persistent CNS lesions following DM-CHOC-PEN therapy. DM-CHOC-PEN was identified in samples from all subjects - 90-212 ng/g tumor [subjects had been treated with 39-98.8 mg/m2 of drug]. Five subjects (1-sarcoma & 4-NSCLC) who had been treated with DM-CHOC-PEN for 6-wks - 8-mos had persistent NSCLC lesions involving the CNS were treated with SRS or WBRT. All five subjects had excellent objective results (OS 8+ - 29+ mos) with no CNS toxicity. Preclinical in vitro studies supported the clinical data: NSCLC cells treated with DM-CHOC-PEN (0.1 -1.0 µg/mL) demonstrated 50 & 100% cytotoxicity @ 0.4 & 1.0 µg/mL; for SRS alone (6, 9 &12 Gy) - cell kill was 20 & 65% @ 6 & 12 Gy [100% kill was not observed at this dose range]; for DM-CHOC-PEN (0.25 µg/mL) + SRS (6-12 Gy) - cell kill was 80 & 100% @ 6 & 12 Gy. Thus, in combination - less drug (0.25 µg/mL) and 12 Gy - produced a 100% cell kill, as compared to either SRS or drug, alone. Photon induced charge transfer reactions with DM-CHOC-PEN will be discussed. Conclusion: Preliminary data is presented that supports DM-CHOC-PEN’s cytotoxicity and radiosensitizing properties in cancers involving the CNS