Abstract CT129: Phase II clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in NSCLC involving the CNS
Authors: Weiner Roy S. , Mahmood T , Gordon C , Ware ML , Morgan LR , Cosgriff TM , Rodgers AH , Bastian G , Kawauchi R , Matrana M , Zou J-J 
Published: July 2016

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 a Phase I study [AACR #1185, 2013] and is being evaluated in a Phase II trial in patients with primary brain cancers and with melanoma, breast, and lung cancers with metastases to brain. The aims are to assess clinical response when DM-CHOC-PEN is administered I.V. at MTD and to monitor duration of responses and safety (IND 68,876). We report here the responses and toxicities seen in patients with NSCLC involving the CNS.

Patients & Methods: In Phase I, DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to patients with advanced cancer; cohorts received escalating doses from 39 - 111 mg/m2. The Phase II dose schedule is 2-tiered: 85.8 mg/m2 for patients with liver involvement and 98.7 mg/m2 for patients with normal livers. Results: Fifty two (52) patients have been treated to date - 26 in Phase I (cancer patients with or without CNS involvement) and 26 in Phase II (with CNS involvement). The drug was well tolerated; the most common adverse effects were fatigue (17%), reversible liver dysfunction (9%) and nausea (11%). No neuro/psychological, hematological, cardiac or renal toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels (39-111 mg/m2). The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) were 3 and 24 hours, respectively. Both DM-CHOC-PEN and DM-PEN were detected 3 to 15 days after administration associated (up to 50%) with rbcs. DM-CHOC-PEN was also detected in CNS tumor tissue obtained surgically from five (5) patients - concentrations of 75-210 ng/g, 22 days to 9 mos. post treatments at doses of 39 or 98.7 mg/m2 of drug. To date, 16 patients with lung cancer (11 with NSCLC involving the CNS) have been treated. Seven of the 11 patients with NSCLC involving the CNS (incl. 6 with cerebellar disease) have responded with CR/PR (RECIST 1.1) and improved OS/QOL/PFS (Kaplan-Meier) lasting 6+ - 21+ mos. Conclusion: DM-CHOC-PEN is safe at these dose levels and has produced objective responses with manageable toxicities in NSCLC involving the CNS. Complete data on patient responses and observed toxicities will be presented. We propose a 2-stage mechanism for drug entry into the CNS and into NSCLC cells via reversible binding with RBCs and then L-glutamine transport into cells. Supported by NCI/SBIR grants - R43/44CA132257 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center.

Citation Format: Roy S. Weiner, T Mahmood, C Gordon, ML Ware, LR Morgan, TM Cosgriff, AH Rodgers, G Bastian, R Kawauchi, M Matrana, J-J Zou. Phase II clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in NSCLC involving the CNS. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT129.