Abstract 1185: A first-in-humans phase I cancer clinical trial for 4-Demthyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN).
Authors: Weiner Roy S. , Friedlander Philip , Gordon Craig , Saenger Yvonne , Ware Marcus , Mahmood Tallat , Rodgers AH , Bastian Gerard , Urien S , Morgan Lee Roy 
Published: August 2014

Abstract
Purpose: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate whose MOA is via alkylation of DNA @ N7 - guanine and induces oxidative stress. The main aims of this first-in human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs) and pharmacokinetics (PK) of DM-CHOC-PEN - IND 68,876.
Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21-days in 21 patients with melanoma (n=3), colorectal CA (CRC, n=3), and glioblastoma multiforme (GBM) (n= 6); the most frequent diagnoses. The trial allowed enrollment of patients with advanced cancer +/- CNS involvement. The starting dose was 39 mg/m2 with escalations to date up to 98.7 mg/m2.
Results: Twenty-one (21) patients have been treated to date. MTD was 2-tiered and defined as 85.8 mg/m2 for patients with liver involvement and, for patients without liver abnormality it is not yet defined but is at least 98.7 mg/m2, for the latter population. The drug was well tolerated with the most common adverse effects being fatigue (n=2), liver dysfunction - elevated bilirubin (Gr-3, n=2; Gr-2, n=1), ALT/AST (Gr-2, n=3), alk phos (Gr-2, n=3) and an allergic reaction (Gr-2, n=1). No neuro/psychological, hematological or renal toxicity observed.
Two (2) patients with liver metastasis demonstrated hyperbilirubinemia (Gr-3 SLT) at the 98.7 mg/m2 dose level. Five (5) additional patients with liver disease have been treated at 85.8 mg/m2 level without toxicity - the MTD for that stage of cancer. Dose cohorts @ 98.7 mg/m2 are in progress for non-liver staged patients. PK studies in humans revealed the following profile for DM-CHOC-PEN 70 mg/kg: AUC o-t = 980 mg.h/L, CL - 0.141L/h, T1/2 α - 0.63 h & Tβ - 24.1 h. DM-CHOC PEN and DM-PEN showed a rebound phenomenon @ ∼ 50 hours post-infusion with a T release of 26.7h. Same phenomenon is observed in RBCs (estimation using Monolix 3.2). DM-CHOC-PEN and DM-PEN were detected 3 and 15 days bound to RBCs (after 70 mg/m2); DM-CHOC-PEN was also detected in the urine (Cmax=17.5 μg/mL) until day 15. The AUC was linear for all doses. Similar to the rats, the total lipid profiles in the patients were erratic (2o to the lipid emulsion vehicle) during the 3-h infusion period, and then returned to pre-treatment values after 24 h. The triglycerides were the most significantly affected. DM-CHOC-PEN could be identified in spinal sarcoma tissue (in 190 ng/g quantities) obtained surgically from a patient 21- days post single injection of 39 mg/m2. Conclusion: DM-CHOC-PEN is safe at the presented dose levels and shows a favorable PK profile. Seven (7) patients have observed responses or significant PFS, including 5 with CNS involvement. DM-CHOC-PEN is well tolerated with manageable toxicities. Complete patient responses/toxicities will be presented. Supported by NCI/SBIR grant -1R43CA132257.
Citation Format: Roy S. Weiner, Philip Friedlander, Craig Gordon, Yvonne Saenger, Marcus Ware, Tallat Mahmood, AH Rodgers, Gerard Bastian, S Urien, Lee Roy Morgan. A first-in-humans phase I cancer clinical trial for 4-Demthyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1185. doi:10.1158/1538-7445.AM2013-1185