Abstract CT225: A phase I cancer clinical trial for 4-demethyl-4cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) IND 68.876
Authors: Weiner Roy S. , Friedlander Philip , Gordon Craig , Saenger Yvonne , Mohmood Tallat , Ware Marcus , Rogers AH , Bastian Gerard , Urien S , Morgan LR 
Published: May 2015

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 via oxidative stress. The aims of this clinical trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), pharmacokinetics (PK) and monitor for clinical responses - IND 68,876.
Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21-days to patients with advanced cancer. Melanoma (n=3), colorectal CA (CRC, n=3), breast (n=3) and glioblastoma multiforme (GBM) (n=6) the most frequent diagnoses. The starting dose was 39 mg/m2 with escalations to 111 mg/m2.
Results: Twenty-six (26) patients have been treated. The MTD was 2-tiered and defined as 85.8 mg/m2 for patients with liver involvement and 98.7 mg/m2 for patients without liver abnormalities. The drug was well tolerated with the most common adverse effects being fatigue (n=2), liver dysfunction - elevated bilirubin (Gr-3, n=3; 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 have been observed. Three (3) patients with liver metastasis demonstrated hyperbilirubinemia (Gr-3 SLT) - 2 at the 98.7 mg/m2 and one (1) at the 111 mg/m2 levels Five (5) additional patients with liver disease have been treated at 85.8 mg/m2 level without toxicity. 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 (metabolite) showed a rebound phenomenon @ ∼ 50 hours post-infusion with a T release of 26.7 h. 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 21. 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. Patients receiving dexamethasone demonstrated lower blood levels of DM-CHOC-PEN, 2o induction of steroid esterase activities. The latter will be discussed.
Conclusion: DM-CHOC-PEN is safe at the presented dose levels and shows a favorable PK profile. Eight (8) patients have had responses or significant PFS, including 6 with CNS involvement. Patient responses/toxicities will be presented. A Phase II trial has begun in patients with primary brain cancer and brain metastases from melanoma, breast cancer and lung cancer. Supported by NCI/SBIR grant - R43/44CA132257.
Citation Format: Roy S. Weiner, Philip Friedlander, Craig Gordon, Yvonne Saenger, Tallat Mohmood, Marcus Ware, AH Rogers, Gerard Bastian, S Urien, LR Morgan. A phase I cancer clinical trial for 4-demethyl-4cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) IND 68.876. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT225. doi:10.1158/1538-7445.AM2014-CT225