A Phase I Cancer Clinical Trial For 4-Demethyl-4cholesteryloxycarbonylpenclomedine (Dm-Choc-Pen) Ind 68.876

Purpose: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate whose MOA is via alkylation of DNA @ N 7 - 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/m 2 with escalations to 111 mg/m 2 . Results: Twenty-six (26) patients have been treated. The MTD was 2-tiered and defined as 85.8 mg/m 2 for patients with liver involvement and 98.7 mg/m 2 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/m 2 and one (1) at the 111 mg/m 2 levels Five (5) additional patients with liver disease have been treated at 85.8 mg/m 2 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, T 1/2 α - 0.63 h & T β - 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/m 2 ); DM-CHOC-PEN was also detected in the urine (C max =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 (2 o 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/m 2 . Patients receiving dexamethasone demonstrated lower blood levels of DM-CHOC-PEN, 2 o 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