Abstract CT218: Results from the early cancer clinical trials for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN)
Authors: Weiner Roy S. , Friedlander P , Mahmood T , Hormigo Adilia , Gordon C , Saenger Y , Ware ML , Thirukonda VK , Patel VM , Cosgriff TJ , Rodgers AH , Morgan LR , Bastian G 
Published: August 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 N6 - cytosine and via oxidative stress. DM-CHOC-PEN underwent a phase I study in patients with advanced cancer +/- CNS involvement and is being evaluated in a phase II trial in patients with primary brain cancer and brain metastases from melanoma, breast, and lung cancers. The aims are to assess clinical responses when DM-CHOC-PEN is administered I.V, at maximum tolerated dose (MTD) and to monitor safety/toxicities, pharmacokinetics, and cardiac functions - IND 68,876.
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 - melanoma (n = 3), colorectal CA (n = 4), breast (n = 3), lung (n = 8) and glioblastoma multiforme (GBM) (n = 9) - the most common tumor treated. Cohorts were treated with escalating doses from 39 to 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: Forty (40) patients have been treated to date - 27 in phase I and 13 in phase II. The drug was well tolerated; the most common adverse effects were 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), nausea (Gr-1/2, n = 5) and an allergic reaction (Gr-2, n = 1). Three (3) patients with liver metastasis had hyperbilirubinemia (Gr-3 SLT) - two (2) at 98.7 mg/m2 and one (1) at 111 mg/m2 levels. No neuro/psychological, hematological, cardiac or renal toxicities were observed. PK studies revealed the following profile for DM-CHOC-PEN 98.7 mg/m2: AUC o-t = 1850 mg.h/L, CL - 3.0 L/h, T1/2 α - 3.3 h & Tβ - 79.1 h. DM-CHOC PEN and DM-PEN (metabolite) showed a rebound phenomenon at ∼50 hours post-infusion with a T release of 26.7 h for plasma and rbcs. DM-CHOC-PEN and DM-PEN were detected 3 and 15 days bound to RBCs (70 - 111 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. DM-CHOC-PEN was detected in spinal sarcoma and in lung cancer tissues (75 & 190 ng/g, resp.) surgically obtained from patients 21-days post single injection of 39 & 98.7 mg/m2, resp. Patients receiving dexamethasone demonstrated lower blood levels of DM-CHOC-PEN along with induction of steroid esterase activities. After multiple doses, DM-CHOC-PEN also induced steroid esterase levels, which reversed within 4 weeks. Steroid esterase assays may be a valuable companion assay.
Conclusion: DM-CHOC-PEN is safe at the presented dose levels and shows a favorable PK profile. To date, 15 patients have had responses with significant PFS/OS, including 10 with CNS involvement. DM-CHOC-PEN is well tolerated with manageable toxicities. Complete patient responses/toxicities will be presented. Supported by NCI/SBIR grant - R43/44CA132257
Citation Format: Roy S. Weiner, P Friedlander, T Mahmood, Adilia Hormigo, C Gordon, Y Saenger, ML Ware, VK Thirukonda, VM Patel, TJ Cosgriff, AH Rodgers, LR Morgan, G Bastian. Results from the early cancer clinical trials for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT218. doi:10.1158/1538-7445.AM2015-CT218