Early Phase I Results for 4-Demethyl-4-cholesteryloxypenclo-medine [DM-CHOC-PEN] as Therapy in Adolescent and Young Adult (AYA) Subjects with Advanced Malignancies

Abstract

4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine carbonate with a MOA via bis-alkylation of DNA @ N 7-guanine and N 4-cytosine that has completed adult clinical Phase I and II trials in individuals with malignancies involving the CNS. We report here objective clinical observations seen in a clinical Phase I DM-CHOC-PEN trial with AYA subjects that have cancer (some of which had CNS involvement). Subjects & Methods: DM-CHOC-PEN was administered as a single 3-hr IV infusion once every 21 days in escalating doses from 50-98.7 mg/m 2 to individuals (aged 15-39 years of age) with advanced malignancies. Results: Twelve (12) AYA individuals have been treated to date (with or without CNS involvement). The drug was well tolerated with fatigue (17%) being the most common adverse effect. No neuro/cognitive, liver dysfunction, hematological, cardiac, renal or GI toxicities were observed. Pharmacokinetic profiling revealed higher AUCs for all dose levels (50-98.7 mg/m 2) than had been seen previously in adults. Three (3) AYA individuals treated (1 each with NSCLC, ALL, and astrocytoma involving the CNS) have responded with CR/PR (RECIST 1.1), improved QOL/PFS (Kaplan-Meier) and OS from 8 to 35+ mos. Conclusion: DM-CHOC-PEN is safe in doses of 50-98.7 mg/m 2 and produced objective responses with improved OS and manageable toxicities in AYA individuals with malignancies involving the CNS. Complete data on subject responses and observed toxicities will be presented. The data support a 3-stage mechanism for tumor cytotoxicity: entry into the CNS and into the tumor via reversible binding to RBC membranes; then transported into cancer cells with L-glutamine; and bis-alkylation as described above.

New Approaches in the Treatment of Glioblastoma Multiforme

“…Table 1 reviews the results reported during Phase I/II clinical trial with DM-CHOC-PEN in primary brain tumors in adults [5,17]. Unfortunately, as noted in Table 1, DM-CHOC-PEN is not active in all GBMs treated to date [5,17]. During the trials, tumor tissue from several patients that received the drug were obtained and analyzed.…”

“…Thus, developing immune modulators that prevent impairment of cytotoxic lymphocytes is of potential importance and could be useful alone or with cytotoxic agents [1]. [5,17]; NED-no evidence of disease [5,17].…”

The use of 4-Demethyl-4-cholesteryloxypenclomedine [DM-CHOC-PEN] as Therapy in Adolescent and Young Adult (AYA) Subjects with Advanced Malignancies Involving the Central Nervous System (CNS)

“…++ DM-CHOC-PEN was administered IV once every 21-days; *No CNS disease -no responses; **CNS -CR, w/ peripheral progression The pharmacokinetic profile for DM-CHOC-PEN in the AYA subjects with a lower T 1/2 β -28:71 h reflects a 'healthier' metabolic profile for the drug compared with older adults, who may have been receiving medications for associated comorbidities resulting in induced hepatic metabolic activity (9). Moreover, AYA subjects-15-39 years old -are of major interest since they are not commonly enrolled in clinical trials and typically managed by pediatric and adult oncologists, rather than AYA oncology specialists who also appreciates the physical, psychosocial, emotional, sexual, spiritual, financial, dietary, etc.…”

“…Thus, DM-CHOC-PEN may be multifunctional -killing micrometastases, inhibiting DNA repair and inducing an 'abscopal' immune-type effect (7,8). The latter mechanism of action continues to be supported (9). peculiarities of this age group and, therefore apply specialized knowledge to their care (10,11).…”