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

• L.R. Morgan

  DEKK-TEC, Inc., New Orleans, LA, USA

• R.S. Weiner

  Tulane University Medical Center, New Orleans, LA, USA

• M.L. Ware

  Ochsner Medical Center, New Orleans, LA, USA

• M. Bhandari

  The Christ Hospital, Cincinnati, OH, USA

• T. Mahmood

  Detroit Clinical Research Centers, Owosso & Lansing, MI, USA

• P. Friedlander

  Mount Sinai Medical Center, New York, NY, USA

4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine carbonate with a MOA via bis-alkylation of DNA @ N⁷-guanine and N⁴-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/m² 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/m²) 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/m² 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.

Siegel RL, Miller KD, Jemal A. Cancer Statistics. CA Cancer J Clin 2017; 67: 7-30. https://doi.org/10.3322/caac.21387

Wilson E. Brain tumors affect adolescents and young adults differently. Hem Onc Today 2016; 8-9.

Termini J, Neman J, Jandial R. Role of the neural niche in brain metastatic. Cancer Res 2014; 74: 4011-4015. https://doi.org/10.1158/0008-5472.CAN-14-1226

Franklin A. A Growing identity for adolescent and young adult oncology. Oncology Times 2016; 38: 8-10. https://doi.org/10.1097/01.COT.0000508317.51300.6e

Hayes-Lattin. Integrating AYA oncology care into the worlds of pediatric and adult oncology care to improve cancer outcomes. The ASCO Post 2016; 10: 82-83.

Pemmaraju N. Adolescent & young adults with chronic myeloid leukemia. Oncology Times 2017; 39(Issue 10): 25-26. https://doi.org/10.1097/01.COT.0000520172.33444.4e

Weiner RS, Ware ML, Bhandari M, Mahmood T, Friedlander P, Morgan LR. The tolerance and safety of 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in adolescent and young adult (AYA) subjects with advanced malignancies. J Transl Sci 2017; 3: 1-4.

Morgan LR, Struck RF, Waud WR, Jursic BS, Serota D, Papagiannis C, Rodgers AH. Carbonate and carbamate derivatives of 4-demethylpenclomedine as novel anticancer Agents. Cancer Chemotherapy Pharmacology 2009; 64: 618-623. https://doi.org/10.1007/s00280-009-0933-9

Morgan LR, Rodgers AH, Bastian G, Benes E, Waud WS, Papagiannis C, Krietlow D, Jursic E, Thompson R. Comparative preclinical pharmacology and toxicology for 4-demethyl-4-cholestryloxylcarbonylpenclomedine (DM-CHOC-PEN) – a potential neuro-alkylating agent for glioblastoma (GBM) and metastatic cancers involving the central nervous system. In: Morgan, LR, editor. Tumors of the Central Nervous System – Primary and Secondary. Rijeka: InTech; 2014; pp. 239-263.

Weiner RS, Friedlander P, Gordon C, Saenger Y, Ware RL, Mahmood T, Rodgers AH, Bastian G, Urien S, Morgan LR. A phase I cancer clinical trial for 4-demethyl-4-cholesteryl-oxycarbonylpenclomedine (DM-CHOC-PEN). Proc Am Assoc Cancer Res 2014; 56: 746.

Weiner RS, Friedlander P, Gordon C, Saenger Y, Ware RL, Mahmood T, Rodgers AH, Bastian G, Urien S, Bhandari M, Morgan LR, Zu J-J. Results of Phase II cancer clinical trials for 4-demethyl-4-cholesteryoxycarbonylpenclomedine (DM-CHOC-PEN). Proc Am Assoc Cancer Res 2016; 58: 236.

Morgan LR, Benes E, Rodgers AH, Weiner RS, Mahmood T. Penetration of NSCLC involving the CNS via L-glutamine transport. 16th Int. Lung Cancer Congress 2015: Abstr. 6.

Toronezos ES. Discussions on adolescent and young adult survivorship. Cancer Survivorship Symposium 2017.

Doyle C. What do we still need to know about adolescent and young adult survivorship? Oncology Practice Management 2017; 34-35.

• PDF