4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN: A Phase II Clinical Trial in Adolescents/Young Adults (AYA)with CNS Malignancies

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Abstract – The goal of this Phase II clinical trial application will be to evaluate 4-demethyl-4- cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as anticancer therapy for adolescents and young adults (AYA) with cancer involving the brain in a Phase II clinical trial. DM-CHOC-PEN (Fig. 1) is a polychlorinated pyridine cholesteryl carbonate (Fig. 1) that is lipophilic, electrically neural, is able to cross the blood brain barrier (BBB), localizes in CNS tumors with MOAs – alkylation of DNA @ N7 – guanine and is not transported out of the brain via Pgp (p-glycoprotein). The drug fulfills all the criteria to be a CNS active anticancer agent and recently received Orphan Drug Designation approval as therapy for NSCLC involving the CNS. The drug will complete a Phase I clinical trial in AYA subjects with advanced cancer 1st quarter – 2018 - IND 68,876. Objective responses, acceptable toxicities and no evidence of neurotoxicity have been noted in the AYA Phase I trial involving subjects with cancers involving the CNS. Hepatic toxicity that was observed in the adult Phase I trial has not been observed with the AYA subjects. Novelty and Potential Clinical Advantage – Current reviews report that almost 700,000 people in the US are living with brain or CNS tumors. Nearly 15% of these tumors involve the adolescent/young adult (AYA) population, aged 15-39 years of age. It is predicted that 10,617 AYA individuals will be diagnosed with brain or CNS tumors resulting in 434 deaths this year. For males and female individuals <20 years of age, primary brain and central nervous system tumors are the most common causes of death from cancer and in the 20-39 year age group the first cause of cancer-related deaths in males and the fifth cause of cancer-related deaths in females. However, the incidence and histology of cancer types vary according to subject age. Trends in CNS tumors have sharply increased since 1989 for AYA individuals with a history of cancer, who appeared to have ‘beaten the odds’ to have a reoccurrence from cancer, only to develop involvement in the CNS after years of remission. The aims will include: 1) Initiation of a Phase II trial with DM-CHOC-PEN administered IV to AYA subjects with cancer involving the CNS and/or spinal nervous systems (SNS) and varication that the proposed doses are acceptable, monitor pharmacokinetics/pharmacodynamics and toxicities. 2) Monitor tumor responses per imaging/examinations using RECIST guidelines. 3) Electronically store/analyze clinical data for responses, toxicity, and PK relationships. 4) Continue to bank blood and tumor tissue from pre- and post-treated patients when possible tumor tissue assays for tumor - drug/metabolite content and bio-markers; for future studies. 5) Prepare a FDA Orphan Drug Designation (ODD) presentation/application for DM-CHOC-PEN as therapy for AYA subjects with malignancies involving the CNS/SNS. 6) Manage a platform to provide support information for AYA subjects with CNS/SNS malignancies. Thus, DEKK-TEC’S goal continues to be the development of DM-CHOC-PEN as therapy for subjects with cancer, with an emphasis on primary or metastatic central and spinal nervous system involvement. The present study will involve documenting that DM-CHOC-PEN has a role in treating AYA subjects with cancer involving the CNS or SNS and bringing together a team that can design a complete management approach – a ‘platform’ for support sources that can be disseminated to these individuals that ‘often fall through the cracks’ of health care and are not treated appropriately because of their age deferential – too old for pediatric oncologists and too young for conventional medical oncologists.