? 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.
Summary ? 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. A critical component in designing an agent to cross the protective BBB is selecting one that will be readily transported intracerebrally, does not produce local irritation and is not rejected back into the general circulation. DM-CHOC-PEN satisfies these requires - penetrates the BBB, plus is not a substrate for the transporter protein P-glycoprotein (P-gp) and not recycled out of the CNS. No neuropsycho-performance alterations or neuro-adverse events have been attributed to the drug in either the animal studies, or in any of the adult subjects treated. DM-CHOC-PEN?s MOA is via bis-alkylation of DNA [forms adducts with N7- guanine and N4 - cytosine] with no hematological/renal toxicities observed, thus the combination should be compatible, however will be monitored closely. The specific objectives of the Phase I study will be to: 1) Initiation of a Phase II trial with DM-CHOC-PEN administered IV to AYA subjects with malignancies involving the CNS and/or spinal nervous systems (SNS). 2) Monitor tumor responses per imaging/examinations using RECIST guidelines. 3) Verify that the proposed doses are acceptable, monitor pharmacodynamics and toxicities. 4) Continue to bank blood/urine/tumor tissue from pre- and post-treated patients for tumor - drug/metabolite content and bio-markers; store blood samples 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) Develop a platform to provide support information for AYA subjects with CNS/SNS malignancies. Drs. T Mahmood, P Friedlander, RS Weiner, T Singleton, Ali Baghian, and ML Ware, will be the coop- clinical trial center directors. They are well-established clinical investigators, a combination of medical, pediatric and neuro-oncologists, most of whom were involved in previous Phase I/II trials with DM-CHOC- PEN and are well qualified to co-direct this binary trial. Consultants are identified in the Relevant Experience Section. Plus, the FDA supports the proposed Phase II trial as described.
