A Phase II: Safety and Tolerance of 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in Adolescent and Young Adults (AYA) With Malignancies Involving the CNS

The primary goal of this Phase II AYA oncology clinical trial was to evaluate the safety and efficacy of 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN), as anticancer therapy in AYA individuals with advanced cancer involving the central or spinal nervous system (CNS \& SNS). DM-CHOC-PEN is a polychlorinated pyridine cholesteryloxycarbonate that crosses the blood brain barrier (BBB), accumulates in CNS tumor tissue in humans and has produced objective responses, with acceptable/reversible hepatic toxicities (in patients with prior liver disease) and no evidence of hematological, renal, neuro-toxicities with improved quality of life and overall survival in adolescent, young adult and adult Phase I/II clinical trials - IND - 68,876. The FDA has supported the Phase II clinical trial designed to identify safety and efficacy in AYA cancers subjects and the trial has been completed with acceptable toxicity and MTDs identified. Almost 700,000 people in the US are living with tumors involving the CNS or spinal nervous system (SNS) 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 in the US. Trends in CNS tumors have sharply increased since 1989 for AYA individuals with a history of cancer, who appeared to have 'beaten the odds', only to have a re-occurrence from cancer involving the CNS after years of remission; the most common types of cancer in AYA individuals are - melanoma, leukemia and sarcomas. This group of individuals deserves special attention. For males and female individuals <20 years of age, primary brain and secondary cancers of the CNS and spinal nervous system (SNS) 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. The incidence and histology of cancer types does vary according to subject age. A critical component in designing an agent that will cross the protective blood brain barrier (BBB) is that the agent must be readily transported intracerebrally, does not produce local irritation/neurotoxicity and is not recycled back into the general circulation. After IV administration DM-CHOC-PEN readily penetrates the BBB, is not a substrate for the transporter protein P-glycoprotein (P-gp) and has shown anticancer activity in CNS tumors. The effective transport of DM-CHOC-PEN into CNS tumors in adults without neurotic behavioral alterations and associated events supports the drug's use in children with CNS tumors at an age in which brain development and maturation is still very active with cognitive lability. The observed responses noted in adults with metastatic cancers involving the CNS and cerebellum treated with DM-CHOC-PEN may also occur in medulloblastoma in AYA. Thus, the drug's unique properties and lack of toxicities noted in the adult studies merits the Phase I trial proposed here in children. The specific objectives of this Phase I study were to: 1. Conduct a Phase II clinical trial with DM-CHOC-PEN in AYA individuals that have advanced cancers with central or spinal nervous systems involvements and monitor safety and document anticancer activity for the drug. All data was between investigators communicated through an e-RAP program. This was accomplished through IND - 68.876. 2. Verify the pharmacokinetic/dynamic profiles of DM-CHOC-PEN and metabolites in AYA subjects with advanced cancers involving the central nervous system. 3. Analyze data and prepare an Orphan Drug Designated package for FDA submission for AYA subjects with CNS involvement from cancer for review.