DM-CHOC-PEN Plus Radiation for Brain Tumors

The primary goal of this Phase I oncology clinical trial will be to evaluate the safety and use of 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) plus radiation, as anticancer therapy for adults with advanced cancer involving the central nervous system (CNS) involvement. 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 adult Phase I/II clinical trials - IND - 68,876. The drug recently received Orphan Drug designation for NSCLC involving the brain. The FDA supports the proposed Phase I clinical trial designed to identify safety, toxicities and an acceptable MTD of the drug in combination with radiation in adult cancers subjects with CNS involvement. Almost 700,000 people in the US are living with tumors involving the CNS or spinal nervous system (SNS) tumors. Trends in CNS tumors have sharply increased since 1989 for individuals with a history of cancer, who appeared to have 'beaten the odds', only to have a reoccurrence from cancer involving the CNS after years of remission; the most common types of cancer in AYA individuals are - from lung, breast, melanoma, and sarcoma malignancies. This group of individuals deserves special attention. 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 neurotoxic behavioral alterations and associated events supports the drug's use in combination with radiation in the treatment of CNS tumors. The observed responses noted in adults with metastatic cancers involving the CNS and cerebellum treated with DM-CHOC-PEN is encouraging. Thus, the drug's unique properties and lack of toxicities noted in the adult studies merits the Phase I trial proposed here in combination with radiation. The specific objectives of this Phase I study will be to: 1. Conduct a Phase I clinical trial with DM-CHOC-PEN plus radiation in adults with advanced cancers involving the central nervous system to document toxicities, define an acceptable maximum tolerated dose (MTD), and identify anticancer activity for the binary treatment DM-CHOC-PEN plus radiation. All data will be communicated through an e-RAP program. This will be accomplished through IND - 68.876. 2. Studying the pharmacokinetic/dynamic profiles of DM-CHOC-PEN and metabolites in adults after being treated with DM-CHOC-PEN and radiation. 3. Analyze data and prepare a Phase II clinical trial or a Designation Orphan Drug application for FDA review.