Phase I Clinical trial with Demethyl cholesteryloxycarbonylpenclomedine DM CHOC PEN in Children with Cancer Involving the CNS

DESCRIPTION provided by applicant The primary goal of this Phase I pediatric oncology clinical trial will be to evaluate the safety and use of demethyl cholesteryloxycarbonylpenclomedine DM CHOC PEN as anticancer therapy for children with advanced cancer involving the central nervous system CNS 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 The FDA supports the proposed Phase I clinical trial designed to identify safety toxicities and an acceptable MTD in children with CNS cancers now that the adult Phase I trial has been completed with acceptable toxicity and MTDs identified Primary malignant cancers of the central nervous system CNS account for less than of all malignancies yet brain tumors are the nd most common cause of death in children Some childhood malignancies e g intrinsic diffuse pontine gliomas are located such that surgery is not attempted 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 drugandapos s use in children with CNS tumors at an age in which brain development and maturation is still very active with cognitive ability The observed responses noted in adults with metastatic cancers involving the CNS and cerebellum treated with DM CHOC PEN Table may also occur in medulloblastoma a primitive cerebellar tumor of neuroectodermal origin that is the nd most common brain tumor in children Thus the drugandapos 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 will be to Conduct a Phase I clinical trial with DM CHOC PEN in children that have advanced cancers involving the central nervous system to document toxicities define an acceptable maximum tolerated dose MTD and identify anticancer activity for the drug All data will be communicated through an e RAP program This will be accomplished through IND Studying the pharmacokinetic dynamic profiles of DM CHOC PEN and metabolites in children with advanced cancers involving the central nervous system Analyze data and prepare a Phase II clinical trial in children for FDA review Dr Johannes Wolff Chief Department of Pediatric Oncology Cleveland Clinic Cleveland OH will be the trial site director Dr Wolff is an established pediatric neurooncologist and qualified to direct the clinical trial Consultants are identified in the Design Section PUBLIC HEALTH RELEVANCE Primary malignant cancers of the central nervous system CNS account for less than of all malignancies yet brain tumors are the nd most common cause of death in children Surgery is the primary treatment with radiation always a concern and often not offered secondary to long term changes in development and cognitive functions in brain function Some childhood malignancies e g intrinsic diffuse pontine gliomas are located such that surgery is not attempted effective chemotherapy is not available 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 or neuro toxicities with improved quality of life and overall survival in adul Phase I II clinical trials IND The FDA supports a Phase I clinical trial with DM CHOC PEN designed to identify safety toxicities and an acceptable MTD in children with CNS cancers now that the adult Phase I trial has been completed with safety acceptable reversible toxicity and MTDs identified 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 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 drugandapos s use in children with CNS tumors at an age in which brain development and maturation is in progress with cognitive ability The drugandapos s unique properties and lack of toxicities noted in the adult studies merits the Phase I trial proposed here in childre The specific objectives of this Phase I study will be to Conduct a clinical Phase I trial with DM CHOC PEN in children that have advanced cancers involving the central nervous system to document toxicities define an acceptable maximum tolerated dose MTD and identify anticancer activity for the drug This will be accomplished through IND Studying the pharmacokinetic dynamic profiles of DM CHOC PEN and metabolites in children with advanced cancers involving the central nervous system Prepare a Phase II clinical trial in children for FDA review Dr Johannes Wolff MD Chief Department of Pediatric Oncology Cleveland Clinic Cleveland OH will be the trial site director Established and qualified consultants are included in the Relevant Experience Section