SBIR-STTR Award

The primary goal of this Phase I pediatric oncology clinical trial will be to evaluate the safety and use of 4-demethyl-4-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 - 68,876 (1-6). 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 (2, 3, 5, 6). Primary malignant cancers of the central nervous system (CNS) account for less than 2% of all malignancies, yet brain tumors are the 2nd most common cause of death in children (7). Some childhood malignancies, e.g., intrinsic diffuse pontine gliomas - are located such that surgery is not attempted (8). 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 (4). 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 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 1) may also occur in medulloblastoma, a primitive cerebellar tumor of neuroectodermal origin, that is the 2nd most common brain tumor in children (7, 9). 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 will be to: 1) 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 - 68.876. 2) Studying the pharmacokinetic/dynamic profiles of DM-CHOC-PEN and metabolites in children with advanced cancers involving the central nervous system. 3) 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 Statement:


Public Health Relevance:
Primary malignant cancers of the central nervous system (CNS) account for less than 2% of all malignancies, yet brain tumors are the 2nd 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 - 68,876. 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 drug's use in children with CNS tumors at an age in which brain development and maturation is in progress with cognitive ability. The drug'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: 1) 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 - 68.876. 2) Studying the pharmacokinetic/dynamic profiles of DM-CHOC-PEN and metabolites in children with advanced cancers involving the central nervous system. 3) 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.

Project Terms:
Accounting; adduct; Adolescent; Adult; Advanced Malignant Neoplasm; Age; Animals; anticancer activity; Back; Behavior Therapy; Behavioral; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Neoplasms; cancer therapy; Carrier Proteins; Cause of Death; Central Nervous System Neoplasms; Cerebellar Neoplasms; Cerebellum; chemotherapy; Child; Childhood; Clinic; Clinical; Clinical Investigator; Clinical Trials; Clinical Trials Design; cognitive ability; cognitive function; Cytosine; Data; Data Analyses; design; Development; Diagnosis; Diffuse; Disseminated Malignant Neoplasm; DNA Alkylation; Drug Kinetics; Drug usage; Event; experience; Glioma; Goals; Growth; Guanine; Hepatic; Human; Impairment; improved; irritation; Kidney; Liver diseases; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant neoplasm of central nervous system; Malignant neoplasm of cerebellum; Malignant Neoplasms; Maximum Tolerated Dose; medulloblastoma; Monitor; Neuraxis; neurotoxic; neurotoxicity; Operative Surgical Procedures; P-Glycoprotein; Patients; Pediatric Oncology; Performance; Pharmaceutical Preparations; Phase; phase 1 study; Phase I Clinical Trials; phase I trial; Phase I/II Trial; Phase II Clinical Trials; phase II trial; Pontine structure; programs; Property; public health relevance; pyridine; Qualifying; Quality of life; Radiation; Radiation therapy; Recycling; Research Project Grants; response; Safety; Secondary to; Site; Toxic effect; Tumor Tissue

The primary goal of this Phase I pediatric oncology clinical trial will be to evaluate the safety and use of 4-demethyl-4-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 - 68,876 (1-6). 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 (2, 3, 5, 6). Primary malignant cancers of the central nervous system (CNS) account for less than 2% of all malignancies, yet brain tumors are the 2nd most common cause of death in children (7). Some childhood malignancies, e.g., intrinsic diffuse pontine gliomas - are located such that surgery is not attempted (8). 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 (4). 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 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 1) may also occur in medulloblastoma, a primitive cerebellar tumor of neuroectodermal origin, that is the 2nd most common brain tumor in children (7, 9). 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 will be to: 1) 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 - 68.876. 2) Studying the pharmacokinetic/dynamic profiles of DM-CHOC-PEN and metabolites in children with advanced cancers involving the central nervous system. 3) 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 Statement:


Public Health Relevance:
Primary malignant cancers of the central nervous system (CNS) account for less than 2% of all malignancies, yet brain tumors are the 2nd 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 - 68,876. 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 drug's use in children with CNS tumors at an age in which brain development and maturation is in progress with cognitive ability. The drug'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: 1) 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 - 68.876. 2) Studying the pharmacokinetic/dynamic profiles of DM-CHOC-PEN and metabolites in children with advanced cancers involving the central nervous system. 3) 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.

Project Terms:
adduct; Adolescent; Adult; Advanced Malignant Neoplasm; Age; Animals; anticancer activity; Back; Behavior Therapy; Behavioral; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Neoplasms; cancer therapy; Carrier Proteins; Cause of Death; Central Nervous System Neoplasms; Cerebellar Neoplasms; Cerebellum; chemotherapy; Child; Childhood; Clinic; Clinical; Clinical Investigator; Clinical Trials; cognitive ability; cognitive function; Cytosine; Data; design; Development; Diagnosis; Diffuse intrinsic pontine glioma; Disseminated Malignant Neoplasm; DNA Alkylation; Drug Kinetics; Drug usage; Event; experience; Goals; Growth; Guanine; Hepatotoxicity; Human; Impairment; improved; irritation; Kidney; Liver diseases; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant neoplasm of central nervous system; Malignant neoplasm of cerebellum; Malignant Neoplasms; Maximum Tolerated Dose; medulloblastoma; Monitor; Neuraxis; neurotoxic; neurotoxicity; Operative Surgical Procedures; P-Glycoprotein; Patients; pediatric department; Pediatric Oncology; Performance; Pharmaceutical Preparations; Phase; phase 1 study; Phase I Clinical Trials; phase I trial; Phase I/II Trial; Phase II Clinical Trials; phase II trial; programs; Property; public health relevance; pyridine; Quality of life; Radiation; Radiation therapy; Research Project Grants; response; Safety; Secondary to; Site; Toxic effect; trial design; Tumor Tissue