SBIR-STTR Award

The object of the proposed research is to conduct a Phase 1 clinical trial with 4-demethyl-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN), a carbonate derivative of 4-demethyl-penclomedine (DM-PEN) in patients with advanced cancer. The latter is the antitumor active, non-neurotoxic metabolite of penclomedine (PEN). PEN was active in clinical trials but possessed significant neurotoxicity and the trial was cancelled. DM-CHOC-PEN was synthesized as a derivative that could cross the blood brain barrier and not be toxic. DM-CHOC-PEN produced complete remissions with long term survival (and no weight loss) vs. intracerebrally (IC) implanted gliomas and breast cancer xenograft models in mice. In contrast DM-PEN did not produce complete responses in the IC models. DM-CHOC-PEN has completed pre-clinical/toxicology/formulation studies, is being manufactured and will be ready for clinical studies. The product will be administered via a single dose schedule. DM-CHOC-PEN is also active in vitro vs. human breast cancer explants and glioma cells, supporting the concept that it does not require prior activation. The product will be administered as an emulsion, the formulation has been stable for > 2 year at refrigerator storage conditions. The package has been reviewed by the FDA - IND 68,876. The specific objectives of this Phase I study will be to: 1) Conduct a Phase 1 evaluation of DM-CHOC-PEN in patients with advanced cancer to determine the maximum tolerated dose (MTD) and characterize the related principal toxicities. 2) Study the pharmacokinetic and pharmacodynamic profiles of DM-CHOC-PEN in the Phase I clinical trial. 3) Evaluate antitumor activity and electronically store/analyze data.

Public Health Relevance:
DM-CHOC-PEN is a novel cholesteryl carbonate derivative of PEN that was designed at DEKK-TEC and screened at Southern Research Institute. It has demonstrated impressive abilities to cross the BBB and produce CR and LTS in intracranially implanted U251 and D54 gliomas and MX-1 breast cancer xenograft models. Subsequently, DEKK-TEC has completed the pre-clinical studies, developed a formulation -validated, prepared the IND and the product is ready for a Phase 1 clinical trial. The product will be ready in the Fall '07 for clinical use as an emulsion. The project has been reviewed by the FDA -IND 68,876.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
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The object of the proposed research is to conduct a Phase 1 clinical trial with 4-demethyl-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN), a carbonate derivative of 4-demethyl-penclomedine (DM-PEN) in patients with advanced cancer. The latter is the antitumor active, non-neurotoxic metabolite of penclomedine (PEN). PEN was active in clinical trials but possessed significant neurotoxicity and the trial was cancelled. DM-CHOC-PEN was synthesized as a derivative that could cross the blood brain barrier and not be toxic. DM-CHOC-PEN produced complete remissions with long term survival (and no weight loss) vs. intracerebrally (IC) implanted gliomas and breast cancer xenograft models in mice. In contrast DM-PEN did not produce complete responses in the IC models. DM-CHOC-PEN has completed pre-clinical/toxicology/formulation studies, is being manufactured and will be ready for clinical studies. The product will be administered via a single dose schedule. DM-CHOC-PEN is also active in vitro vs. human breast cancer explants and glioma cells, supporting the concept that it does not require prior activation. The product will be administered as an emulsion, the formulation has been stable for > 2 year at refrigerator storage conditions. The package has been reviewed by the FDA - IND 68,876. The specific objectives of this Phase I study will be to: 1) Conduct a Phase 1 evaluation of DM-CHOC-PEN in patients with advanced cancer to determine the maximum tolerated dose (MTD) and characterize the related principal toxicities. 2) Study the pharmacokinetic and pharmacodynamic profiles of DM-CHOC-PEN in the Phase I clinical trial. 3) Evaluate antitumor activity and electronically store/analyze data.

Public Health Relevance:
DM-CHOC-PEN is a novel cholesteryl carbonate derivative of PEN that was designed at DEKK-TEC and screened at Southern Research Institute. It has demonstrated impressive abilities to cross the BBB and produce CR and LTS in intracranially implanted U251 and D54 gliomas and MX-1 breast cancer xenograft models. Subsequently, DEKK-TEC has completed the pre-clinical studies, developed a formulation -validated, prepared the IND and the product is ready for a Phase 1 clinical trial. The product will be ready in the Fall '07 for clinical use as an emulsion. The project has been reviewed by the FDA -IND 68,876.

Thesaurus Terms:
0-11 Years Old; 21+ Years Old; 3,5-Dichloro-2,4-Dimethoxy-6-Trichloromethylpyridine; Accounting; Adult; Advanced Cancer; Advanced Malignant Neoplasm; Analysis, Data; Animals; Autopsy; Back; Blood - Brain Barrier Anatomy; Blood Circulation; Blood-Brain Barrier; Bloodstream; Body Tissues; Body Weight Decreased; Brain; Brain Neoplasia; Brain Neoplasms; Brain Tumors; Breast; Cns Neoplasms, Malignant; Cancer Cause; Cancer Etiology; Cancer Cell Line; Cancer Of Brain; Cancer Of Breast; Cancer Of The Cns; Cancers; Canine Species; Canis Familiaris; Carbonates; Cause Of Death; Central Nervous System; Central Nervous System Cancer; Cessation Of Life; Child; Child Youth; Childhood; Children (0-21); Circulation; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Data Analyses; Death; Diagnosis; Diffuse; Disease Remission; Dogs; Dorsum; Dose; Drug Formulations; Drug Kinetics; Early-Stage Clinical Trials; Emulsions; Encephalon; Encephalons; Evaluation; Formulation; Formulations, Drug; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Glioma; Hemato-Encephalic Barrier; Hepatic; Human; Human, Adult; Human, Child; Human, General; Implant; In Vitro; In Complete Remission; Lts; Liver; Long-Term Survivors; Lung; Malignant Neoplasms; Malignant Tumor; Malignant Tumor Of The Brain; Malignant Tumor Of The Breast; Malignant Tumor Of The Cns; Malignant Tumor Of The Central Nervous System; Malignant Neoplasm Of Brain; Malignant Neoplasm Of Breast; Malignant Neoplasm Of Central Nervous System; Mammals, Dogs; Mammals, Mice; Mammals, Rodents; Man (Taxonomy); Man, Modern; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Medical; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Tumor; Mice; Modeling; Monitor; Murine; Mus; Neoplasm Metastasis; Neoplasms Of Neuroglia; Nervous System, Brain; Nervous System, Cns; Neuraxis; Neuroglial Neoplasm; Neuroglial Tumor; Operation; Operative Procedures; Operative Surgical Procedures; Pathology; Patients; Penetration; Pharmacodynamics; Pharmacokinetics; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Pons; Pons Cerebelli; Pons Varolii; Pontine; Pontine Structure; Process; Property; Property, Loinc Axis 2; Pyridine, 3,5-Dichloro-2,4-Dimethoxy-6-(Trichloromethyl)-; R01 Mechanism; R01 Program; Rmsn; Rpg; Refrigeration; Remission; Research; Research Grants; Research Institute; Research Project Grants; Research Projects; Research Projects, R-Series; Respiratory System, Lung; Rodent; Rodentia; Rodentias; Sched; Schedule; Secondary Neoplasm; Secondary Tumor; Supporting Cell; Surgical; Surgical Interventions; Surgical Procedure; Survivors, Long-Term; Temperature; Tissues; Toxic Effect; Toxicities; Tumor Cell Migration; Tumors Of Neuroglia; U251; Weight Loss; Weight Reduction; Xenograft Model; Adult Human (21+); Analog; Anticancer Activity; Body System, Hepatic; Body Weight Loss; Cancer Metastasis; Canine; Children; Clinical Investigation; Clinical Toxicology; Complete Response; Design; Designing; Domestic Dog; Falls; Improved; Irritation; Liver Function; Malignancy; Malignant Breast Neoplasm; Necropsy; Neoplasm/Cancer; Neuron Toxicity; Neuronal Toxicity; Neurotoxic; Neurotoxicity; Novel; Organ System, Hepatic; Pediatric; Penclomedine; Phase 1 Study; Phase 1 Trial; Phase I Trial; Postmortem; Pre-Clinical; Preclinical; Preclinical Study; Protocol, Phase I; Public Health Relevance; Pulmonary; Pyridine; Response; Surgery; Tumors In The Brain; Wt-Loss; Youngster