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NEW ORLEANS, LA, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 837.22K | Year: 2010

DESCRIPTION (provided by applicant): 7-Butyl-10-aminocamptothecin (BACPT), as a water-soluble dipeptide pro-drug - BACPTDP, is a novel camptothecin analog that has increased activity in hypoxic/acidic tumor tissues, characteristic of fast growing cancers that characteristically have deficient vasculature and outgrow their blood supply. Both in vitro and in vivo studies support the potential usefulness of BACPTDP in the treatment of pancreatic cancer. The significant responses seen with BACPTDP in the human PANC-1 xenograft model vs. other CPT controls are reviewed in support for the pre-clinical studies proposed in this application. The specific objectives of this Phase II study will be to: 1. Synthesize 7-butyl-10-aminocamptothecin dipeptide (BACPTDP) in 10-20 g quantities - sufficient for preclinical studies and formulation studies. 2. Conduct mouse and dog toxicity and pharmacokinetic studies. 3. Formulate the drug as a lyophilized powder. Document stability and potential clinical usefulness. 4. Develop and assay tissue/blood biomarkers as indicators for BACPTDP absorption and efficacy (pharmacodynamics). 5. Prepare the IND for future Phase I studies. Upon completion of these studies an FDA IND submission will be made. PUBLIC HEALTH RELEVANCE: BACPTDP is a novel camptothecins that was originally designed at Duke University to be used in the treatment of hypoxic, poorly vascularized tumors that possessed acidic environments. Studies conducted in the Phase I grant in pancreas, colon, ovarian and lung cancer xenograft models and reviewed herein, support our decision to move the product forward and ready it for clinical trials. Subsequently, DEKK-TEC has partnered with Duke and Research Triangle Institute (RTI) to complete the pre-clinical development, prepare the IND and ready the products for a Phase 1 clinical trial. Prior to the latter, DEKK-TEC proposes conducting the necessary pre- clinical toxicity, pharmacokinetic, formulation and stability studies. The studies as described will fulfill the requirements for a Phase I study to be designed.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 90.36K | Year: 2016

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


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 191.52K | Year: 2001

DESCRIPTION: (Applicant's Description) 4,4'-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) has recently completed a Phase I clinical trial in advanced cancer with minimal toxicity and objective responses noted. Preliminary observations suggest that A-007 is able to stimulate lymphocyte mobilization when applied topically to normal skin, as well as, to metastatic cutaneous lesions. The specific objectives of this Phase I study will be to document A-007's ability to stimulate lymphocyte migration/activation in cancers associated with immunodeficiency related infections. A-007's functional groups will be modified to maximize pharmacophore activities. All new hydrazones, as well as, A-007 will be assayed in vitro/in vivo for lymphocyte stimulation properties. These studies will be expanded for use as a stimulant of local cervical immunity in a simian immunodeficiency virus (SIV) monkey model and as local treatment for young females with HPV-associated cervical cancers. PROPOSED COMMERCIAL APPLICATION: 4,4'-Dihydroxybenzophenone-2, 4-dinitrophenylhydrazone (A-007) is showing lymphocyte stimulation and anticancer activities in clinical trials. A new agent with anticancer/immune modulation activity in HPV associated cervical cancer would have wide use as a single agent or in combinations therapy.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 272.66K | Year: 2008

DESCRIPTION (provided by applicant): 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 ad vanced 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 coul d 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 produc e 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 act ive 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 gt 2 year at refrigerator storage conditi ons. 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 characte rize 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 n ovel 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 clin ical use as an emulsion. The project has been reviewed by the FDA -IND 68,876.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 539.12K | Year: 2006

DESCRIPTION (provided by applicant): 4-Hydroperoxyifosfamide (HOO-IFOS) is a stable, pre-activated form (peroxide) of 4-HO-IFOS, the initial metabolite of Ifosfamide (IFOS). Under physiological conditions HOO-IFOS under goes spontaneously ring opening and conversion to isophosphoramide mustard (IPM), the active cytotoxic metabolite of IFOS. The objective of the proposed research is to synthesize 4-hydroperoxyifosfamide (HOO-IFOS) in sufficient quantity to document and validate purity and stability. A lyophilized product will be prepared at The University of Iowa, Pharmaceutical Services under GLP/GMP guidelines for clinical use in patients with advanced cancer. GC/MS and HPLC assays will be validated for quantification of bulk and pharmaceutical grade drug. Toxicology studies using a 3-day dosing regime in mice and dogs will be conducted at a GLP facility using the final product. An assay to monitor plasma HOO-IFOS PK and acrolein/chloroacetaldehyde levels in dogs receiving HOO- IFOS will be finalized. An IND package will be prepared after all the above has been finalized and submitted to the FDA. In summary - HOO-IFOS had improved anticancer activities vs. human glioblastoma and breast cancer xenografts and CPA-resistant leukemia murine models. The goal of the SBIR application will be to develop a new pro-drug, 4-hydroperoxyifosfamide (HOO-IFOS) that will generate in vivo - isophosphoramide mustard (IPM) - with reduced formation of associated toxic - chloroacetaldehyde and acrolein - by-products, normally produced during IFOS.

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