SBIR-STTR Award

7-butyl-10-aminocamptothecin (BACPT) and its water-soluble dipeptide pro-drug, are novel camptothecins that were designed to be used in the treatment of childhood neuroblastoma. These CPT analogs are lactones that have increased activity in acidic hypoxia tissues, characteristic of fast growing cancers that characteristically out grow their blood supply. Preliminary in vitro and in vivo studies are presented to support documenting other tumor models that might be more sensitive. The specific objectives of this Phase I study will be to: 1. Synthesize 7-butyl-10-aminocamptothecin (BACPT) and its water-soluble dipeptide pro-drug, BACPTDP in 100 g quantities - sufficient for preclinical studies. 2. Verify the anticancer profile in xenograft studies. 3. Develop the analytical assays required to document purity and stability and develop/validate protocols for pharmacokinetic studies. Upon completion of these studies a Phase II application will be submitted for completion of preclinical studies required for IND submission. BACPT and BACPTDP are novel camptothecins that were originally designed at Duke University to be used in the treatment of childhood neuroblastoma. 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 screening the analogs in a wide spectrum of tumor models to insure the best cancer applications for the products

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.

Thesaurus Terms:
(S)-4-Ethyl-4-Hydroxy-1h-Pyrano-[3',4'[{..}]6,7]indolozino[1,2-B]quinoline-3,14(4h,12h)-Dione;1h-Pyrano(3',4'[{..}]6,7)Indolizino(1,2-B)Quinoline-3,14(4h,12h)-Dione, 4-Ethyl-4-Hydroxy-, (S)-;1h-Pyrano[3',3'.6,7]indolizino[1,2-B]quinoline-3,14(4h,12h)-Dione, 4-Ethyl-4hydroxy-(S)-(9ci);20-(S)-Camptothecine;21, 22-Secocamptothecin-21-Oic Acid Lactone;9-Ac;9-Aminocamptothecin;9-Amino-20-Camptothecin;9-Amino-Cpt;9-Amino-Camptothecin;Absorption;Aminocamptothecin;Animals;Assay;Bioassay;Bioavailability;Biologic Assays;Biologic Availability;Biological Assay;Biological Availability;Blood;Blood Plasma;Body Tissues;Camptothecin;Camptothecin Analogue;Cancer Treatment;Cancer Of Lung;Cancers;Canine Species;Canis Familiaris;Characteristics;Clinical;Clinical Trials;Clinical Trials, Phase I;Clinical Trials, Unspecified;Colon;Development;Dipeptides;Dogs;Drug Formulations;Drug Kinetics;Drug Precursors;Drugs;Early-Stage Clinical Trials;Environment;Formulation;Formulations, Drug;Future;Gastrointestinal Tract, Pancreas;Grant;Guidelines;Human;Human, General;Hydrogen Oxide;Hypoxia;Hypoxic;In Vitro;Institutes;Malignant Neoplasm Therapy;Malignant Neoplasm Treatment;Malignant Neoplasms;Malignant Pancreatic Neoplasm;Malignant Tumor;Malignant Tumor Of The Lung;Malignant Neoplasm Of Lung;Malignant Neoplasm Of Pancreas;Mammals, Dogs;Mammals, Mice;Man (Taxonomy);Man, Modern;Medication;Mice;Molecular;Murine;Mus;Ovarian;Oxygen Deficiency;Pancreas;Pancreas Cancer;Pancreatic;Pancreatic Cancer;Pharmaceutic Preparations;Pharmaceutical Preparations;Pharmacodynamics;Pharmacokinetics;Phase;Phase 1 Clinical Trials;Phase I Clinical Trials;Phase I Study;Physiologic Availability;Plasma;Powder Dose Form;Powders;Pro-Drugs;Process Of Absorption;Prodrugs;Pulmonary Cancer;Pulmonary Malignant Neoplasm;Research;Research Institute;Reticuloendothelial System, Blood;Reticuloendothelial System, Serum, Plasma;Serum, Plasma;Tissues;Toxic Effect;Toxicities;Tumor Tissue;Universities;Vascular Blood Supply;Water;Xenograft Model;Absorption;Anticancer Therapy;Bioavailability Of Drug;Biomarker;Blood Supply;Cancer Therapy;Canine;Clinical Investigation;Design;Designing;Domestic Dog;Drug/Agent;In Vivo;Lung Cancer;Malignancy;Neoplasm/Cancer;Novel;Phase 1 Study;Phase 1 Trial;Phase 2 Study;Phase I Trial;Pre-Clinical;Preclinical;Preclinical Study;Protocol, Phase I;Public Health Relevance;Response;Tumor;Vascular Supply