1 / 14

A continued phase I clinical trial of CP-DOX in dogs

This study aims to determine the maximum tolerated dose of CP-DOX in dogs and evaluate its biodistribution profile and accumulation in healthy dogs. It also includes a Phase II clinical trial for canine high-grade B-cell lymphoma using CP-DOX. The study utilizes nanoparticles of elastin-like polypeptide (ELP) for drug delivery and purification.

cusson
Télécharger la présentation

A continued phase I clinical trial of CP-DOX in dogs

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. A continued phase I clinical trial ofCP-DOX in dogs AshutoshChilkoti – DUKE Steven Suter – NCSU 4th Annual Consortium for Canine Comparative Oncology Symposium February 15, 2019

  2. PrincipalInvestigators AshutoshChilkoti, PhD Duke University Alan L. Kaganov Professor of Biomedical Engineering Chair of the Department of Biomedical Engineering Steven Suter, VMD, PhD NC State University Associate Professor of Medical Oncology Medical Director of Canine Bone Marrow transplant Unit

  3. SpecificAims • Production of large quantities of CP-DOX (Chilkoti Lab, Duke) • Determine the MTD of CP-DOX in normal dogs using an abbreviated 3 + 3 dose escalation trial (Suter Lab, NCSU) • Perform a PD study to examine the biodistribution profile and accumulation of CP-DOX in different organs in healthy dogs-paying particular attention to cardiac and gastrointestinal tissue ( Suter Lab, NCSU -Chilkoti Lab, Duke) • Perform a small Phase II clinical trial using CP-DOX at the MTD determined in SA1 against canine high-grade B-cell lymphoma (Terry Center Veterinary Hospital,Suter, NCSU )

  4. Nanoparticles of Elastin-Like Polypeptide (ELP) to deliver chemotherapeutics • (VPGXG)n • Recombinantly produced in E. coli • Thermoresponsive • Monodisperse • Biocompatible • Biodegradable • Tunable (X, n) Ideal platform for drug delivery and purification

  5. Drugconjugation ELP EMCH Doxorubicin Conjugation efficiency: 4-5 DOX molecules per ELP chain CP-DOX

  6. Canine Model Trends in Molecular Medicine, July 2011, Vol. 17, No. 7 Pharmacogenomics(2013) 14(16), 1929–1931 Acta Vet Scand. 2017 Oct 24;59(1):71 ImmunolRev. 2015 Jan;263(1):173-91.

  7. Previous canine CP-DOX PK data

  8. Pharmacodynamics CP-DOX injection (1 mg/kg BW) Tissue collection after 2 h and 24 h Tissue homogenization Acid incubation to release the Dox* Measurement of Dox concentration via fluorescence * Dox fluorescence is quenched upon conjugation to CP

  9. Pharmacodynamics Lower heart accumulation ----> reduced Doxcardiotoxicity * * *

  10. Pharmacodynamics CP-DOX has a longer plasma half-life than native DOX in dogs CP-DOX accumulates in the liver at higher levels than native DOX in dogs CP-DOX exhibits lower accumulation in the heart muscle than native DOX in dogs Canine PD Data Recapitulates our murine data Suggests that higher cumulative doses of CP-DOX can be given compared to native DOX while limiting cardiotoxicity Suggests that CP-DOX may have greater efficacy than native DOX due to the extended plasma half-life profile

  11. 3x3 CP-DOX dose escalation • Highest dose injected so far: • 3.5 mg/kg BW • No CBC/serum chemistry/GI • abnormalities have been observed (At 2mg/kg of native DOX (double the MTD) we would expect 100% of dogs to exhibit significant AEs.) • Temporary allergic reactions during the infusion are the only adverse events seen thus far-all dogs are now pre-medicated with diphenhydramine and prednisone Next dose *In the murine model, MTD of CP-Dox was 4-fold higher than that of native DOX

  12. Acknowledgements • Parisa Yousefpour (Duke): CP-DOX conjugate synthesis and characterization • Central Procedures Laboratory (CPL) staff-NCSU • Duke/NCSU C3O Scientific Advisory Board • Questions?

More Related