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NCI Development Resources for Cancer

NCI Development Resources for Cancer. Jill Johnson, DTP October 29, 2001. http://dtp.nci.nih.gov. Overview.

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NCI Development Resources for Cancer

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  1. NCI Development Resources for Cancer Jill Johnson, DTP October 29, 2001

  2. http://dtp.nci.nih.gov

  3. Overview • DTP provides resources for discovery (compounds, informatics, cell lines, screening), and development (formulation, in vivo testing, pharmacology, toxicology), to academic, non-profit, and corporate investigators. • Main avenues of access: Grants, Routine services, R*A*N*D, BEC, RAID, DDG

  4. For Information on various GrantsPrograms see: http://dtp.nci.nih.gov and click on: Grants/Contracts

  5. Features & Benefits of Using NCIResources • Almost all of our services are cost free. • Only in rare instances is IP involved. • The application processes are relatively simple. • We are always open to suggestions for additional needed resources and methods of improving our service.

  6. Definition of NCI Terminology • “Routine” Services - • In vitro cell line testing of single pure compounds • (on-line application) • In vitro testing of libraries (by letter request sent • to us) • requests for research samples (on-line request • form and requires simple letter agreement) • requests for “sets” of plated compounds (letter • sent to us and requires MTA) • All decisions are made by DTP staff.

  7. Definition of NCI Terminology • BEC - (Biological Evaluation Committee) - Cmpds • with interesting results from 60 cell line testing are • referred to BEC for possible action. One can also apply w/o • 60 cell line testing for resources - in vivo testing, PK/PD, • early formulation and tox work. (Requires application - all • decisions are made by DTP staff.) • DDG - (Drug Development Group) - Approves • resources for mid to late stage development leading to • NCI-filed IND and trials (Requires application - all • decisions are made by NCI staff with non-voting peer • review).

  8. Definition of NCI Terminology • R*A*N*D - (Rapid Access to NCI Discovery • Resources) - for academics and non-profits. Utilize for • analog or library synthesis, assay development assistance, • microarray technology, early formulation or PK/PD work • in order to select best candidate from multiple early • leads (Requires application and is peer-reviewed) • RAID - (Rapid Access to Intervention Development) • for academics and non-profits. Mid- to late- • development resources: formulation, range-finding • and IND-directed toxicology, Bulk synthesis of drug. • (Requires application and is peer-reviewed)

  9. Which resource do I need? DDG BEC RAID R*A*N*D NCI IND-filing and Clinical Trials Lead Selection Candidate Development Target Id Assay Devel Hit Screen PK/PD, tox, formulation, synth. As a general rule: R*A*N*D/BEC - multiple hits, no in vivo data, good target info. RAID/DDG - 1 lead candidate with some in vivo data, activity relates to novel target.

  10. Resource Utilization Examples - Development • Early stage: • You have one or more lead compounds and you would like to confirm target and/or acquire initial indications of pharmaceutical tractability • Apply to Biological Evaluation Committee (BEC) • contact ncidtpddginfo@mail.nih.gov

  11. Resource Utilization Examples -Development • Middle stage: • You have a lead candidate which requires additional formulation, PK/PD and range-finding toxicology • Apply to DDG (Drug Development Group) contact: ncidtpddginfo@mail.nih.gov • Can lead to NCI-filed IND and Trial • Or……..

  12. Resource Utilization Examples -Development • Middle-Late stage: • Apply to the RAID (Rapid Access to Intervention Development) program • PI files IND as opposed to NCI • Peer-reviewed • Modular task approach • Applications accepted twice yearly • more info: ncidtpraidinfo@mail.nih.gov

  13. RAID Example - Alan Solomon, U TennImmunotherapy in Patients with Light-chain-Associated (AL) Amyloidosis • Finding: • administration of certain murine anti-human light chain MoAbs capable of recognizing an epitope present on fibrils results in complete degradation of human ALκ or ALλ amyloid deposits. • RAID will: • support production of the chimeric anti-AL MoAb first. Additional in vivo data supporting production of the anti-MoAb are needed before proceeding to humanized Ab.

  14. RAID Example - Alan Solomon, U Tenn • RAID tasks (con’t): • Non-GMP production of murine anti-Alκ MoAb • Non-GMP production of chimerized anti-Alκ MoAb • In vivo testing of murine and chimerized MoAbs in model system • Good performance: • will support further applications to allow full-scale GMP production and/or humanization of the chimeric MoAb.

  15. RAID Example - Mathias Gromeier, Duke University Medical Center - Oncolytic Poliovirus • Raid Task: • Production of Non-Pathogenic Oncolytic Poliovirus Chimeras for the Treatment of Brain Tumors • Rationale: • Polioviruses can be generated by exchanging the cognate internal ribosomal entry site of poliovirus with its counterpart from human rhinovirus type 2. • This yields PV1(RIPO), a poliovirus strain which does not replicate in normal neuronal cells but which exhibits activity against malignant gliomas or medulloblastomas.

  16. RAID Example - Mathias GromeierDuke Univ Med Center. • Approved: • for production of cGMP-grade material and IND-directed toxicology studies in non-human primates. • Progress: • based on safety recommendations, BDP will develop recombinant virus using the Sabin vaccine. • Dr. Gromeier has demonstrated that inoculation with the new virus PVS-RIPO, completely eradicates growth of astrocytoma tumor cells in mouse xenografts.

  17. Resource Utilization Examples -Development • Late stage: • Apply to the DDG for NCI-held IND • IND-Directed Toxicology • Clinical Lot Manufacturing • IND-filing and NCI-Monitored Trials • DDG utilizes same contract resources as RAID • Meetings are held quarterly • more info: ncidtpddginfo@mail.nih.gov

  18. DDG Example - (NSC 639829)DimethylBenzoylphenylurea (Ishihara Sangyo Kaisha) • Rationale: • Tubulin mechanism predicted by COMPARE and confirmed in lab studies • Good in vivo activity (breast tumors) and other tumors resistant to standard agents • Structurally unrelated to paclitaxel • DDG tasks: • Non-GMP synthesis of agents • detailed in vivo studies to select best analog

  19. DimethylBenzoylphenylurea • Good Performance (selection of best analog) leads to: • pharma studies in rodents • formulation studies • range-finding toxicology • IND-filing • Current Status: • Orally active drug (BPU) now in phase I clinical trials

  20. Which program is best for you? • DTP staff will be happy to assist you in determining which of these resources fits your needs, and, more importantly, which process will give you the best chance of success in the approval process.

  21. Thank you! Any questions?

  22. Our next speaker is: Dr. Steve Creekmore Biopharmaceuticals Resources Branch Developmental Therapeutics Program

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