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Evaluation of Dose Escalation Scheme in Oncologic Phase I Gene Therapy and Development of New Dose Escalation Scheme.

Research Project

Project/Area Number 13671049
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionThe University of Tokyo

Principal Investigator

NAGAMURA Fumitaka  The University of Tokyo, The Institute of Medical Science, Research Associate, 医科学研究所, 助手 (90282491)

Co-Investigator(Kenkyū-buntansha) TANI Kenzaburo  Kyushu University, Medical Institute of Bioregulation, Professor, 生体防御医学研究所, 教授 (00183864)
TOJO Arinobu  The University of Tokyo, The Institute of Medical Science, Associate Professor, 医科学研究所, 助教授 (00211681)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
KeywordsGene Therapy / Oncologic Disease / Dose Escalation Scheme
Research Abstract

We evaluated the results of Oncology Phase I gene therapy which used dose escalation scheme as the followings : I) The incidence of intratumoral injection was 42.6% and that of subcutaneous was 10.6%. On the contrary, the incidence of systemic administration was low. Those of intravenous and imtramuscular were 4.3% and 4.3%, respectively ; II) Forty-five studies enrolled the same number of patients on each dose levels. Three patient cohorts was used in 75.6% of studies. One or two patient cohorts were used in one study ; III) The median numbe of dose levels was 4, and the range was 2-12 levels ; IV) About half the studies used 1 log or half-log dose increments. Seventeen percent of studied increased their dose for 1 log for a while, and then changed to half-log. The maximum dose increment was 2-log ; V) Four studies (8.2%) displayed Dose Limiting Toxicities, none of studies was based on the Immunotherapy. Only the three studies (6.3%) could determine Maximum Tolerated Dose.
Based on the above findings, we tried to develop a novel dose escalation scheme using pharmacologically-guided model, mathematical model, toxicity-based model. Finally, we developed a novel dose escalation model based on toxicity. The model is : available when the concept of gene therapy is based on immunotherapy ; Local adminstration, such as intratumoral and subcutaneous ; dose increment is 2-log until the occurrence of any injection site grade 【greater than or equal】 2 (NCI CTC ver.2) adverse events. Thereafter, dose increment is 1-log. When we applied this model to the past studies, it is estimated that one or two dose level can be eliminated and reached Maximum Administered Dose with sufficient safety. We plan to apply this model prospectively for the future gene therapy to evaluate the exact benefit of this model.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Nagamura F et al.: "Comparative Review of Oncology Phase I Dose Escalation Designs of New Molecular Entities"Journal of Clinical Oncology. 21. 89a (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Gregory Frykman, Fumitaka Nagamura, et al.: "Regulatory Oncology Drug Development Strategies : FDA Experience and an Electronic Resource"Journal of Clinical Oncology. 21. 260a (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kawaki K, Tani K, et al.: "Advanced renal cell carcinoma treated with granulocyte macrophage colony-stimulating factor gene therapy : a clinical course of the first"International Journal of Urology. 9. 462-466 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagamura F et al.: "Effect of Cyclophosphamide on Serum Cyclosporine Levels at the Conditioning of Hematopoietic Stem Cell Transplantatior"Bone Marrow Transplantation. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagamura F et al.: "One allele deletion of the RB1 gene in a Case of MDS RA with del (13)(q12q14): Fluorescence in situ Hybridization Study of the RB1 gene"Cancer Genetics Cytogenetics. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iijima Y, Tojo A, et al.: "Transformation of Ba./F3 cells and Rat-1 cells by ETV6/ARG"Oncogene. 21. 4374-4383 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagamura F, et al.: "Comparative Review of Oncology Phase I Dose escalation Designs of New Molecular Entities"Journal of Clinical Oncology. 21. 89a (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Gregory Frykman, Fumitaka Nagamura, et al.: "Regulatory Oncology Drug Development Strategies : FDA Experience and an Electronic Resource"Journal of Clinical Oncology. 21. 260a (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kawai K, Tani K, et al.: "Advanced renal Cell carcinoma treated with granulocyte-macrophage colony-stimulating factor gene therapy : a clinical course of the first Japanese experience"Journal of Urology. 9. 462-466 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagamura F, et al.: "Effect of Cyclophosphamide on Serum Cyclosporine Levels at the Conditioning of Hematopoietic Stem Cell Transplantation"Bone Marrow Transplantation. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] "One allele deletion of the RB1 gene in a Case of MDS RA with del(13)(q12q14) : Fluorescence in situ Hybridization Study of the RB1 gene"Cancer Genetics and Cytogenetics. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iijima Y, Tojo A, et al.: "Transformation of Ba/F3 cells and Rat-1 cells by ETV/ARG"Oncogene. 21. 4374-4383 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagamura F, Collins J, et al.: "Comparative Review of Oncology Phase I Dose Escalation Designs of New Molecular Entities"Proceedings of American Society of Clinical Oncology. 21(1). 89 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Frykman G, Nagamura F, et al.: "Regulatory Oncology Drug Development Strategies : FDA Experience and an Electronic Resource"Proceedings of American Society of Clinical Oncology. 21(1). 260 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takahashi T, Nagamura F, et al.: "Effect of cyclophosphamide at conditioning of hematologic stem cell transplantation on serum cyclosporine level"Blood. 98(11). 199a (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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