Bayesian dose-finding designs for longitudinal toxicity data in molecularly targeted agents

• Project/Area Number: 17K00045
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Statistical science
• Research Institution: Tokyo Medical and Dental University (2020); The University of Tokyo (2017-2019)
• Principal Investigator: Hirakawa Akihiro 東京医科歯科大学, 医学部附属病院, 教授 (90609330)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 臨床試験デザイン / 臨床統計学 / ベイズ流デザイン / がん臨床試験 / 分子標的薬 / マスタープロトコル / バスケットデザイン / 用量探索デザイン / ベイズ統計学 / 用量探索法 / アダプティブデザイン

Outline of Final Research Achievements

We investigated longitudinal toxicity profile of molecularly targeted agents using the data of phase I trials conducted in U.S. National Cancer Institute. Based on the result of this analysis, we developed two dose-finding methods based on the Lasso method and relative dose intensity (RDI) for determining optimal dose of molecularly targeted drugs. Master protocol trials have been emerged in cancer clinical trials in recent times. We also developed a new statistical design for basket trials.

Academic Significance and Societal Importance of the Research Achievements

医薬品開発の効率化・迅速化を目的に、革新的臨床試験デザインの研究開発が進んでいる。本研究では、ベイズ統計学を利用した新しい臨床試験デザインを開発した。この成果は、本邦の医薬品開発に資するものであると考える。

Research Products

• [Int'l Joint Research] National Cancer Institute(米国)
• [Int'l Joint Research] National Cancer Institute(米国)
• [Int'l Joint Research]
• [Journal Article] A Bayesian basket trial design accounting for uncertainties of homogeneity and heterogeneity of treatment effect among subpopulations. (2020)
  • Author(s): 2.Asano J, Hirakawa A
  • Journal Title: Pharmaceutical Statistics Volume: 19 Issue: 6 Pages: 975-1000
  • DOI: 10.1002/pst.2049
  • Peer Reviewed
• [Journal Article] A dose-finding approach for genomic patterns in phase I trials. (2020)
  • Author(s): Kaneko S, Hirakawa A, Kakurai Y, Hamada C.
  • Journal Title: Journal of Biopharmaceutical Statistics Volume: - Issue: 5 Pages: 834-853
  • DOI: 10.1080/10543406.2020.1744619
  • Peer Reviewed
• [Journal Article] Pragmatic dose-escalation methods incorporating relative dose intensity assessment for molecularly targeted agents in phase I trials. (2019)
  • Author(s): Hirakawa A, Tanaka Y, Kaneko S.
  • Journal Title: Contemporary Clinical Trial Communications Volume: 16 Pages: 100489-100489
  • DOI: 10.1016/j.conctc.2019.100489
  • Peer Reviewed / Open Access
• [Journal Article] A comparative study of longitudinal toxicities of cytotoxic drugs, molecularly targeted agents, immunomodulatory drugs, and cancer vaccines (2019)
  • Author(s): Hirakawa A, Sudo K, Yonemori K, Sadachi R, Kinoshita F, Kobayashi Y, Okuma SH, Kawachi A, Tamura K, Fujiwara Y, Rubinstein L, Takebe N.
  • Journal Title: Clinical Pharmacology & Therapeutics Volume: 106 Issue: 4 Pages: 803-809
  • DOI: 10.1002/cpt.1442
  • Peer Reviewed
• [Journal Article] がん臨床試験におけるベイズ流バスケットデザインの理論と実装 (2019)
  • Author(s): 平川晃弘，浅野淳一，佐藤宏征，橋本大哉，手良向聡
  • Journal Title: 計量生物学 Volume: 39 Pages: 103-122
  • NAID: 130007644700
  • Peer Reviewed
• [Journal Article] マスタープロトコルに基づくがん臨床試験 (2019)
  • Author(s): 平川晃弘，浅野淳一，佐藤宏征，手良向聡
  • Journal Title: 計量生物学 Volume: 39 Pages: 85-101
  • NAID: 130007644694
  • Peer Reviewed
• [Journal Article] Dose individualization and variable selection using Bayesian Lasso in early phase dose-finding trials (2019)
  • Author(s): Kakurai Y, Kaneko S, Hamada C, Hirakawa A
  • Journal Title: Applied Statistics Volume: 68 Issue: 2 Pages: 445-460
  • DOI: 10.1111/rssc.12326
  • Peer Reviewed
• [Journal Article] Master protocol trials in oncology: Review and new trial designs (2018)
  • Author(s): 33.Hirakawa A, Asano J, Sato H, Teramukai S
  • Journal Title: Contemporary Clinical Trial Communications Volume: 12 Pages: 1-8
  • DOI: 10.1016/j.conctc.2018.08.009
  • Peer Reviewed / Open Access
• [Journal Article] Potential utility of a longitudinal relative dose intensity of molecularly targeted agents in phase 1 dose-finding trial. (2018)
  • Author(s): Hirakawa A, Yonemori K, Kinoshita F, Kobayashi Y, Okuma H. Kawachi A, Tamura K, Fujiwara Y, Rubinstein L, Harris PJ, Takebe N.
  • Journal Title: Cancer Science Volume: 1 Issue: 1 Pages: 207-214
  • DOI: 10.1111/cas.13436
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Dose-Finding Method for Molecularly Targeted Agents Incorporating the Relative Dose Intensity in Phase I Oncology Clinical Trials. (2019)
  • Author(s): Tanaka Y, Sozu T, Hirakawa A
  • Organizer: ENAR 2019 Spring Meeting
  • Int'l Joint Research
• [Presentation] Heterogeneity Assessment of Treatment Effect among Subpopulations in Basket Trials (2019)
  • Author(s): Sadachi R, Hirakawa A
  • Organizer: ENAR 2019 Spring Meeting
  • Int'l Joint Research
• [Presentation] A Basket Trial Design using Bayesian Model Averaging. (2019)
  • Author(s): Hirakawa A, Sadachi R
  • Organizer: ENAR 2019 Spring Meeting
  • Int'l Joint Research
• [Presentation] A clustering-based basket design (2019)
  • Author(s): Hirakawa A
  • Organizer: 3rd Pacific Rim Cancer Biostatistics Workshop
  • Int'l Joint Research
• [Presentation] Utility of Bayesian single-arm design in new drug application for rare cancers in Japan: application to basket trial data (2019)
  • Author(s): Hirakawa A
  • Organizer: 6th International Society of Biopharmaceutical Statistics
  • Int'l Joint Research
• [Book] Modern Dose-Finding Designs for Cancer Phase I Trials: Drug Combinations and Molecularly Targeted Agents (2018)
  • Author(s): Hirakawa, A., Sato, H., Daimon, T., Matsui, S.
  • Total Pages: 104
  • Publisher: Springer
  • ISBN: 9784431555728