Bayesian / Adaptive Trial Design

一行要約

Bayesian adaptive trial design は事前分布 + 蓄積データから posterior を逐次更新し、dose escalation, randomization ratio, sample size, futility/efficacy stopping を data-driven に変更する試験設計手法。Phase I では BOIN / mTPI / CRM が 3+3 を超えて MTD identification の精度・効率を向上、phase II/III では response-adaptive randomization (BATTLE-2, I-SPY 2), master protocol (basket / umbrella / platform) で biomarker-defined subpopulation に高速対応。Oncology drug development の主流設計の一つ。

原理

Bayesian foundation

posterior ∝ likelihood × prior。phase I では DLT 確率を Bayesian model (BLRM, CRM) で更新し、各 dose の posterior probability で escalation 判断。BOIN は non-parametric 簡略版で実装容易、phase I の世界標準化が進行。

主要 design

• BOIN (Bayesian Optimal Interval): dose escalation を simple decision rule で実装、3+3 を上回る MTD identification、Yuan/Liu MD Anderson 開発
• CRM (Continual Reassessment Method): dose-toxicity model を Bayesian に逐次更新
• Response-adaptive randomization: 効果群への randomization ratio を高める (I-SPY 2: biomarker × treatment 各 arm graduate / drop)
• Group sequential: O’Brien-Fleming, Pocock 等で interim 検定
• Sample size re-estimation: blinded / unblinded で interim variance / treatment effect から N 再計算
• Master protocol: basket (single drug, multi-tumor with shared biomarker), umbrella (single tumor, multi-biomarker, multi-drug), platform (multi-drug, perpetual, e.g. STAMPEDE / I-SPY 2)

主要エビデンス / 適用領域

• NSCLC: LIBRETTO-001 (selpercatinib RET basket), TRIDENT-1 (repotrectinib ROS1/NTRK basket), B-FAST / BLOOM (umbrella)
• Breast cancer: I-SPY 2 (response-adaptive, neoadjuvant), graduated drugs include pembrolizumab, durvalumab+olaparib
• Phase I oncology: BOIN が 3+3 を凌駕する efficiency、FDA も recognize
• STAMPEDE (prostate): platform trial で複数 arm を同時試験、control 共有
• COVID RECOVERY (oncology 外): platform trial paradigm の汎用化例

適用分野と限界

• 強み: 効率向上 (smaller N, faster decision), biomarker-driven subpopulation 高速 evaluation, drug attrition rate 改善, ethical (患者を有効 arm に多く)
• 限界: regulatory acceptance は design 依存 (basket は OK、response-adaptive RCT は limited use)、複雑性で IRB / DSMB review burden 増加、interim simulation で type-1 error 厳密制御要、small subgroup での precision 制限、stat 専門人材依存

Open Questions

• AI / RL-based adaptive design: reinforcement learning で adaptive policy 最適化
• External control arm + Bayesian borrowing: RWD を informative prior に
• Decentralized / digital trial との統合
• Biomarker uncertainty を組込んだ design: imperfect biomarker assay の影響を design 段階でモデル化

関連エンティティ

• 補完手法: Clinical-trial-design / Basket-umbrella-platform-trial / Real-world-data-analysis / Machine-learning-AI
• 関連概念: Tumor-mutational-burden / KRAS-co-mutation-landscape

関連論文

Basic-Immunotherapy

• Melero et al. NatCancer 2026 — Safety and activity of ro7300490, a bispecific CD40 agonist targeted to fibroblast activation protein, in patients with

Basic-Oncogene and genetics

• Schott et al. CancerRes 2015 — Genome medicine in cancer what’s in a name
• Ding et al. Nature 2008 — Somatic mutations affect key pathways in lung adenocarcinoma

Basic-Others

• Atkins et al. ClinCancerRes 2018 — Pembrolizumab plus pegylated interferon alfa-2b or ipilimumab for advanced melanoma or renal cell carcinoma
• Ahmed et al. JClinOncol 2015 — Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the

Clinical-Methodology

• Postel-Vinay et al. AnnOncol 2016 — Challenges of phase 1 clinical trials evaluating immune checkpoint-targeted antibodies
• Yan et al. AnnOncol 2018 — Phase I-II clinical trial design A state-of-the-art paradigm for dose finding
• Morrissey et al. ClinTranslSci 2016 — Immunotherapy and novel combinations in oncology current landscape, challenges, and opportunities
• Tosi et al. JClinOncol 2015 — Clinical development strategies and outcomes in first-in-human trials of monoclonal antibodies
• Wong et al. NatRevClinOncol 2016 — The changing landscape of phase I trials in oncology

Clinical-NSCLC-ALK

• Lin et al. CancerDiscov 2017 — Targeting ALK Precision medicine takes on drug resistance
• Shaw et al. JClinOncol 2019 — ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung
• Shaw et al. LancetOncol 2017 — Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement an international, multicentre, open-label,

Clinical-NSCLC-Driver negative

• Gettinger et al. JAMAOncol 2021 — Nivolumab plus ipilimumab vs nivolumab for previously treated patients with stage IV squamous cell lung cancer the

Clinical-NSCLC-Driver-Other

• Sharma et al. JClinOncol 2026 — Phase I study of telisotuzumab adizutecan (temab-A, ABBV-400), a novel c-met antibody-drug conjugate, in patients with

Clinical-NSCLC-EGFR

• Yu et al. ClinCancerRes 2017 — A phase I, dose escalation study of oral ASP8273 in patients with non-small cell lung cancers with epidermal growth

Clinical-Novel modalities

• Kubo et al. BioProtocol 2026 — Cite as kubo, N. et al. (2026). A feeder cell-free system for chimeric antigen receptor gene transduction into
• Tolcher et al. ClinCancerRes 2017 — Phase ib study of utomilumab (PF-05082566), a 4-1bbcd137 agonist, in combination with pembrolizumab (MK-3475) in
• DiStasi et al. NEnglJMed 2011 — Inducible apoptosis as a safety switch for adoptive cell therapy
• Wu et al. NatRevImmunol 2026 — Programming the immunological properties of mRNA vaccines for cancer
• Brentjens et al. SciTranslMed 2013 — CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic
• Davila et al. SciTranslMed 2014 — Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia

Clinical-Others

• Naing et al. JImmunotherCancer 2026 — Phase 1 multicenter study of the NKG2A targeting antibody S095029 as a single agent and in combination with anti-pd-1
• Rohrberg et al. JImmunotherCancer 2026 — First-in-human study of lomvastomig, a PD-1-TIM-3 bispecific antibody, in patients with advanced andor metastatic solid

Clinical-SCLC

• Byers et al. NatMed 2026 — SEZ6-targeting antibody-drug conjugate ABBV-706 in advanced small cell lung cancer and solid tumors a phase 1 trial