Basket-umbrella-platform-trial

Basket / Umbrella / Platform trial (Master Protocol)

一行要約

Master protocol は単一試験骨格の下で複数 hypothesis を並行検証する設計枠組み。Basket = 1 drug × 多 tumor (共通 biomarker, e.g. larotrectinib NTRK basket), Umbrella = 1 tumor × 多 biomarker × 多 drug (LUNG-MAP, BATTLE), Platform = 多 drug が長期間 perpetual に開閉 (I-SPY 2, STAMPEDE)。Driver mutation 中心の精密医療時代に rare driver の efficacy を効率的に評価する gold standard で、tissue-agnostic 承認 (larotrectinib, entrectinib, dostarlimab MSI-H, pembrolizumab MSI-H/TMB-H) の基盤となった。

原理

設計パターン

設計	構造	代表 trial
Basket	1 drug, 多 tumor (共通 marker)	LIBRETTO-001 (selpercatinib RET), TRIDENT-1 (repotrectinib), VE-BASKET (vemurafenib BRAF), KEYNOTE-158 (pembrolizumab MSI-H)
Umbrella	1 tumor, 多 biomarker → 多 drug	LUNG-MAP, BATTLE, NCI-MATCH (一部)
Platform	perpetual, multi-drug, shared control	I-SPY 2 (breast), STAMPEDE (prostate), REMAP-CAP (sepsis), ProBio (prostate)

Statistical considerations

• Bayesian hierarchical model で sub-cohort 間 borrowing (Berry method)
• Type-1 error 補正 (multiplicity, family-wise vs FDR)
• Master protocol governance (DSMB, biomarker test standardization)
• Adaptive enrollment: 効果群拡大 / 無効群早期 closure
• Tissue-agnostic 承認には ≥3 tumor type, prespecified ORR threshold が FDA standard

主要エビデンス / 適用領域

• Tissue-agnostic 承認: larotrectinib (NTRK), entrectinib (NTRK + ROS1), pembrolizumab (MSI-H, TMB-H), dostarlimab (dMMR), repotrectinib (NTRK)
• NSCLC rare driver: LIBRETTO-001 (selpercatinib), GEOMETRY-mono-1 (capmatinib MET ex14), KRYSTAL-1 (adagrasib)
• LUNG-MAP: NSCLC second-line で biomarker arm 並行
• I-SPY 2: neoadjuvant breast platform で adaptive randomization、>20 drug graduate / drop
• STAMPEDE: prostate cancer 多 arm long-running platform
• REMAP-CAP: COVID-19 で oncology 外の platform trial 成功例

適用分野と限界

• 強み: rare biomarker 効率的評価、tissue-agnostic approval pathway、shared control で N 削減、infrastructure 再利用 (perpetual platform)
• 限界: tumor-tumor heterogeneity (basket で同じ marker でも tumor 間で response 差: BRAF V600 melanoma vs CRC)、biomarker assay standardization、regulatory landscape は country dependent、small subset で statistical precision 限定、operational complexity (multi-site, multi-sponsor)

Open Questions

• Tumor-tumor heterogeneity within basket: 共通 marker でも tumor type で response 差の予測モデル
• Biomarker assay standardization (NGS, IHC) の cross-platform reproducibility
• Regulatory framework: tissue-agnostic 承認の post-marketing commitment
• Co-clinical trial: PDX / organoid と並行 master protocol で前向き integration

関連エンティティ

• 補完手法: Clinical-trial-design / Bayesian-adaptive-trial-design / Real-world-data-analysis / NGS-panel
• 関連薬剤: NTRK-inhibitor / RET-inhibitor / KRAS-G12C-inhibitor / MET-TKI / PD-1-inhibitor / Repotrectinib / Selpercatinib
• 関連 trial: LIBRETTO-001 / TRIDENT-1 / GEOMETRY-mono-1 / CodeBreaK-200
• 関連概念: Oncogene-addiction / Tumor-mutational-burden

関連論文

直近 30 件のみ表示中 (関連 33 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Immunotherapy

• Srivastava et al. CancerImmunolRes 2015 — STAT1-induced HLA class I upregulation enhances immunogenicity and clinical response to anti-EGFR mAb cetuximab therapy

Basic-Liquid-biopsy

• Powles et al. Nature 2021 — ctDNA guiding adjuvant immunotherapy in urothelial carcinoma

Basic-Oncogene and genetics

• Schott et al. CancerRes 2015 — Genome medicine in cancer what’s in a name
• Chalmers et al. GenomeMed 2017 — Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden
• Lopez-Chavez et al. JClinOncol 2015 — Molecular profiling and targeted therapy for advanced thoracic malignancies a biomarker-derived, multiarm,
• Flaherty et al. JClinOncol 2020 — Molecular landscape and actionable alterations in a genomically guided cancer clinical trial national cancer institute
• Weinstein et al. NatGenet 2013 — The cancer genome atlas pan-cancer analysis project
• Friedman et al. NatRevCancer 2015 — Precision medicine for cancer with next-generation functional diagnostics
• Rotow et al. NatRevCancer 2017 — Understanding and targeting resistance mechanisms in NSCLC

Basic-Others

• Winslow et al. CancerDiscov 2026 — A roadmap to transform lung cancer outcomes priorities in biology, therapeutic innovation, early detection, prevention
• Chakravarty et al. JCOPrecisOncol 2017 — OncoKB A precision oncology knowledge base
• OLeary et al. NatRevClinOncol 2016 — Treating cancer with selective CDK46 inhibitors

Clinical-Mesothelioma

• Dungey et al. TrendsCancer 2026 — Mesothelioma a systemic therapy clinical trials snapshot

Clinical-Methodology

• Spreafico et al. CancerDiscov 2021 — The future of clinical trial design in oncology
• 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

Clinical-NSCLC-Driver negative

• Marinelli et al. CancerTreatRev 2026 — PD-(l)1 containing rechallenge strategies in patients with advanced NSCLC previously treated with immunotherapy A
• 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

• Hong et al. AnnOncol 2019 — Larotrectinib in adult patients with solid tumours a multi-centre, open-label, phase I dose-escalation study
• Mazieres et al. AnnOncol 2020 — Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations
• Vaishnavi et al. CancerDiscov 2015 — TRKing down an old oncogene in a new era of targeted therapy
• Zehir et al. NatMed 2017 — Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients

Clinical-NSCLC-ROS1

• Moro et al. AnnOncol 2019 — Sibilot-Crizotinib in c-MET-or ROS1-positive NSCLC results of the AcSe phase II trial
• Yu et al. ClinLungCancer 2019 — Multiple biomarker testing tissue consumption and completion rates with single-gene tests and investigational use of
• Pal et al. JClinPathol 2017 — ROS1 corrected

Clinical-Others

• Medina et al. ClinCancerRes 2026 — AI-based pathology classifier predicts sensitivity to enzalutamide in metastatic hormone-sensitive prostate cancer A

Clinical-SCLC

• Frese et al. CancerCell 2021 — Small cell lung cancer enters the era of precision medicine
• Gray et al. ClinCancerRes 2017 — Therapy of small cell lung cancer (SCLC) with a topoisomerase-I-inhibiting antibody-drug conjugate (ADC) targeting
• Trigo et al. LancetOncol 2020 — Lurbinectedin as second-line treatment for patients with small-cell lung cancer a single-arm, open-label, phase 2