Table 1.

Representative basket and umbrella trials

StatusRecruitingTreatment phase completed, follow-up in progressRecruitingRecruitingNot yet openRecruitingNot yet open
Number of sites700+1223Est. 2,4001ND
Design and enrollment to screening and to substudies of molecularly targeted therapeuticsUmbrella designUmbrella designUmbrella designUmbrella designBasket designBasket designUmbrella design
Phase II/IIIPhase IIPhase IIPhase IIPhase IIPhase IIPhase II/III
3,125–6,250 planned for screening enrollment; 2,500–5,000 planned for randomization to substudies over 5 years341 enrolled 255 randomized 244 evaluable400 planned for enrollment to substudies800 planned for randomization to substudies3,000 planned for screening; 1,000–1,500 anticipated for assignment to substudies700 planned for screening; 180 anticipated to be evaluable; feasibility study to be conducted in first 60 evaluable patients.2,000 estimated for randomization to substudies
Substudies compare molecularly targeted drug(s) with or without standard therapy to standard therapy; drugs meeting phase II efficacy criteria continue to phase III; regulatory approval may be sought for drugs meeting phase III efficacy criteriaOpen-label, equal randomization for 97 patients across biomarkers and drugs followed by adaptive randomization on biomarker status for 158 patients based on DCR results for patients previously evaluatedOpen-label; Stage 1: 200 patients adaptively randomized on the basis of DCR at 8 weeks and KRAS status; predictive biomarkers/biomarker signatures to be developedOpen label; adaptive randomization based on pCR results (and MRV) and combination of MammaPrint, ER/PR, and HER2 statusSubstudies compare molecularly targeted drugs matching patients' molecular profiles with drugs not specific for the patients' molecular profilesMultiarm, multistage randomized trial design; patients are evaluated for the presence of relevant biomarkers during 16 weeks of standard first-line chemotherapy; patients who respond or have stable disease at the end of the 16 weeks are assigned to a substudy with drug(s) relevant to their biomarkers
Stage 2: 200 patients adaptively randomized on the basis of biomarkers/signatures developed in stage 1Molecularly targeted drugs are tested with standard neoadjuvant chemotherapy (including anti-HER2 therapy, as appropriate); concurrent control arms are includedSubstudies compare molecularly targeted drugs with placebo; drugs meeting phase II efficacy criteria continue to phase III
Overall duration8+ years9 years6 years5+ yearsND4 yearsND (9 year est.)
Estimated number of substudies4–7 concurrent throughout study duration448+20–2545
DiseaseAdvanced squamous NSCLCAdvanced NSCLCAdvanced NSCLCAdvanced locally invasive breast cancer (neoadjuvant setting)Advanced solid tumors or lymphomasAdvanced solid tumorsAdvanced or metastatic colorectal cancer
Endpoints1′ PFS/phase II, PFS and/or OS/phase III1′ PFS at 8 weeks1′ DCR at 8 weeks1′ pCR up to 26 weeks1′ RR1′ RR (CR+PR) and/or PFS at 16 weeks1′ PFS in phase II
2′ RR, toxicity2′ RR, OS, TTP, safety, biomarker, drug PK2′ prognostic biomarkers for PFS and fs (RCB and MRV), RFS and OS at 3 and 5 years, safety2′ PFSPFS and/or OS in phase III
Time to analysisPhase II: at progression; phase III: at progression and at death (specified number of events)8 weeks8 weeks26 weeks26 weeks16 weeksAt progression (specified number of events)
NCI and literature citationsNCT02154490NCT00409968, NCT00411671, NCT00411632, NCT00410059, NCT00410189 (18)NCT01248247 (19)NCT01042379 (16)(15)NCT01827384(17)
DiagnosticArchival or fresh tumor biopsy: NGS supplemented as needed with IHC and other assay methodologies. See Table 2 for initial biomarkers assayed.Fresh tumor biopsy: EGFR mutation and CN, KRAS/BRAF mutation, VEGF/VEGFR-2 expression, RXR/cyclin D1 and CCND1 CNFresh tumor biopsy: KRAS mutations and assays of predictive biomarkers for EGFR, PI3K/AKT, and MEK inhibitorsFresh tumor biopsy: MammaPrint, IHC for ER and PR, IHC or FISH or TargetPrint for ERBB2Fresh tumor biopsy: NGS supplemented as needed with IHC and FISH assays; approximately 200 genes evaluated; drugs chosen will target major cancer pathwaysFresh tumor biopsy:gene mutations and amplifications relevant to DNA repair, PI3K, or RAS/RAF pathwaysTumor biopsy: analysis for BRAF, PIK3CA, KRAS, and NRAS mutations, epiregulin mRNA, and IHC for MMR and PTEN

Abbreviations: CCND, cyclin D gene; CN, copy number; DCR, disease control rate; ER, estrogen receptor; MEK, mitogen-activated kinase kinase; MMR, mismatch repair; MRV, magnetic resonance imaging volume; ND, no data; NGS, next-generation DNA sequencing; pCR, pathologic complete response; PK, pharmacokinetics; PR, progesterone receptor; RCB, residual cancer burden; RFS, relapse-free survival; RR, response rate; RXR, retinoid x receptor; TTP, time to progression.




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FOCUS4: (ref. 17)