Background and Terminology Basket Trials Umbrella Trials Considerations and Conclusions Basket Trials: Features, Examples, and Challenges Lindsay A. Renfro, Ph.D. Associate Professor of Research Division of Biostatistics University of Southern California ASA Biopharm / Regulatory / Industry Statistics Workshop Washington, DC 13 September 2018 1/ 42 Lindsay A. Renfro Basket and Umbrella Trials
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Basket Trials: Features, Examples, and Challenges · Basket vs. Umbrella Big Picture New ways of treating cancer !New trial designs! 5/ 42 Lindsay A. Renfro Basket and Umbrella Trials.
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Basket Trials: Features, Examples, andChallenges
Lindsay A. Renfro, Ph.D.Associate Professor of Research
Division of BiostatisticsUniversity of Southern California
ASA Biopharm / Regulatory / Industry Statistics WorkshopWashington, DC
13 September 2018
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
TerminologyBasket vs. Umbrella
Background
I New treatment paradigm in oncologyI Organ-specific cancers → molecularly-defined sub-cancersI Cytotoxic → cytostatic drugs
I Targeted therapyI Hypothesized to “hit” a molecular targetI Interrupts cancer cell growth and division along 1+ cellular
“pathways”
I ImmunotherapyI Unleashes patient’s own immune system against disease
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
TerminologyBasket vs. Umbrella
Recent FDA (USA) Approvals
I EGFR inhibitors (e.g., cetuximab, panitumumab)1
I KRAS-WT metastatic colorectal cancer
I Trastuzumab2
I HER-2 positive metastatic breast cancer
I Vemurafenib3
I BRAF-V600E-mutant melanoma
I Erlotinib4 / crizotinib5
I EGFR-mutated / ALK-mutated lung cancer
1Jonker et al. (2007). New Engl J Med 357: 2040-2048.2Slamon DJ et al. (2001). New Engl J Med 344: 783-792.3Chapman et al. (2011). N Engl J Med 364: 2507-2516.4Zhou et al (2011). Lancet Oncol 12: 735-7425Shaw et al (2013). New Engl J Med 368: 2385-2394.
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
TerminologyBasket vs. Umbrella
Groundbreaking FDA Approval in June 2017
I Pembrolizumab (immunotherapy)1
I Unresectable metastatic solid tumors with microsatelliteinstability (MSI-H) or mismatch-repair deficient (dMMR)status
I Approval based on biomarkers rather than location: FDA first!
1www.fda.gov/newsevents/newsroom/pressannouncements/ucm560167.htm4/ 42 Lindsay A. Renfro Basket and Umbrella Trials
Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
TerminologyBasket vs. Umbrella
Big Picture
New ways of treating cancer → New trial designs!
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
TerminologyBasket vs. Umbrella
Biomarker-Based Designs
I Many types: Enriched or targeted designs, interaction ormarker-stratified designs, adaptive enrichment designs, etc.
I Special class of biomarker designs: “Master protocols”I Basket trials, umbrella trials, platform trials1,2
I Goals:I Personalized medicineI Increased efficiency in drug development when target-drug
combinations exist
1Renfro and Sargent, Ann Oncol 2017; 28: 34-432Woodcock and LaVange, NEJM 2017; 377: 62-70.
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
TerminologyBasket vs. Umbrella
Biomarker-Based Designs
I Many types: Enriched or targeted designs, interaction ormarker-stratified designs, adaptive enrichment designs, etc.
I Special class of biomarker designs: “Master protocols”I Basket trials, umbrella trials, platform trials1,2
I Goals:I Personalized medicineI Increased efficiency in drug development when target-drug
combinations exist
1Renfro and Sargent, Ann Oncol 2017; 28: 34-43.2Woodcock and LaVange, NEJM 2017; 377: 62-70.
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
TerminologyBasket vs. Umbrella
Basket and Umbrella Trials: Terminology
I Not straightfoward...
I Early literature: terms like “basket trial” and “umbrella trial”used inconsistently
I “Basket trial”: some disagreement about what is the “basket”
I More recently, terms becoming somewhat standardized1,2
1Renfro and Sargent, Ann Oncol 2017; 28: 34-432Woodcock and LaVange, NEJM 2017; 377: 62-70.
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
TerminologyBasket vs. Umbrella
Proposed Definitions
I Master Protocol: An over-arching protocol or trial mechanismcomprised of several parallel sub-trials differing by molecularfeatures or other objectivesI Basket Trial: A master protocol where each sub-trial enrolls
multiple tumor types (“the basket”)I Umbrella Trial: A master protocol where all patients (and all
sub-trials) share a common tumor type (“the umbrella”)I Platform Trial: A master protocol where sub-trials may be
added or removed in an operationally seamless way
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Basket Trial: General Schema
…
Tumor Type C
Tumor Type A
Tumor Type Z
Tumor Type X
Target 1 + Drug 1
Target N + Drug N
Molecular Portrait
Tumor Type Y
Tumor Type B
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Definition of “Basket”
…
Tumor Type C
Tumor Type A
Tumor Type Z
Tumor Type X
Target 1 + Drug 1
Target N + Drug N
Molecular Portrait
Tumor Type Y
Tumor Type B
“Basket” = Individual Sub-Trial
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Alternative Definition of “Basket”
…
Tumor Type C
Tumor Type A
Tumor Type Z
Tumor Type X
Target 1 + Drug 1
Target N + Drug N
Molecular Portrait
Tumor Type Y
Tumor Type B
“Basket” = Individual Tumor Type Within A
Sub-Trial
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Basket Trials: Defining Features
I Sub-Study Design: Usually single-arm phase II, single ortwo-stage with futility rules
I Objective: Identify large, unambiguous signals of activitybased on molecular features (rather than tumor type)I Preliminary target-treatment hypothesesI “Success” within a sub-study may lead to larger confirmatory
study
I Usually 20-30 patients per “basket” or molecular sub-study
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Basket Trials: Advantages
I Operational efficiencies compared to designing and conductingindividual targeted trials without shared infrastructure
I Relatively small sample size per sub-study
I Increased “hit rate” by enrolling patients with rare molecularfeatures across tumor types
I Array of novel therapeutics offered to a broader group ofpatients who may benefit
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Basket Trials: Disadvantages
I Prognostic heterogeneity across tumor types
I Single arm sub-studies generally require a tumor response rateendpoint (with a high bar)
I Challenging to define historical controls across diseasesI For this reason, time-to-event endpoints (though often
relevant) usually not primary
I Practical challenges with screening may arise
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Example: NCI Match
I NCI Molecular Analysis for Therapeutic Choice (NCI-MATCH)
I Second-and-later line treatment of advanced solid tumors andlymphoma
I 30 planned (initially 10) histology-independent marker-basedcohorts, 17+ therapies
I 6,000+ patients (initially 3,000) centrally screened by NGS →35-70 eligible patients per cohort
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
NCI Match Cohort Design
I Most cohorts: 35 eligible → 31 evaluable patients
I Endpoint: overall response rate (ORR) by RECIST v1.1
I 90% power to detect ORR improvement 5% → 25% with<2% type I error
I Observed (empirical) ORR of 16% → success
I Strong efficacy within a tumor type → separate phase II or IIIstudy
I Patients who progress may be re-screened for another cohort
I Key secondary endpoint: progression-free survival (PFS)
I Target: 25% rare cancers (actual: > 60%)
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
NCI Match Schema
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
NCI Match Update / Challenges
I Opened in 2015, initial cohort results in 2017, 20181
I Screening registration rapid: 6,000 patient cap 2 years earlyI 18% of screened patients “matched”; 69% of those enrolled to
sub studyI Low enrollment of “common” subtypes ; will need to screen
tens of thousands moreI Relaxed screening process (to include more laboratories)I 18 cohorts open; some expanding to enroll 70 patientsI Results for 4 cohorts announced to date
2Kang et al. Clin Pharmacol Ther 2015; 98:124-1263https://clinicaltrials.gov/ct2/show/NCT023048094http://www.eortc.org/sites/default/files/90101.pdf
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Umbrella Trials
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Umbrella Trial: Definition
I Umbrella Trial: A master protocol where all patients (and allsub-trials) share a common tumor type (“the umbrella”)
Woodcock and LaVange. NEJM 2017;377:62-70.
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Umbrella Trial: General Schema
… …
Single Tumor Type
Control
Matched Drug N
Control
Matched Drug B
Control
Matched Drug A
Target N
Target A
Target B Molecular Portrait
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Umbrella Trials: Defining Features
I Mid-to-late phase sub-studies
I Design: often randomized with futility stopping or“graduation” to phase III
I Better understood target-treatment hypothesesI Objective remains identification of large effects (within a
single tumor type)I ...to keep trial size feasible, particularly for rare molecular
cohorts
I Sub-studies generally larger than those of basket trials
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Umbrella Trials: Advantages
I Relatively improved prognostic homogeneity (all patients fromsame tumor group)I Any observed benefit may be more readily attributed to the
markerI Particularly true when randomization against a control
treatment occursI Even more true when marker-negative patients concurrently
randomized to same treatmentsI → Treatment-by-marker interaction may be computed
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Umbrella Trials: Disadvantages
I Larger size, particularly when sub-trials are randomized
I Longer duration
I Difficulty enrolling rare molecular subtypes of a single tumortype
I Susceptibility to changes in the “treatment landscape” duringthe trialI E.g., introduction of a new standard of care (may change
control arm)
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Example: Lung-MAP
I Lung-MAP (SWOG S1400)
I Patients with previously-treated advanced squamous cell lungcancer
I Initially 3 parallel randomized phase II/III sub-trials fortargeted therapy vs. SOC (docetaxel)
I Goal: 500-1,000 patients screened per year
I Contains 4th cohort: non-match study for patients not eligiblefor target cohorts
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Lung-MAP Design
I Phase II endpoint: PFSI 68-124 patients per sub-study
I Phase III endpoint: overall survival (OS) with phase IIpatients contributingI 272-336 patients per sub-study
I No cross-cohort comparisons
I Initially, non-match patients randomized to anti-PD-L1immunotherapy vs. SOC
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Lung-MAP Schema (Original)
Ferrarotto et al. (2015). Chin Clin Oncol 4(3).
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Lung-MAP Updates / Challenges
I One cohort (c-MET) closed early for toxicity; reopened 2018I March 2015: FDA approved nivolumab in same patient
populationI Control arm (docetaxel) no longer the standard of care
I Lung-MAP re-opened with modifications: 1
I Control arm dropped in phase II → single arm onlyI Non-match arm: single vs. combo immunotherapy
I July 2018: 1,700+ patients screened, 1325 assigned, 600registered to sub-studies
I Several sub-studies closed and reported, more added
I Late 2018: Sub-study for PD-1/PD-L1-resistant patients,opening to all histologies
1http://www.lung-map.org36/ 42 Lindsay A. Renfro Basket and Umbrella Trials
Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Lung-MAP Revised Schema
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
Definition and FeaturesAdvantagesDisadvantagesExample
Other Umbrella Trials
I ALCHEMIST1
I FOCUS42
1Gerber et al. ALCHEMIST, Clin Pharmacol Ther 2015; 97: 447-450.2Kaplan R et al. J Clin Oncol 2013; 36: 4562-4570.
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
ConsiderationsConclusions
Basket and Umbrella Trials: Practical and Statistical Issues
I Practical Issues:I New collaboration paradigmI Logistics far beyond a single trialI Trials must adapt to external changes over years, decades
I Statistical Issues:I Effect size vs. sample sizeI Whether to include an all-marker-negative subgroupI Classification of patients with multiple markers or genetic
mutationsI How to maintain feasibility without compromising objectives
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
ConsiderationsConclusions
Conclusions
I Basket and umbrella trials → potential solution to challengesof precision medicine
I Expected increase in popularity as larger, traditional trialsbecome less feasible
I Need for improved statistical methodology to address designchallenges, e.g., rare molecular subtypes
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Background and TerminologyBasket Trials
Umbrella TrialsConsiderations and Conclusions
ConsiderationsConclusions
References / Resources
I Renfro, L.A., Mandrekar, S.J. (2017). Definitions and statisticalproperties of master protocols for personalized medicine in oncology.Journal of Biopharmaceutical Statistics, published online.
I Renfro, L.A., Sargent, D.J. (2017). Basket trials, umbrella trials,and other master protocols: a review and examples. Annals ofOncology 28(3): 34-43.
I Renfro, L.A., An, M.W., Mandrekar, S.J. (2017). Precisiononcology: a new era of cancer clinical trials. Cancer Letters 387:121-126.
I Woodcock, J., LaVange, L.M. (2017). Master protocols to studymultiple therapies, multiple diseases, or both. New England Journalof Medicine 377:62-70.
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