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GBM AGILE Platform Trial
Brian Alexander, MD, MPHNEWDIGS DESIGN LAB: LEAPS PROJECT
July 18, 2018
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Glioblastoma
• Incurable brain tumor– Radiation and temozolomide “standard”
• Most patients would like to receive an experimental therapy– Only ~10% enroll on trials Vanderbeek et al. 2018
• Despite much research, minimal advances over decadesCONFID
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DRUG B
DRUG C
DRUG D
CONTROL DRUG A
DRUG E
DRUG B
Clinical practiceClinical research
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Vanderbeek et al. Neuro Oncol 2018
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www.lonza.com
Canadian Institutes of Health Research
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Target selection and lead
validationPreclinical Phase I Phase II Phase III
IND NDACONFID
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Target selection and lead
validationPreclinical Phase I
IND
NDA
Phase II Phase III
Phase II Phase III
Phase II Phase III
Phase II Phase III
Phase II Phase III
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Target selection and lead
validationPreclinical Phase I
IND
NDA
Phase II Phase III
Phase II Phase III
Phase II Phase III
Phase II Phase III
Phase II Phase III
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Biomarkers are different
Pao and Hutchinson. Nature Med 2012 TCGA Nature 2008
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Targets are different
Vivanco et al. Cancer Discov 2012
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Endpoints are different
Pseudo-response Pseudo-progression
Wen et al. J Clin Oncol 2010
Brandes et al. J Clin Oncol 2008Gilbert et al. NEJM 2014
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Endpoints are different
Blumenthal et al. J Clin Oncol 2015 Han et al. Neuro Oncol 2014CONFID
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Vanderbeek et al. Neuro Oncol 2018
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Platform trial for GBM• Create one trial infrastructure
– Common biomarker, endpoint evaluations– Add/drop arms as trial is ongoing– Preserves indication-specific knowledge
• Replace serial trials– Eliminate “downtime”– Avoid “recreating the wheel”
• Ongoing concern to provide incentives for proactive therapeutic identificationCONFID
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GBM Development is different than other cancers
u Imaging-based endpoints can be misleading
u Historical control comparison can under- and overestimatetreatment effect leading to bad decisions
u Different targets, different biomarkers for similar pathways
u Biomarker subgroups are not well defined• Overlapping genomic groups
• No gold standard for MGMT
Use OS
Use controls
GBM-specific agents
Multiplex markers, learn in trial
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Subtypes with Stratification Biomarkers Only
Subtypes with Enrichment Biomarkers
Subtype• Characteristic of the patient/tumor• Partitions the biomarker space• Where randomization probabilities can
vary
Newly diagnosed methylated
Newly diagnosed
unmethylated
Recurrent disease
NDM+
NDU+
RD+
RD-NDU-
NDM-
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Subtypes with Stratification Biomarkers Only
Subtypes with Enrichment Biomarkers
Newly diagnosed methylated
Newly diagnosed
unmethylated
Recurrent disease
NDM+
NDU+
RD+
RD-NDU-
NDM-
Signature• Characteristic of the experimental therapy• Can be overlapping• Best indication for further development
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Subtypes with Stratification Biomarkers Only
Subtypes with Enrichment Biomarkers
Newly diagnosed methylated
Newly diagnosed
unmethylated
Recurrent disease
NDM+
NDU+
RD+
RD-NDU-
NDM-
Signature• Characteristic of the experimental therapy• Can be overlapping• Best indication for further development
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not fo
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Subtypes with Stratification Biomarkers Only
Subtypes with Enrichment Biomarkers
Newly diagnosed methylated
Newly diagnosed
unmethylated
Recurrent disease
NDM+
NDU+
RD+
RD-NDU-
NDM-
Signature• Characteristic of the experimental therapy• Can be overlapping• Best indication for further development
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not fo
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ributi
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Subtypes with Stratification Biomarkers Only
Subtypes with Enrichment Biomarkers
Newly diagnosed methylated
Newly diagnosed
unmethylated
Recurrent disease
NDM+
NDU+
RD+
RD-NDU-
NDM-
Signature• Characteristic of the experimental therapy• Can be overlapping• Best indication for further development
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Advantages of GBM AGILE for Drug Development
uGBM AGILE platform• Regulatory buy-in• Access to diverse group of experts in the field, operational expertise
enabling trial to evolve with success• Common infrastructure: harmonization of imaging, tissue acquisition,
trial data
uCost - commercial grade development vehicle at reduced Phase II/III pricing• Efficiencies in patient utilizations: common controls, adaptive
randomization• Right-sized” (# of patients = outcome of utility)
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Advantages of GBM AGILE for Drug Development
u Speed• Accelerates time from “hand shake” to arm initiation to last patient out
• “Seamless” transition to Phase III, Phase II patients are used in final analysis
u Defines subsets of patients most likely to benefit from therapy
u Can incorporate predictive biomarkers (hypothesis testing and generating)
u *Forms the foundation for future combinations through the time machine/non-concurrent controls
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DRUG B
DRUG C
DRUG D
CONTROL DRUG A
DRUG E
DRUG B
Clinical practiceClinical research
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Clinical practice
Clinical research
Adaptive platform
trials
CONTROL DRUG A DRUG B DRUG C DRUG D DRUG E DRUG E
“Real world evidence”
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Learning system
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Doctors
Patients
Sponsors Regulators
Payers
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THANK YOU
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