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An IT Solution for Targeted Drug Matching and Evidence Collection
Sunday February 19, 2017
Richard L. Schilsky, MD, FACP, FASCO
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Senior Vice President and Chief Medical Officer
American Society of Clinical Oncology
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Richard L. Schilsky, MD, FACP, FASCO
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Conflict of Interest
Richard L. Schilsky, MD, FACP, FASCO
Has no real or apparent conflicts of interest to report.
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Learning Objectives
• Summarize the goals and process of ASCO’s TAPUR study
• Explain how ASCO’s IT solution enhances automated matching of
patients to targeted drugs
• Describe how the IT platform enables ASCO to collect structured
patient outcome data
• Recognize early successes in TAPUR study conduct
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Problem• Patient with advanced cancer; no standard Rx
options
• Genomic profile test performed
• Potentially actionable variant detected
• How to get the drug?
• How to learn from the treatment?
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Overall Goals of TAPUR
• To learn from the real world practice of prescribing targeted therapies to patients with advanced cancer whose tumor harbors a genomic variant known to be a drug target
• To educate oncologists about implementation of precision medicine in clinical practice
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TAPUR Study Primary Objective
• To describe the anti-tumor activity and toxicity of
commercially available, targeted anti-cancer drugs
prescribed for treatment of patients with advanced solid
tumors, B cell NHL or MM with a genomic variant known to
be a drug target or to predict sensitivity to a drug.
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Secondary Objectives• To record the treatment-related adverse events.
• To create a prospective database of patient outcomes following treatment.
• To create a prospective database of commercially available tumor genome profiling tests used by clinical oncologists in the usual care setting.
• To determine the concordance of the treatment plan proposed by the treating oncologist with that recommended by the molecular tumor board in applicable situations.
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TAPUR Eligibility
• Patients with advanced solid tumors, B cell NHL and multiple myeloma for whom no standard treatment options exist
• Adequate organ function; PS 0-2
• Results available from a genomic test (FISH, PCR, NGS, WES, IHC for gene expression) performed in a CLIA certified, CAP accredited lab. Labs located or offering services to residents of NY must also have NY State accreditation. Test should be registered with NIH Genetic Test Registry.
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MD reviews
results of
genomic test
performed in
CLIA
certified/CAP
accredited lab
MD determines if
drug match exists
in protocol
Patient enrolled
on study
Matched therapy
administered;
safety and
efficacy outcomes
recorded
Data monitoring
committee
regularly
reviews RR of
tumor-variant-
drug groups
Results released
when protocol-
specified
endpoints met
MTB
IC
EC1 EC2
No match, Rx at
MD discretion
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TAPUR Matching Rules• Specific genomic inclusion and exclusion criteria included for each
drug
• Matching at variant level if possible
• Automated rules engine approves/rejects match proposed by treating
MD
• If no match proposed or match rejected, treating MD may consult
TAPUR MTB
• MTB identifies TAPUR drugs or other options based on tumor
genomics
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Endpoints
• Primary endpoint: Objective response rate per standard response criteria or SD at 16 w
• Other endpoints: Progression-Free survival
– Overall survival
– time on treatment
– grade 3-5 AEs per CTCAE
– SAEs
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Statistical Design
• Simon’s two-stage design
• Each tumor type-gene-drug is a “cohort”
• Null Hypothesis: ORR<15% vs. Alternative Hypothesis: ORR ≥ 35%
• Enroll 10 patients/cohort
– If 0-1 response, stop
– If 2 or more responses, enroll additional 18 pts
• Reject null hypothesis if 7 or more responses/28
• 85% power and a one-sided Type 1 error rate of 0.10
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What Makes TAPUR a Pragmatic Trial?• Broad eligibility criteria
• Physician discretion on genomic testing, drug dosing, dose modifications
• Minimum necessary data collection
• Investigator assessment of response
• Data validation procedures but no auditing/monitoring
• IND exempt per FDA
• However, specific inclusion/exclusion criteria, genomic matching rules and
standard response criteria
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TAPUR Study: Patients with HIV
• Not explicitly excluded per general study eligibility criteria
– Clinician judgement whether HIV disease would interfere or HIV medication would interact
• Per drug-specific eligibility criteria, patients with HIV are excluded from receiving pembrolizumab or olaparib
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TAPUR Study: Brain Metastases
• Patients with previously treated brain metastases are eligible, so long as the patient is:
– Not on treatment
– Not progressive
– Has not experienced a seizure or had a clinically significant change in neurological status within the 3 months prior to registration
– Off steroids for at least one month prior to enrollment.
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TAPUR Study: Organ Dysfunction
• Patients must have acceptable organ function as defined by:
– Absolute neutrophil count ≥ 1.5 x 106/µl
– Hemoglobin > 9.0 g/dl
– Platelets > 75,000/µl
– Total bilirubin < 2.0 mg/ dl
– AST (SGOT) and ALT(SGPT) < 2.5 x institutional ULN (or < 5 x ULN in patients with known hepatic metastases)
– Serum creatinine ≤ 1.5 × ULN or calculated or measured creatinine clearance ≥ 50 mL/min/1.73 m2
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TAPUR Study: Other Considerations
• Pediatric Population:
– Current TAPUR study eligibility criteria requires that the patient is ≥ 18 years old
– Plan to lower minimum age to 12 years
• Prior Malignancy:
– No exclusion for prior malignancy
• Performance Status (PS):
– Performance status of 0-2 per general eligibility
– Patients receiving pembrolizumab or regorafenibmust have PS 0-1
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Participating Drug Companies
• Astra-Zeneca
• Bayer
• Bristol-Myers Squibb
• Genentech
• Lilly
• Merck
• Pfizer
7 companies, 17 drugs,
15 treatments
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Drugs Available in TAPUR
Pharmaceutical Company(Number of Drugs)
Drug(s) Provided for TAPUR Study
AstraZeneca (1) Olaparib
Bayer (1) Regorafenib
Bristol-Meyers Squibb (1) Dasatinib
Eli Lilly (1) Cetuximab
Genentech (6)Erlotinib, Trastuzumab + Pertuzumab,
Vemurafenib + Cobimetinib, Vismodegib
Merck (1) Pembrolizumab
Pfizer (6)Axitinib, Bosutinib, Crizotinib, Palbociclib,
Sunitinib, Temsirolimus
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Supporting Vendors
• Syapse Precision Medicine Software
– Electronic data collection platform & study workflows
• Cardinal Health Specialty Pharmacy
– Central drug distribution
Copyright © 2015 Syapse. Proprietary & Confidential.
Syapse-TAPUR Application Automates TAPUR Workflows
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MD confirms
eligibility criteria;
enters pre-treatment data;
ASCO approves CohortResponse assessment &
adverse event reporting
Ordering of
targeted therapy
Automatic check
for drug-variant
match in protocol
MD reviews
genomic test results
& study eligibility criteria
Knowledge base
provider sends
analysis to MTB
TAPUR MTB reviews
knowledge base
provider’s recommendation
Yes
No
Query & data mining by
ASCO, pharma partners
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Syapse Screenshot – Determining Treatment Proposal
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Syapse Screenshot – Adverse Event Reporting
2
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Syapse-TAPUR Application
• Customized version of Syapse commercial precision medicine product
• Enables patient registration, eligibility checks
• Automated rules engine facilitates matching drug-genomic alterations
• Support for MTB workflows
• Supports patient enrollment and drug ordering
• Captures required efficacy and safety data including all AEs
• Allows data export for analysis
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TAPUR Clinical Sites
Current participating centers (37)
ActivatedFall/Winter 2016 (21)
Planned for Spring 2017 (42)
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Key Milestones
• FDA reviewed and determined TAPUR Study IND-exempt (08/31/15)
• Chesapeake Institutional Review Board approval (02/09/16)
• Registered on ClinicalTrials.gov
– NCT ID# 02693535 granted (02/20/16)
• TAPUR Study Launch 03/14/16
• 306 participants registered as of 2/13/17
• 172 patients on treatment as of 2/6/17
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TAPUR Enrollment by Study Drug
Drug Name Total participants
enrolled on drug
Axitinib (INLYTA) 1
Bosutinib (BOSULIF) 1
Cetuximab (ERBITUX) 24
Cobimetinib (COTELLIC) + Vemurafenib (ZELBORAF) 5
Crizotinib (XALKORI) 5
Dasatinib (SPRYCEL) 4
Erlotinib (TARCEVA) 0
Olaparib (LYNPARZA) 26
Palbociclib (IBRANCE) 38
Pembrolizumab (KEYTRUDA) 11
Pertuzumab (PERJETA) + Trastuzumab (HERCEPTIN) 10
Regorafenib (STIVARGA) 5
Sunitinib (SUTENT) 25
Temsirolimus (TORISEL) 16
Vismodegib (ERIVEDGE) 1
Total 172
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Challenges in TAPUR Implementation
• Determining profiling strategy
• Setting the matching rules
• Defining/analyzing cohorts
• Building the team and infrastructure inside ASCO
• Clinical site training on protocol/matching rules
• Organization of Molecular Tumor Board
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Who Benefits if TAPUR Succeeds?
• Patients receive targeted agent matched to tumor genomic profile; drugs at no cost
• Physicians receive guidance in interpretation of genomic test results and treatment options, access to drugs, clinical data on off-label use
• Pharma receives data on drug use and outcomes to inform R&D plans and life cycle management
• Payers receive data on test and drug use and outcomes to inform future coverage decisions
• Regulators receive data on extent and outcomes of off label drug and test use and real world safety data
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Questions?
