Informatics in Breast Cancer ResearchI-SPY 2 TRIAL & TRANSCEND

Sarah Davis, MSUniversity of California, San FranciscoDecember 6, 2011

I-SPY 2 TRIAL

Five Critical Components

• Neoadjuvant Setting

• Molecular and Imaging Biomarker Guidance

• Multiple Drugs Tested Simultaneously

• Adaptive Trial Design

• Common Platform for Sharing Data

The I-SPY 2 TRIAL Changes the Paradigm

I-SPY 2 TRIAL

• Screen phase 2 agents in combination with standard chemotherapy in neoadjuvant setting– Endpoint is pCR– Intermediate endpoint is MRI Volume

• Accelerate process of identifying drugs that are effective for specific breast cancer subtypes– Integration of biomarkers

• Reduce the cost, time, and number of patients needed to get effective drugs to market– “threshold” is 85% predicted likelihood of success in a 300-patient

phase 3 trial for drug-biomarker pair

Design goals of I-SPY 2

I-SPY 2 TRIAL

S

U

R

G

E

R

Y

* HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab.

Tissue

Paclitaxel* +Investigational Agent C AC

MRIBiopsy

Blood Draw

MRIBlood Draw

MRIBlood Draw

Paclitaxel* +Investigational Agent D AC

Paclitaxel* +Investigational Agent E AC

Paclitaxel* +Investigational Agent B AC

Paclitaxel* +Investigational Agent A AC

Paclitaxel*

AC

ON

STUDY

MRIBiopsy

Blood DrawMUGA/ECHO

CT/PET

Screening

RANDOMIZE

Consent #2Treatment Consent

Consent #1

I-SPY 2 Adaptive Trial Design

I-SPY 2 TRIAL

S

U

R

G

E

R

Y

Tissue

Paclitaxel* +Investigational Agent C AC

MRIBiopsy

Blood Draw

MRIBlood Draw

MRIBlood Draw

* HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab.

Paclitaxel* +Investigational Agent D AC

Paclitaxel* +Investigational Agent E AC

Paclitaxel* +Investigational Agent B AC

Paclitaxel* +Investigational Agent A AC

Paclitaxel*

AC

ON

STUDY

MRIBiopsy

Blood DrawMUGA/ECHO

CT/PET

Screening

RANDOMIZE

Consent #2Treatment Consent

Consent #1

I-SPY 2 Adaptive Trial Design (con’t)

I-SPY 2 TRIAL

S

U

R

G

E

R

Y

Tissue

Paclitaxel* +Investigational Agent C AC

MRIBiopsy

Blood Draw

MRIBlood Draw

MRIBlood Draw

* HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab.

Paclitaxel* +Investigational Agent D AC

Paclitaxel* +Investigational Agent E AC

Paclitaxel* +Investigational Agent B AC

Paclitaxel* +Investigational Agent A AC

Paclitaxel*

AC

ON

STUDY

MRIBiopsy

Blood DrawMUGA/ECHO

CT/PET

Screening

RANDOMIZE

Consent #2Treatment Consent

Consent #1

Paclitaxel* +Investigational Agent FG AC

I-SPY 2 Adaptive Trial Design (con’t 2)

I-SPY 2 TRIALI-SPY 2 Adaptive Trial Schema:Screening & Randomization

Patient presents with newly diagnosed

≥ 2.5cm invasive tumor consents to be Screened

Core biopsy to assess eligibility

Eligibility determined by: Ability to tolerate MRI Ability to generate 44k

Agilent microarray Other clinical variables Patient not on study

Not considered good candidate for chemotherapy

Patient On StudyRandomized to treatment arm based on: ER, PR status HER2 Status MammaPrint

scoreIs patient:• MammaPrint

Low Risk• ER + and

HER2 -

Yes

NoEligibility Assessment Process

I-SPY 2 TRIAL

How biomarkers are used in I-SPY 2

Qualifying Biomarkers

RPMA Pathway Markers Drug Sensitivity Predictor RCB Predictor (Affy Array) ....

Used to Validate Response to Therapy, done in CLIA Lab

Exploratory Biomarkers

Reflects Next Generation Technology (keeping pace)

DNA Methylation Exon Sequencing RNA Sequencing miRNA Circulating Tumor Cells Pharmacogenomics MRI SER Segmentation ....

StratificationBiomarkers

Used for Stratification, Response to Therapy

(may require IDE)

ER, PR, HER2 (Community)MammaPrint (Agilent array)TargetPrint (Agilent array)MRI Volume (Sentinelle)

I-SPY 2 TRIAL

Biospecimen Processing in I-SPY 2

Biospecimen Collected

Biospecimens Processed Tissue sectioned, tumor cellularity assessed Tissue processed (per SOP) Samples aliquoted, stored (per SOP)

Ship to I-SPY Lab

Assays Performed, Results Obtained(Stratification, Qualifying, Exploratory)

Ship to Research Labs (per Protocol)

caIntegratorTolven eCHR(Case Report Form)

Assays Results Reported

Stratifying Qualifying, Exploratory

I-SPY 2 TRIAL

Informatics Needs of I-SPY 2

• Manage information across multiple sites• Data gathering must be closely monitored as the trial

depends on rapid eligibility determination and therapeutic intervention - do not want to delay therapy

• Randomization as a web service (automated - but with review)

• Combining evaluation of drugs and biomarkers together– Biomarker data is of various types (arrays, imaging volume,

numeric scales, etc..)

• Scientists need access to data early and in an integrated fashion (one stop shopping)

I-SPY 2 TRIAL

What is TRANSCEND?

TRANslational Informatics System to Coordinate Emerging Biomarkers,

Novel Agents, and Clinical Data

An IT Bundle to Support Adaptive Trials with Novel Agents and Emerging Biomarkers

I-SPY 2 TRIAL

TRANSCEND Objectives

• Develop an information management infrastructure to support adaptive clinical trials like I-SPY 2

• Provide real-time data verification for more efficient analysis of trial data

• Provide a demonstration of caBIG infrastructure in use in a large multi-center trial

• Demonstrate integration of a clinical system (electronic health record system) with a clinical research infrastructure

I-SPY 2 TRIAL

Physician Reported Data

• A large fraction of clinically produced data in EHRs is ‘narrative’ text and not computable

• EHRs typically focus on ‘primary use’ of data, so narrative text is fine for this – provisioning clinical processes and care

• “Secondary Use”– Eg: Prospective/Retrospective research, Quality Improvement,

Comparative effectiveness– Typically requires analytics, which require structured, high-

quality, “controlled” data

I-SPY 2 TRIALWhat is new or different about TRANSCEND?

• Using a clinical information system rather than Clinical Trials Management System to collect patient data through CRFs

• Everything is web accessible without the need of downloadable plug-ins

• Randomization is adaptive, functions via web service• Integration of caTISSUE with a clinical information system

in the context of a trial• Using caINTEGRATOR v2.0 as a scientist portal to study

data– caARRAY for storing data that is accessible via caINTEGRATOR

I-SPY 2 TRIAL

Tolven eCHR

Data Coordinating

Center

Study SitesCase Report

Forms

Agendia

Integration Hub

(caXchange)

caTissue Suite caIntegrator

caAers caArray

Research Labs

MD Anderson

Randomization Engine

Automated interface

Manual interface

TRANSCEND - Systems Overview

I-SPY 2 TRIAL

TRANSCEND Interoperability

Standards for Data Exchange• Open-source HL-7 RIM (eCHR)• Semantic Interoperability modeled on BRIDG 2.1

– Use of caDSR Common Data Elements

Systems for Data Exchange• caExchange• iHUB-Mirth Connect (Enterprise Service Bus)

I-SPY 2 TRIALImplementation and Use of TRANSCEND in an Adaptive Clinical Trial

• Web-based and very easy to use for the end-user– Study Coordinators, Monitors, and Investigators

• Auto-population of data across systems reduces manual data entry errors– Specimen IDs in caTissue

• Real time data collection & review reduces delays in getting trial data to Data Review Committees and Trial Investigators

I-SPY 2 TRIAL

• Electronic copy of source documentation with each CRF

• Easy to complete case report forms with smart logic

TRANSCEND – eCHR Data Collection

I-SPY 2 TRIAL

• Real-time data review and verification

• Instant submission of CRF with source documentation to Data Coordination Center

TRANSCEND – eCHR Data Verification

I-SPY 2 TRIAL

TRANSCEND – eCHR Data Collection (con’t) • Email alerts to when a CRF is

ready for review & verification

• Email alerts when a CRF is rejected by the DCC

I-SPY 2 TRIAL

TRANSCEND – eCHR Data Collection

I-SPY 2 TRIAL

What Were the Challenges for End-Users?

• Change in Clinical Research Culture– Real time data collection & verification

Study Coordinators:• Cannot wait weeks to complete a case report form• Need case report forms to be verified before patient can proceed in

trial• Make source data available electronically and de-identified

Trial Monitors:• Cannot wait weeks/months to review case report forms for data

entry accuracy• Challenges normal way of business – drastically reduce time spent

on-site at each study site

• Identified gaps in standards of verifying data– Trial Monitors are also playing the role of Data Auditor

I-SPY 2 TRIAL

What Were the Challenges Technically?

• Overall– Move towards ‘enterprise bus’ as an integration rather than API-

based point-to-point integration – Install systems early to deal with logistical issues far in advance

of needing the systems

• caExchange– Required custom Java programming– Transaction rollback not an option

• However iHub has this capability

• caTissue– Transaction rollback not an option

• Requires manual removal of an entry

I-SPY 2 TRIAL

Future Direction with 2TRANSCEND

Integrate additional platforms• Web-based Patient Communication and Care Plan

– Aids in decision making about participating in a clinical trial as well as enabling study staff to communicate with patient’s regarding study appointments

• Web interface allowing patients to directly input:– Adherence to treatment regimens– Adverse events (PRO-CTCAE)– Follow-up information

• Adopt Annotation Imaging Mark-up (AIM) tool to enable researches ability to centrally review and analyze images

I-SPY 2 TRIALHow to Achieve TRANSCEND Functionality with Other Systems

TRANSCEND-like interoperability with other systems in support of clinical trials & biobanking

•OpenClinica•Local Institutional CTMSs •Cooperative Group Trial Management Systems •? Others ??

I-SPY 2 TRIAL

• Dr. Laura Esserman – I-SPY TRIAL, TRANSCEND PI (UCSF)• Dr. Michael Hogarth - TRANSCEND Technical Director (UC Davis)• Meg Young – TRANSCEND Project Manager (UCSF)• Sarah Davis – I-SPY 2 TRIAL Manager (UCSF)

– Joyce Lee, Julia Lyandres (software testing, quality control)

• Sorena Nadaf – Informatics Design (UCSF)• Dr. Angela DeMichele – Clinical Oncology (UPenn)• Don Berry & Kyle Wathen – Randomization Engine (MDACC)• John Churin – Software Lead Engineer (Tolven)• Ashwin Koleth – Software Development (Cyrus-XP)• John Koisch – Architecture (NCI)• Kathy Hajopoulos – Project Oversight (UCSF)• Nancy Roche – Project Oversight (SAIC)

TRANSCEND TEAM

TRANSCEND development funded by the National Cancer Institute (NCI), Subcontract # 28XS197

I-SPY 2 TRIAL

• Dr. Laura Esserman – I-SPY TRIAL, 2TRANSCEND PI (UCSF)• Dr. Michael Hogarth - 2TRANSCEND Technical Director (UC Davis)• Sarah Davis– 2TRANSCEND Project Manager (UCSF)• Meredith Buxton – I-SPY 2 Program Director (UCSF)• Dr. Angela DeMichele – Clinical Oncology (UPenn)• Don Berry & Kyle Wathen – Randomization Engine (MDACC)• John Churin – Software Lead Engineer (Tolven)• Ashwin Koleth – Software Development (Cyrus-XP)• Eve Shalley – Project Manager (NCI)• Santosh Joshi & CBIIT caCIS Team (NCI)• Ian Fore & CBIIT caTissue Team (NCI)• Paul Baumgarnter & CBIIT caAERS Team (NCI)• Juli Klemm & CBIIT caArray Team (NCI)• Shine Jacob & CBIIT caIntegrator Team (NCI)• Robert Shirley & CBIIT Architechture Team (NCI)

2TRANSCEND TEAM

2TRANSCEND development funded by the National Cancer Institute (NCI), Agreement No. 12ST1002

I-SPY 2 TRIAL

TRANSCEND

Breakout B – End-User Session

• Detailed Workflow from End-Users Perspective

• Questions & Feedback from Community

I-SPY 2 TRIAL

Tolven eCHR

Data Coordinating

Center

Study SitesCase Report

Forms

Agendia

Integration Hub

(caXchange)

caTissue Suite caIntegrator

caAers caArray

Research Labs

MD Anderson

Randomization Engine

Automated interface

Manual interface

TRANSCEND - Systems Overview

I-SPY 2 TRIAL

TRANSCEND & caTissue - WorkflowTolven eCHR

Data Coordinating

Center

Study SitesCase Report

Forms

Agendia

Integration Hub

(caXchange)

caTissue Suite

Automated interface

Manual interface

I-SPY 2 TRIAL

TRANSCEND & caTissue – Workflow (con’t)

Study Coordinator (CRA)

- In Clinic - In Tolven

Collect Sample

CRF Completed

(specimen ID created)

Specimen Created with ID,

etc.

Specimen Processed,

details recorded

Lab Staff

- In caTissue

I-SPY 2 TRIALTRANSCEND & caTissue – Workflow (con’t 2)Study Coordinator (CRA)

- In Clinic - In Tolven

Collect Sample

CRF Completed

(specimen ID created)

Specimen Created with ID,

etc.

Specimen Processed,

details recorded

Lab Staff

- In caTissue

I-SPY 2 TRIALTRANSCEND & caTissue – Workflow (con’t 3)

Collect Sample

CRF Completed

(specimen ID created)

Specimen Created with ID,

etc.

Specimen Processed,

details recorded

Study Coordinator (CRA)

- In Clinic - In Tolven

Lab Staff

- In caTissue

I-SPY 2 TRIALTRANSCEND & caTissue – Workflow (con’t 4)

I-SPY 2 TRIALTRANSCEND & caTissue – Workflow (con’t 5)

I-SPY 2 TRIALImplementation of caTissue in the Lab

• Set up of Lab workflows and caTissue– Setting up actual freezer and mapping– Printing of Labels from caTissue– Setting up child-specimen in caTissue

• Lessons learned– Engage Lab users in how caTissue works/capabilities

• Helps with setting up workflows/collection protocols

I-SPY 2 TRIAL

Questions & Feedback

• Can other Institutions/Groups extend interoperability of caTissue as used in TRANSCEND?

• What other systems would you integrate with caTissue?

I-SPY 2 TRIAL

Questions & Feedback (con’t)

• Differences in biobanking for adaptive clinical trials vs. traditional?

• What standards are used in clinical research?– Does this pose any challenges?

I-SPY 2 TRIAL

Questions & Feedback (con’t 2)

• How to engage participation from End-Users in design/set-up?

I-SPY 2 TRIAL

Questions & Feedback (con’t 3)

• How would you go about setting up IT systems to support your projects/workflow?– What would be the architecture?– Who would be the user of each system?