HARMONIZING AP & H SERVICES IN SUPPORT OF GLOBAL ONCOLOGY CLINICAL TRIALS

Paul Kirchgraber, MD, FCAP

Covance Central Laboratory Services

Steven Brodie, Ph.D. FACMG

NeoGenomics Laboratories, Inc.

May 21, 2014

SESSION AGENDA / INTRODUCTION

• Challenges Inherent in Conducting Oncology Clinical Trials

• Pre Analytic and Analytic Variability• Understanding Disease Complexity

and the Need for Flexibility in Trial Design

• Testing Methodologies Required to Support Oncology Trials

Importance of Oncology Clinical Trials

ONCOLOGY IS NEARLY A $100 BILLION SEGMENT

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Already highest # of clinical trials, oncology increased 4.9% (2013 vs ‘14)

But Hold the Lowest FDA Approval Rate (approval from Phase1 = 6.7%)

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SOURCEs:

Citeline Pharma R&D Annual Review 2014 (Trialtrove)

Nature Biotechnology volume 32 NUMBER 1 Jan 2014

Fierce Pharma May 2014

Covance Existing Histology Network & Experience

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Our oncology protocols, 2009-13 1000+ protocols 75+ countries 24,000+ investigator sites 141,000+ patients

47 of the 50 best selling oncology

drugs were developed in partnership

with Covance

Complexity of Anatomic Pathology for Global Oncology Trials EXAMPLE: THROUGH LENS OF BREAST CANCER

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ER / PR and HER2 testing

Pre-analytical:Differences in pre-fixation cold ischemic timesFixative time

Analytical:Technical: Different IHC Antibodies may have different sensitivity to receptorsProfessional: Subjectivity/variability in interpretation

ALTTO trial – central review pre-randomization confirmation of receptor status at the European Institute of Oncology (EIO) N > 1000; 4.3 % false positive for ER on central review, and 20 % false negative

JNCI 2006;98(21):1571

In ECOG 2197, 11 percent of local ER-negative tests were scored positive upon central testing; concordance rate for ER of approximately 90 percent

J Clin Oncol. 2008;26(15):2473.

Recent Guidelines address ER/PR/HER2 IHC VariabilityCAP/ASCO 2010

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Standards:

Defined cut point for positivity of ER/PR as >/= 1%

Use of and interpretation of controls

Standardized specimen rejection criteria (controls, crush artifact, lack of normal epithelium in negative)

Guidelines address IHC Variability (cont.)

Validation and Repeat criteria

Laboratory Accreditation (CAP or equivalent); n.b. IHC validation and PT not required by CLIA

Guidelines for other IHC/other clinical indications receive less attention

Recent CAP IHC validation guidelines- generalized to other TA’s outside Breast CA

CAP/ASCO 2010

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Arch Path Lab Med 2010 134:907

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One Approach to Combining Technical and Professional Expertise in AP & H Services

New Covance Lab co-located with NeoGenomics facility in Fort Myers, Florida

► Covance performs technical component services globally

► Images digitalized

► NeoGenomics performs professional component services centrally

Technical Component

Professional Component

Mitigating the Variability In Oncology Trials with Tissue MarkersTHE KEY IS COMBINABILITY

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• Pre-fixation cold ischemia time and fixation time remains with sites, usually prior to any consideration for clinical trial;

• More education needed. ER/PR/HER2 guidelines help

• Analytical controls very important.

• Same Ventana Benchmark instrumentation in Ft Myers, Shanghai, soon in GVA, Singapore

• Sequestered lot numbers of antibodies for trials• Same SOPs globally • Training in IHC/FISH by Neo staff• Digital pathology utilized for centralized IHC reading by small

number of experts• Bioview FISH TC by Covance; PC by NeoGenomics

• Central reading more consistent than numerous sites

• LIMs and digital images allow for 3rd party adjudication in near real time

Steven G. Brodie, Ph.D., FACMG

Director of Molecular Genetics and Cytogenetics

NeoGenomics Laboratories

Harmonizing AP & H Services in Support of Global Oncology Clinical Trials

Benefits of Harmonizing AP + Histology Services

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• Complete integration of cancer diagnostic testing methodologies

• Cytogenetics• Flow cytometry• Fluorescence in-situ hybridization (FISH)• Immunohistochemistry (IHC)• Molecular genetics

• Specialization in AP enables confident diagnosis of cancer

• Macroscopic, microscopic, biochemical, immunologic and/or molecular examination of organs and tissues

• Flexible LIS system + extensive network of pathologists

• Reduced sample and data variability via localization of testing services

Access to Professional Network

Tap expertise of 700+ Pathologists KOL professional services

• Broad array of pathology subspecialties, global locations

• Sponsor can control / direct who performs professional component services on all trials

• Seamless delivery of clinical data

Flexible, global and high quality

reviews w/o compromising consistency

Flexible, global and high quality

reviews w/o compromising consistency

Genetics Neighborhood - Testing “resolution”

• IHC -picture of a neighborhood like Google Maps analogous to human tissue architecture.

• Cytogenetics -picture of a neighborhood with 46 houses from 1000 feet up. Each house is analogous to a human chromosome.

• Flow Cytometry –picture walkways and trim around a single house from 500 feet. The trim around the house is analogous to the cell surface markers.

• FISH gives you a close-up view of the doors and windows of one house. The doors and windows are analogous to a gene located on a chromosome.

• Molecular testing gives you a close-up view of the serial number on the door lock. The serial number is analogous to a DNA sequence.

CytogeneticsCytogenetics

IHCIHC

Flow CytometryFlow Cytometry

FISHFISH

MolecularMolecular

HER2 FISH and 2013 Guidelines

Normal

Amplified

Positive

Reported as positive

Negative

Reported as negative

FISH

Antibody test

Equivocal

Reported as negative

Not amplified

Reported as positive

Amplified

>10% moderate/strong, complete membrane staining

No staining

HER2 Testing Algorithm

Clinical categorizati

on is critical for treatment decisions

Clinical categorizati

on is critical for treatment decisions

HER2 FISH Testing Algorithm

Protocol design should include flexibility to reflex to additional

markers

Protocol design should include flexibility to reflex to additional

markers

HER2 Equivocal Testing

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• Diagnoses: Lung Cancer >220,000 cases in USA anticipated in 2011; 2nd most common type of cancer

• Deaths: ~157,000 anticipated.

More common than colon, breast & prostate combined

• 85% of all lung cancers are non-small cell lung cancer (NSCLC) which includes:oAdenocarcinomaoSquamous cell carcinomaoLarge cell carcinoma

Source: Nurses’ Health Study

Non-Small Cell Lung Cancer (NSCLC)

Heterogeneity in NSCLC

Normal lung tissue

Abnormal Lung tissue

Complexity of disease requires an informed and precise approach

Complexity of disease requires an informed and precise approach

EGFR (HER1) & HER2 Cell Signaling Pathway

Clinical Trials: NCCN believes that the best management of any

cancer patient is in a clinical Trial. Participation in clinical trials is

especially encouraged.

Clinical Trials: NCCN believes that the best management of any

cancer patient is in a clinical Trial. Participation in clinical trials is

especially encouraged.

Complexity of mutations drive therapy

•EGFR mutations : Increased or reduced sensitivity to erlotinib, gefitinib

•HER2: 4-5%; mutation not amplification: Herceptin benefit unknown

•KRAS mutations: Reduced sensitivity to erlotinib, gefitinib

•BRAF V600E: <2%; potential for future therapy

NCCN Guidelines for NSCLC

Navigating Global Clinical Trials

• Successful oncology clinical trials require the right diagnostic tools, flexible protocol design and seamless execution • Anatomic Pathology specialization• Global network of investigator site support and central labs

• Complexity of disease requires an informed and precise approach

• Clinical categorization is critical for treatment decisions

Reducing sample and data variability in clinical trials begins with standardized testing, smart

logistics and quality data management

Reducing sample and data variability in clinical trials begins with standardized testing, smart

logistics and quality data management

• Challenges Inherent in Conducting Oncology Clinical Trials

• Pre Analytic and Analytic Variability• Understanding Disease Complexity and the

Need for Flexibility in Trial Design• Testing Methodologies Required to Support

Oncology Trials

Session Goals