Cancer Treatment from the DNA Perspective Peter J. O’Dwyer, MD University of Pennsylvania...

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Cancer Treatment from the DNA Perspective Peter J. O’Dwyer, MD University of Pennsylvania ECOG-ACRIN Cancer Research Group

Transcript of Cancer Treatment from the DNA Perspective Peter J. O’Dwyer, MD University of Pennsylvania...

Cancer Treatment from the DNA PerspectivePeter J. O’Dwyer, MD

University of PennsylvaniaECOG-ACRIN

Cancer Research Group

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DNA Mutation

Additions

Deletions

Normal gene

Single base change

DNA

CT

A G C G A A C TAC

A G G C G C T AAC A C T

A G C T A A C TAC

A G A A C TAC

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Oncogenes

Mutated/damaged oncogene

Oncogenes accelerate cell growth and division

Cancer cell

Normal cell Normal genes regulate cell growth

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Tumor Suppressor GenesAct Like a Brake Pedal

Tumor Suppressor Gene Proteins

DNACell nucleus

Signalingenzymes

Growth factor

Receptor

Transcriptionfactors

Cell proliferation

Genomics-Driven Trials

• Assumption: Given a specific mutation, a particular growth or survival pathway will be activated, so therapy can be directed specifically to it

• Disease-Specific– Breast Cancer – I-SPY– Lung Cancer – LUNG-MAP, ALCHEMIST– Colorectal Cancer – ASSIGN (in development)

• “Disease-Agnostic”– MATCH

MATCH – Preliminary Hypothesis

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Primary:

That tumors that share common somatic genetic alterations in oncogenes will be variably responsive to therapies targeting the oncogenic pathway based on lineage specific factors. 

Secondary:

That concomitant somatic genetic alterations will predict responsiveness or resistance.

MATCH TRIAL OVERVIEW

• Identify mutations/amplifications/translocations in patient tumor sample - eligibility determination

• Assign patient to relevant agent/regimen – single-arm Phase II design

• Need to sequence large numbers of tumors (3000pts) and need to have large numbers of targeted treatments

• Tumor biopsies & sequencing at progression to investigate resistance mechanisms– De-identified samples submitted to central labs – Whole-exome sequencing (research purposes) to detect

non-ambiguous germline variants

Alliance Spring Group Meeting / May 9, 2014 7

MATCH: SCHEMA

Tumor Biopsy

Statistical Considerations

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Within each drug-by-mutation category:

Dual Primary Endpoints: Overall Response Rate 5% vs. 25% or Progression Free Survival 6 months 15%

(median PFS 2.2 m) vs 35% (median PFS 4 m) One stage design 31 evaluable patients per arm

ORR = proportion of patients with objective response (PR+CR) on initial course of study agent

PFS6 = proportion of patients alive and progression free at 6 months from initiation of study agent

CLIA LAB NETWORK• Genetic platform: Ion Torrent PGM AmpliSeq custom

panel; Oncomine under evaluation– About 200 genes– SNV, indel, CNV, targeted translocations

• Immunohistochemical expression of PTEN• Validation within and across sites: same SOP• Possibly additional IHC and FISH, if needed• Lead laboratory: Frederick National Laboratory for

Cancer Research (Williams)– Competitively chosen lab sites:

• MD Anderson (Hamilton)• MGH (Iafrate)• Yale (Sklar)

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SUMMARY

• In planning for a year, MATCH slated to open by end 2014.

• Robust state-of-the-art platform finalized September 2014

• Agreements close to final with four companies for genotype-specific drugs

• Strong CTEP-Intergroup collaboration in developing the trial

• Broad community oncologist and advocate input refined design

NCI MATCHPARTICIPATION