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

2. DNA Mutation DNA Normal gene Single base change Additions Deletions C
National Cancer Institute
Understanding Cancer and Related Topics
Understanding Cancer
DNA Mutation C A A G C T A A C T
DNA
Normal gene C A A G C G A A C T
Single base change C A A G G C G C T A A C T
Genes can be mutated in several different ways. The simplest type of mutation involves a change in a single base along the base sequence of a particular gene--much like a typographical error in a word that has been misspelled. In other cases, one or more bases may be added or deleted. And sometimes, large segments of a DNA molecule are accidentally repeated, deleted, or moved.
Additions C T C A A G A A C T
Deletions
NCI Web site:

3. Oncogenes Normal cell Cancer cell Mutated/damaged oncogene Normal
National Cancer Institute
Understanding Cancer and Related Topics
Understanding Cancer
Oncogenes
Normal cell
Normal
genes
regulate
cell growth
One group of genes implicated in the development of cancer are damaged genes, called “oncogenes.” Oncogenes are genes whose PRESENCE in certain forms and/or overactivity can stimulate the development of cancer. When oncogenes arise in normal cells, they can contribute to the development of cancer by instructing cells to make proteins that stimulate excessive cell growth and division.
Oncogenes
accelerate
cell growth
and division
Cancer cell
Mutated/damaged oncogene
NCI Web site:

4. Tumor Suppressor Genes Tumor Suppressor Gene Proteins
Act Like a Brake Pedal
National Cancer Institute
Understanding Cancer and Related Topics
Understanding Cancer
Tumor Suppressor Gene Proteins
Growth factor
Receptor
Signaling
enzymes
Transcription factors
DNA
Cell nucleus
Tumor suppressor genes are a family of normal genes that instruct cells to produce proteins that restrain cell growth and division. Since tumor suppressor genes code for proteins that slow down cell growth and division, the loss of such proteins allows a cell to grow and divide in an uncontrolled fashion. Tumor suppressor genes are like the brake pedal of an automobile. The loss of a tumor suppressor gene function is like having a brake pedal that does not function properly, thereby allowing the cell to grow and divide continually.
Cell proliferation
NCI Web site:

5. 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

6. MATCH – Preliminary Hypothesis
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.

7. Alliance Spring Group Meeting / May 9, 2014
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

8. MATCH: SCHEMA
Tumor Biopsy

9. Statistical Considerations
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

10. 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)

11. 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

12. NCI MATCH
PARTICIPATION