Translational research in colorectal cancer

1
Translational research in colorectal cancer

• Tim Maughan
• Professor of Cancer Studies
• Consultant Clinical Oncologist

2
Developing a clinical research network

• The Wales Cancer Trials Network
• 1998-2006

3
Wales Cancer Trials Network
4
Wales Cancer Trials Network
A network of research staff to support patient
entry into clinical research studies And deliver
high quality data collection
5

• A professional organisation
• Support clinical trial design
• Collaborate to obtain research funding
• Trial run to GCP / EU directive requirements
• Data management
• Pharmacovigilance / monitoring
• Data analysis
• Publication

6
Key achievements

• A contractual mentorship agreement between
  WCTN MRC CTU Dec 2004
• ZICE trial funded by Roche and CTAAC
  approved Jan 2005
• Fragmatic trial approved and funded by CTAAC,
  support from Pfizer Feb 2005
• NCRI accreditation Feb 2005
• New offices Oct 2005
• Associate Director appointed Oct 2005
• Core funding from CR-UK Dec 2005
• First patient in ZICE Jan 2006
• SCOPE trial funded by CTAAC Feb 2006

7
National Cancer Research Institute (NCRI)
Board Sub-Group on Clinical and Translational
research
Wales Cancer Bank
NCRN Operational Steering Group
Clinical Trials Units Committee
National Cancer tissue resource
Wales Cancer Trials Unit
NCRN Coordinating centre
National Cancer Research Networks (41)
NCRI Clinical Study Groups (22)
Wales Cancer Trials Network
Wales investigators
Trial Approval Process CTAAC
TRICC
A whole system approach
8
What are the benefits of the NCRI?

• Trials are completed more quickly
• Metastatic colorectal cancer
• More ambitious trials are designed
• Inoperable lung cancer
• Improved links with industry
• Oesophageal cancer
• Improved translational research programme
• Metastatic colorectal cancer
• Increased breadth of issues addressed
• Prevention, early diagnosis

9
Improved opportunity for translational research

• MRC COIN trial in metastatic
• colorectal cancer
• Chief Investigator Tim Maughan

Merck KGaA
10
COIN
Second Line Chemo Therapy Irinotecan Based As
NICE guidance
ARM A CONTINUOUS CHEMOTHERAPY Oxaliplatin
fluoropyrimidine chemotherapy continued until
progression, cumulative toxicity or patient choice
ARM B CONTINUOUS CHEMO CETUXIMAB OxFp
chemotherapy weekly cetuximab continued until
progression, cumulative toxicity or patient choice
ARM C INTERMITTENT CHEMOTHERAPY Oxaliplatin
fluoropyrimidine chemotherapy Treat for 12
weeks then stop and monitor. Restart on
progression for a further 12 weeks
11
Why intermittent chemotherapy? MRC CR06 overall
survival
Median 2yr Stop 10.8 m 19 Continue11.4 m 13
HR 0.90 (95 CI 0.71-1.13) p0.37
Stop
Continue
Maughan et al, Lancet, 2003 361 457-64. MRC
CR06 Comparison of intermittent and continuous
palliative chemotherapy for advanced colorectal
a multicentre randomised trial.
12
How can we improve overall survival in
metastatic CRC?Epidermal Growth Factor Receptor
EGFR, as a Treatment Target
Expression 60-80 Colorectal cancer
13
Cetuximab

• IgG1 monoclonal antibody
• Exclusive for EGFR and its heterodimers
• Prevents ligand binding to EGFR
• Higher affinity for EGFR compared to natural
  ligands
• Blocks receptor dimerization, tyrosine kinase
  phosphorylation, signal transduction
• Stimulates receptor internalization
• Fc region may induce antibody-dependent
  cell-mediated cytotoxicity (ADCC) (immune
  response)

14
EGFR signal transduction
R
Gene transcription Cell cycle progression
15
EGFR signal transduction
Gene transcription Cell cycle progression
16
EGFR signal transduction
Synergy?
17
Cetuximab in first-line mCRC
AIO/iri ERBI FOLFIRI ERBI IFL ERBI FOLFOX ERBI FUFOX ERBI
No. 21 40 29 42 38
ORR () 14 (67) 17 (43) 14 (48) 34 (81) 21 (55)
SD 6 (29) 18 (45) 3 (11) 7 (17) 7 (23)
(CRPRSD) 95 88 90 98 79
Median Survival (months) OS33 mo N/A N/A PFS 12.3 N/A
1) Folprecht, et al. WCGIC (2005) Abstract and
poster No. P-053 2) Rougier, et al. J Clin
Oncol 200422(Suppl. 14s)248s Abstract and
poster No. 3513 3) Rosenberg et al. ASCO 2002,
(Abstract 536) 4 Diaz Rubio et al. ASCO 2005
3535 5Seufferlein, et al. J Clin Oncol
200523(Suppl. 16s)281s Abstract No. 3644
Lordick, et al. ASCO GI (2005) Abstract No. 247
18
COIN trial endpoints

• Primary Endpoint Overall survival
• Secondary endpoints
• Progression-free survival
• time of disease control
• Response, toxicity
• quality of life
• cost effectiveness.
• Translational endpoints
• Predictors of response and toxicity

19
Tumour block collection
Consent (Not optional)
Consent form record on Rando / pre-treatment
form
Copy consent form pathology request form
Local staff request block from Pathology dept
Document process on Pathology CRF page
Receive block and pathology report from
Pathology dept
Label sample and pathology Report with COIN trial
no Anonymise path report Place in sealed
envelope in jiffy bag
Send to Wales Cancer Bank COIN trial sample
20
Paraffin embedded tumour collection

• Consent required for EGFR IHC
• Blocks collected at Wales Cancer Bank
• TMAs prepared, DNA extracted
• IHC for EGFR,
• FISH for gene copy no
• IGF-1R project

21
Other translational studies

• Optional consent for further bowel cancer
  research
• 96 agreed in MRC FOCUS trial
• Other investigations on paraffin
• Blood sample for DNA extraction
• Subset of 300 fresh tumour collection
• Subset for investigation of link of rash to
  response rate

22
2. Blood sample collection
Consent (optional)
Document process on Pathology CRF page
Take 20ml blood EDTA tube Label with date and
COIN trial no
Send to Dr J Cheadle COIN trial sample lab Inst
Medical genetics Cardiff
Place in sealed postage prepaid Safe box
23
Blood Sample Overview
24
5FU
5FU
25
Patients DNA repair profiles may modify
response to, and side effects from, chemotherapy

• How do we intend to measure repair profiles ?
• assay every cSNP that may alter protein function
  with a minor allele frequency (MAF) gt5, in every
  repair gene in the human genome .131 genes
• for genes lacking cSNPs, we will identify and
  assay other functional polymorphisms in their
  promoters

26
NERMain mechanism of repair of platinum
adduct damage
27
XRCC2 (XPD) Lys751Gln
FOLFOX RR L/L L/G G/G
Park Cancer Res 2001 24 10 10
N9741 Mcleod 2003 49 49 29
28
Do we have sufficient power ?

• single variant analyses
• gt90 power to detect a 20 diff. in response or
  side effect rates for cSNPs with minor allele
  frequencies (MAFs) 5
• 80 power to detect a 10 diff. in response or
  s.e. rates for cSNPs with MAFs 14
• SNP combinationsrepair profiles
• max SNPs which can be analysed simultaneously to
  detect a 30 diff. in response or s.e. rates,
  whilst preserving power of gt80, is eight

29
3. Pharmacogenomics

• Sample of extracted DNA from Cardiff
• Sent to University of Washington, St Louis
• Prof Howard Mcleod
• USA expert in pharmacogenomics of colorectal
  cancer agents
• Funded by NIH grants

30
Macleod et al, Proc ASCO, 2004
31
(No Transcript)
32
4. Fresh tissue collection

• Fresh tissue to RNAlater for rna extraction from
  200 pts
• Almac have developed colorectal specific
  microarray (Johnson)
• 43 new transcripts not in Afymetrix chip
• Gene signatures for response

33
Presence and intensity of acneiform rash predicts
increased survival
16
14
12
10
Survival (months)
8
6
4
2
0
CRC CRC CRC
CRC Pancreatic SCCHN
Grade 3

• How?
• Genetic variance of EGFR pathway in skin and
  tumour?
• Immune reaction?

Propriones acnei mycobacterium parvum Acne is a
delayed hypersensitivity reaction Does this
trigger an anti tumour response? (Layton, Tabi,
Clayton)
1. Saltz et al. Proc Am Soc Clin Oncol 200119
Abstract 7. 2. Saltz et al. J Clin Oncol
2004221201-1208. 3. Cunningham D N Engl J Med
2004351337-345. 4. Van Cutsem et al. EORTC/NCI
Geneva 2004. 5. Abbruzzese et al. Proc Am Soc
Clin Oncol 2001 Abstract 518 5. Kies et al.
Proc Am Soc Clin Oncol 200220 Abstract 925.
34
World class integrated germline and tumour
analysis aiming to identify determinants of
response
35
Collaborating in cancer research

• UK wide academic collaboration
• 73 active cancer centres across UK
• Collaboration of funders CR-UK, MRC, Merck, NHS
  RD, NIH
• Cardiff the hub of the translational research
• Wales Cancer Bank
• Genetics, Pharmacy, College of Medicine