Treatment of Advanced colorectal cancer bedside and bench Wales cancer research center

Translational research in colorectal cancer Tim Maughan Professor of Cancer Studies Consultant Clinical Oncologist Developing a clinical research network The Wales Cancer Trials Network 1998-2006 Wales Cancer Trials Network 1998 5.3 Staff 415 Patients 2.8% in Trials Wales Cancer Trials Network 2003 22.45 Staff 1242 Patients 8% in Trials A network of research staff to support patient entry into clinical research studies And deliver high quality data collection • 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 Key achievements • A contractual mentorship agreement between WCTN & MRC CTU • ZICE trial – funded by Roche and CTAAC approved • Fragmatic trial – approved and funded by CTAAC, support from Pfizer • NCRI accreditation • New offices • Associate Director appointed • Core funding from CR-UK • First patient in ZICE • SCOPE trial funded by CTAAC Dec 2004 Jan 2005 Feb 2005 Feb 2005 Oct 2005 Oct 2005 Dec 2005 Jan 2006 Feb 2006 National Cancer Research Institute (NCRI) Board Sub-Group on Clinical and Translational research NCRN Operational Steering Group NCRN Coordinating centre Wales Cancer NationalCancer Bank tissue resource Clinical Trials Units Committee Wales Cancer Trials Unit National Cancer Research Networks (41) Wales Cancer Trials Network Trial Approval Process NCRI Clinical Study Groups (22) Wales investigators CTAAC TRICC A whole system approach What are the benefits of the NCRI? 1. Trials are completed more quickly Metastatic colorectal cancer 2. More ambitious trials are designed Inoperable lung cancer 3. Improved links with industry Oesophageal cancer 4. Improved translational research programme Metastatic colorectal cancer 5. Increased breadth of issues addressed Prevention, early diagnosis CR10 Improved opportunity for translational research MRC COIN trial in metastatic colorectal cancer Chief Investigator Tim Maughan Merck KGaA COIN 807 ARM A CONTINUOUS CHEMOTHERAPY Oxaliplatin + fluoropyrimidine chemotherapy continued until progression, cumulative toxicity or patient choice 807 ARM B CONTINUOUS CHEMO + CETUXIMAB OxFp chemotherapy + weekly cetuximab continued until progression, cumulative toxicity or patient choice Second Line Chemo Therapy Irinotecan Based As NICE guidance 807 ARM C INTERMITTENT CHEMOTHERAPY Oxaliplatin + fluoropyrimidine chemotherapy Treat for 12 weeks then stop and monitor. Restart on progression for a further 12 weeks Why intermittent chemotherapy? MRC CR06 overall survival 1.0 0.9 0.8 0.7 0.6 Median 2yr Stop 10.8 m 19% Continue11.4 m 13% HR 0.90 (95% CI 0.71-1.13) p=0.37 S u r v 0.5 i v a l 0.4 0.3 0.2 0.1 0.0 0 6 12 Stop Continue 18 24 Patients at risk stop continue Months 178 176 130 128 71 72 39 36 22 17 Maughan et al, Lancet, 2003; 361 : 457-64. MRC CR06 Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal: a multicentre randomised trial. How can we improve overall survival in metastatic CRC? Epidermal Growth Factor Receptor EGFR, as a Treatment Target ligand EGF, TGFa Amphiregulin b-celluli, nHB-EGF Epiregulin Heregulins NRG2 NRG3 Heregulins b-cellulin extracellular domain 100 44 36 48 Cysteine-rich domains Expression 60-80% Colorectal cancer Tyrosine kinase 100 domain 100 82 33 59 24 79 28 C-terminus ErbB-1 Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4 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 antibodydependent cell-mediated cytotoxicity (ADCC) (immune response) EGFR signal transduction R R RAS RAF SOS K K PI3-K pY pY GRB2 pY MEK PTEN AKT STAT MAPK Gene transcription Cell cycle progression P P myc cyclin D1 Cyclin D1 DNA proliferation/ maturation Jun Fos Myc chemotherapy/ radiotherapy resistance metastasis survival/anti-apoptosis angiogenesis EGFR signal transduction R R RAS RAF SOS K K PI3-K pY pY GRB2 pY MEK PTEN AKT STAT MAPK Gene transcription Cell cycle progression P P myc cyclin D1 Cyclin D1 DNA proliferation/ maturation Jun Fos Myc chemotherapy/ radiotherapy resistance metastasis survival/anti-apoptosis angiogenesis EGFR signal transduction R R Synergy? DNA PK NH2 Pt II NH2 A G Reduced DNA repair G G GG Cetuximab in first-line mCRC AIO/iri + FOLFIRI ERBI + ERBI No. 21 40 IFL + ERBI 29 FOLFOX + ERBI 42 FUFOX + ERBI 38 ORR (%) SD (CR+PR+SD) 14 (67) 6 (29) 95 % OS 33 mo 17 (43) 18 (45) 88 % N/A 14 (48) 3 (11) 90 % N/A 34 (81) 7 (17) 98% 21 (55) 7 (23) 79% N/A Median Survival (months) 1) PFS 12.3 Folprecht, et al. WCGIC (2005) [Abstract and poster No. P-053] 2) Rougier, et al. J Clin Oncol 2004;22(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 2005;23(Suppl. 16s):281s [Abstract No. 3644] ; Lordick, et al. ASCO GI (2005) [Abstract No. 247] 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 Tumour block collection Consent (Not optional) Local staff request block from Pathology dept Receive block and pathology report from Pathology dept Consent form + record on Rando / pre-treatment form Copy consent form + pathology request form Document process on Pathology CRF page 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 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 (Moroni et al, Lancet Oncology 2005; 6:279-286 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 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 Blood Sample Overview COIN – trial 2,400 CRC patients metabolism/receptor pathways DNA repair profiles J.Cheadle J.Sampson A.Dallosso + H.Mcleod analyses G.Griffiths –MRC V.Moskvina – BBU I.Nikolov - BBU 5FU Oxali Oxali 5FU ‘Patient’s 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) >5%, 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 NER Main mechanism of repair of platinum adduct damage XRCC2 (XPD) Lys751Gln FOLFOX RR L/L L/G G/G Park Cancer Res 2001 24% 49% 10% 29% N9741 Mcleod 2003 Do we have sufficient power ? • single variant analyses – >90% 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 combinations…repair profiles… – max SNPs which can be analysed simultaneously to detect a 30% diff. in response or s.e. rates, whilst preserving power of >80%, is eight 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 Macleod et al, Proc ASCO, 2004 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 Colorectal cDNA microarray Presence and intensity of acneiform rash predicts increased survival 16 Survival (months) 14 12 1 0 8 6 4 2 0 CRC CRC CRC No reaction CRC Grade 1 Pancreatic Grade 2 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 2001;19: Abstract #7. 2. Saltz et al. J Clin Oncol 2004;22:1201-1208. 3. Cunningham D N Engl J Med 2004;351:337-345. 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 2002;20: Abstract #925. Genome wide DNA repair variance EGFR IHC World class integrated germline and tumour analysis aiming to identify determinants of response Pharmacogenomics of all agents Colorectal cDNA microarray Collaborating in cancer research • UK wide academic collaboration • 73 active cancer centres across UK • Collaboration of funders: CR-UK, MRC, Merck, NHS R&D, NIH • Cardiff the hub of the translational research – Wales Cancer Bank – Genetics, Pharmacy, College of Medicine