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March 19, 2002 Overview of Colorectal Chemoprevention Trials Bernard Levin, M.D. The University of Texas M. D. Anderson

March 19, 2002 Overview of Colorectal Chemoprevention Trials Bernard Levin, M.D. The University of Texas M. D. Anderson Cancer Center. 5-20 yrs. 5-15 yrs. ADENOMA. Normal. Mild. Moderate. Severe. Cancer. K-ras. SMAD 2 SMAD 4 DCC. p53. APC , bcl -2, c- myc Hypomethylation COX-2.

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March 19, 2002 Overview of Colorectal Chemoprevention Trials Bernard Levin, M.D. The University of Texas M. D. Anderson

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  1. March 19, 2002 Overview of Colorectal Chemoprevention Trials Bernard Levin, M.D.The University of Texas M. D. Anderson Cancer Center

  2. 5-20 yrs 5-15 yrs ADENOMA Normal Mild Moderate Severe Cancer K-ras SMAD 2 SMAD 4 DCC p53 APC,bcl-2, c-myc Hypomethylation COX-2 Focus of Technology Development Carcinogenesis is a Chronic Disorder:Dysplasia–Carcinoma Sequence Adapted from Ilyas et al. Eur. J. Cancer 1999; 35:335-351 and Kelloff et al. Oncology 1996; 10:1471-1484

  3. Molecular Targets: Colorectal Neoplasia Chemoprevention • Genetic Mutations • APC • p53 • Growth Factors & Critical Receptors • VEGF • Vitamin D receptor • EGFR • Retinoid receptors • RARs/RXRs/both • Estrogen receptor • PPAR-gamma or -delta • Key Enzymes • COX-2 • Ornithine decarboxylase • Farnysyl transferase • Matrix metalloproteinase • Raf kinase • SAM decarboxylase • Cyclin-dependent kinases • Inducible nitric oxide synthetase (iNOS)

  4. Anticancer Effect of Aspirin-like Drugs:COX-Dependent and Independent Mechanisms COX inhibitor X Sphingomyelin Ceramide Arachidonic Acid Non-COX Targets: P450s PPAR/ PPAR, COX-1 COX-2 Prostaglandins (PGE2) Apoptosis Proliferation Angiogenesis Free Radical Production Carcinogen Activation Immune Function X Carcinogenesis

  5. COX Inhibitors Reduce Colorectal Carcinogenesis – Observational Data

  6. 35 35 Late treatment (days 55-80) Early treatment (days 30-80) 30 30 25 25 20 20 * Multiplicity (tumors/animal) 15 15 * * * 10 10 5 5 0 0 Vehicle 1500 50 Vehicle 150 500 1500 50 500 Piroxicam Celecoxib Celecoxib Piroxicam (mg/kg diet) (mg/kg diet) Celecoxib Inhibits Tumor Multiplicity in the MIN Mouse Model * P < 0.05; n=12/group Jacoby et al: Cancer Res 60:5040-4, 2000

  7. COX-2 Overexpression in Human Neoplasia Anderson WF, et al: Curr Pharm Design, 8:99-110, 2002

  8. Effect of COX-2 Selective Inhibition on Colorectal Adenomas in Patients with FAP Steinbach et al, NEJM, 2000

  9. Clinical Adenoma number Adenoma size Cumulative lesion burden ACF number/size Cellular Proliferation Apoptosis Molecular COX-2 expression CYP-2C9 polymorphisms Genomic microarray Proteomic array Biochemical Prostanoid concentrations Cytokines Potential Endpoints

  10. Cumulative Incidence of Colorectal Cancer (%) National Polyp Study: Adenomas as Reasonable Surrogates of Colorectal Cancer 5 No. expected without polypectomy from Mayo Clinic data 4 No. expected without polypectomy from St. Mark’s data 3 2 No. expected with mixed intervention from SEER data 1 No. observed post polypectomy 0 8 0 1 2 3 5 4 6 7 Years of Follow-up Winawer SJ, et al. N Engl J Med 329: 1977—1981, 1993

  11. Current Secondary Prevention of Sporadic Adenoma Trials • International, multi-center • Placebo controlled • Secondary prevention ofsporadic colorectal adenomas

  12. Secondary Prevention of Colorectal Adenomas:The Rofecoxib Study • Start date 4/2000 • 2,000 pts from 110 centers • Rofecoxib 25 mg qd vs. placebo • Colonoscopy after 1 and 3 yr • Primary end point: number of adenomas

  13. Secondary Prevention of Colorectal Adenomas: The NCI Study • Start date 12/1999 • 1,950 pts from 100 centers • Celecoxib 200 bid, 400 bid vs. placebo • Colonoscopy after 1 and 3 yr • Primary end point: number of adenomas

  14. Secondary Prevention of Colorectal Adenomas: The PRESAP Study • Start date 3/2001 • 1500 pts • Celecoxib 400 mg qd vs. placebo • Colonoscopy after 1 and 3 years • Primary end point: number of adenomas

  15. PRESAP Study Objective • Primary Objective • Evaluate whether celecoxib is safe and effective in reducing the occurrence of new adenomatouspolyps in subjects who have previously undergonea polypectomy • Secondary Objectives • Number of colorectal adenomas • Histopathologic grade of colorectal adenomas • Size of colorectal adenomas following1 and 3 years of study drug treatment

  16. PRESAP Study Inclusion Criteria • Age 30 or older • Photographed cecum •  6 mm adenoma (single) •  1 polyp (any size) • Abstains from NSAIDs or COX-2 inhibitors (low dose ASA allowed)

  17. ASA Use Non-ASA Use Celecoxib Placebo Celecoxib Placebo PRESAP Study Stratification for Low-Dose Aspirin Use

  18. PRESAP Study Timeline Overview Month 1 (Randomization) Begin Study Drug Treatment End Treatment Lead-In Visit Month 38 Single-Blind Placebo Lead-In Period Year 1 (Month 13) Year 3 (Month 37) Double-Blind Randomization Period  90 Days   30 Days  (1 Month) Surveillance Colonoscopy Surveillance Colonoscopy Colonoscopy/Polypectomy Phone Contact  120 Days 

  19. Opportunities for Serial Pharmacologic Synergies in the COX Metabolic Pathway

  20. Nimesulide (Helsinn) Colorectal Neoplasia Prevention Drug Development as of February 2002 (NCI) CDDO Ursolic Acid Sulindac + DFMO (NCI & ILEX) LM4108 (VanderbiltUniv) Celecoxib + DFMO (NCI & ILEX) NS398 (Cayman Chemical/Taisho Pharmaceutical) COX Inhibitors: Aspirin (NCI) JTE522 (Japan Tobacco) P54 (PhytochemicalsReksa) Curcumin (NCI) Celecoxib (Pharmacia & NCI) Meloxicam (Boehringer Ingelheim) Rofecoxib (Merck & Co) Nabumetone (Smith Klein Beecham) Phase III Phase I/II Phase IV Preclinical Lovastatin (Merck & Co) Ursodiol (Novartis & NCI) Inulin (Orafti) Other Agents: Calcium Marimastat(British Biotech) Piromastat(Agouron) EKB-569 (Wyeth Ayerst) GED (Inotek) Sulindac Sulfone (Cell Pathways) Selenium (NCI)

  21. Cooperative Efficacy of COX Inhibitors + DFMO in Animal Models of Colorectal Cancer Prevention Absolute incidence or multiplicity (and percent reduction) in CR neoplasia at study termination †Typically testing each compound at ~50% of the single-agent dose *Statistically significant vs. placebo, p<0.05

  22. NCI-sponsored Clinical Colorectal Prevention Trials with COX-2 Inhibitors *Complete †Closed to accrual

  23. NCI-sponsored Clinical Extracolonic Prevention Trials with COX-2 Inhibitors †Closed to accrual

  24. NCI-sponsored Clinical Extracolonic Prevention Trials with COX-2 Inhibitors

  25. Delay or complement initial screening Complement endoscopic surveillance Improve effectiveness 10-15% polyp miss rate 5-40% “flat” adenomas Reduce procedure-related morbidities and inconveniences Time Sedation Complications Prolong inter-exam intervals Spare or delay primary prophylactic polypectomy or colectomy Reduce or delay the need for secondary colorectal surgeries Inhibit or retard extracolonic neoplasia FAP - duodenal, desmoids HNPCC - GU, uterine, upper GI Sporadic Inhibit or retard several age-related diseases Possible Roles for a Chemopreventive Agent in Management of Colorectal Neoplasia Improve quality of life Reduce neoplasia incidence & mortality

  26. Tensions to be Considered in Absolute vs. Reasonable Medical Assurance • Scientific Practicality • Time • Patients/staff • Finances • Dynamic landscape • Scientific Rigor • Accuracy • Reproducibility • Quantitiation • Predictive assurance Once the determinants of disease risk are understood, management of those risks – rather than fulminant disease alone – creates a clinical dilemma wherein harm may result from errors of interventional omission or comission (i.e., risk itself, may become a “disease” worthy of intervention).

  27. Intermediate Endpoints in CV Prevention “This committee previously recommended, and the Food and Drug Administration concurred, that approval of lipid altering agents should be based on a drug’s biochemical efficacy in decreasing serum lipids. Attempts to establish clinical efficacy in the prevention of coronary artery disease or other manifestations of atherosclerosis, would require prolonged observations and hamper research and development of this class of drugs.” FDA Endocrinologic and Metabolic Drugs Advisory Committee, October 15, 1981

  28. Chemopreventive Drug Development in Populations at Risk for Colorectal Cancer Celecoxib NSAID + DFMO (HD) NSAID + MMPI NSAID + EGFR inhibitor High Risk: FAP, HNPCC, IBD Lifetime risk ~ 40-100% 3º Prevention Celecoxib Ursodiol DFMO Calcium† MMPI Folate/B12*† EGFR inhibitor Selenium Aspirin*†/curcumin Inulin NSAID + DFMO (LD) Moderate Risk: Current/prior adenoma(s), cancer survivor, Lifetime risk ~ 10-20% 2º Prevention General Population: 40% incidence of adenomas; 130,000 CRC cases/yr Lifetime risk ~ 5.6% (2000) Calcium† Selenium Folate/B12*† ASA*†/curcumin P. activity*† High F&V/low fat*† Inulin 1º Prevention *Active against many cancers †Active against many age-related diseases (e.g., CV, CA, Alzheimer’s)

  29. AACR Taskforce Working Conclusion • In CRC risk reduction trials, the adenoma is a disease endpoint (i.e., a point of clinical intervention and risk) • Goal = ~ 30% relative reduction in adenoma incidence • Other potential clinical benefits • Decrease in number of polypectomies and/or procedure-related risks • Delay in time to adenomas with malignant potential (i.e., “advanced” adenomas) • Increase intervals between surveillance procedures • Organ preservation/delay in time to resection (FAP) O’Shaughnessy JA: Clin Cancer Res 8:314-347, 2002

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