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PTK/ZK: An Oral Multi-VEGF Receptor Inhibitor

A Randomized, Double-blind, Placebo-controlled Phase III Study in Patients with Metastatic Colorectal Cancer Receiving First-line Chemotherapy with FOLFOX 4 and PTK/ZK or Placebo (CONFIRM-1).

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PTK/ZK: An Oral Multi-VEGF Receptor Inhibitor

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  1. A Randomized, Double-blind, Placebo-controlled Phase III Study in Patients with Metastatic Colorectal Cancer Receiving First-line Chemotherapy with FOLFOX 4 and PTK/ZK or Placebo (CONFIRM-1) J R Hecht, T Trarbach, E Jaeger, J Hainsworth, R Wolff, K Lloyd, G Bodoky, M Borner, D Laurent, C Jacques

  2. Fit of PTK/ZK (green) into the ATP binding site PTK/ZK: An Oral Multi-VEGF Receptor Inhibitor • Potent inhibitor of all known VEGF receptors • Also inhibits PDGFR and c-Kit • Half life of 3 to 6 hours • Oral once-daily dosing

  3. PTK/ZK Inhibits All Known Receptors of VEGF VEGF-AVEGF-CVEGF-D VEGF-CVEGF-D VEGF-A VEGF-B PlGF Extracellular Endothelial Cell PTK/ZK PTK/ZK PTK/ZK Intracellular VEGFR-1/Flt-1 VEGFR-2/KDR VEGFR-3/Flt-4 Angiogenesis Angiogenesis Lymphangiogenesis Tumor metastasis

  4. Proof of Concept in mCRC Baseline Baseline Day 2 PTK/ZK • Tumor vascularity and permeability decreased rapidly with PTK/ZK and correlated with clinical benefit • Subsequent PTK/ZK-FOLFOX combination showed promising activity Morgan B, et al. J Clin Oncol. 2003;21: 3955-3964 Steward W, et al. ASCO 2004

  5. CONFIRM-1 Trial Design R A N D O M I Z E D 1168 Patients Stratification Factors: PS: 0, 1-2 LDH: ≤, >1.5 x ULN FOLFOX 4 + PTK/ZK 1250 mg po qd FOLFOX 4 + Placebo Multinational randomized phase III trial in previously untreated mCRC

  6. Main Eligibility Criteria • Metastatic colorectal cancer patients • No prior chemotherapy for metastatic disease • Prior adjuvant chemotherapy allowed (> 6 mo) • Measurable disease per RECIST criteria • WHO PS 0-2 • Adequate hematological and organ function • No exclusions for prior coagulopathy or bleeding

  7. Primary Study Objectives • Progression-free survival • Independent central radiological review • Primary analysis • Investigator assessment • Statistical hypothesis • 25% reduction in risk of progression (HR 0.75) • Overall survival • Statistical hypothesis • One-year OS rate from 71% to 76% (HR 0.80)

  8. Patient Characteristics

  9. Patient Disposition • 1168 patients were randomized between February 2003 and May 2004

  10. Safety

  11. Grade 3/4 NCI Adverse Events in >5% of Patients

  12. Grade 3/4 NCI Adverse Events in >5% of Patients

  13. Other Clinically Important Adverse Events

  14. Efficacy

  15. Response Rate

  16. PTK/ZK + FOLFOX4 Placebo + FOLFOX4 Progression-Free Survival: Central Assessment (Primary Analysis)* HR 0.88 (95% CI) (0.74, 1.03) P-value 0.118 *If assessment is delayed or missed, date of PD is adjusted to previous planned assessment date

  17. Progression-Free Survival: Investigator Assessment HR 0.82 (95% CI) (0.69, 0.97) P-value 0.019

  18. PFS:Hazard Ratio HR P-value Overall Central 0.88 0.118 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 In favor of PTK/ZK In favor ofplacebo

  19. PFS:Hazard Ratio HR P-value Overall Central 0.88 0.83 0.118 0.026 Investigator 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 In favor of PTK/ZK In favor ofplacebo

  20. Central Investigator PFS by Pre-Planned Stratum:Hazard Ratio HR P-value 0.88 0.83 0.118 0.026 Overall Population High LDH, PS 0 High LDH, PS 1-2 Low LDH, PS 0 Low LDH, PS 1-2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 In favor of PTK/ZK In favor ofplacebo

  21. Progression-Free Survival:Exploratory Analysis in Patients with High LDH (n=316) Central Assessment Investigator Assessment HR 0.60 (95% CI) (0.44, 0.82) P-value 0.001 HR 0.68 (95% CI) (0.50, 0.92) P-value 0.012 PTK/ZK + FOLFOX4 Placebo + FOLFOX4 PTK/ZK + FOLFOX4 Placebo + FOLFOX4

  22. Future Directions • CONFIRM 1 overall survival data expected second half 2006 • CONFIRM 2 final results expected 2006 • FOLFOX +/- PTK/ZK in second-line CRC • Optimize dosing schedule to reduce early treatment discontinuation and improve efficacy • Explore the biology and clinical relevance of predictive factors such as LDH in CRC

  23. Conclusions • PFS based on central review showed a modest benefit of adding PTK/ZK to FOLFOX which did not reach statistical significance • Preplanned secondary analysis of PFS based on investigator assessment showed a statistically significant improvement favoring PTK/ZK • PTK/ZK in combination with FOLFOX is generally well tolerated • High LDH levels may predict which patients are most likely to benefit from PTK/ZK

  24. UCLA/TORI Dennis Slamon Nancy Ryba David Reese David Chan, Ravi Patel NCCRA Mike and Michele Richman University of Essen Krankenhaus Nordwest, Frankfurt Sarah Cannon Cancer Center MD Anderson Cancer Center Virginia Cancer Institute Szent Laszlo Hospital, Budapest Institute for Medical Oncology, Bern Acknowledgments • The Patients and Their Families • The Investigators in Over 200 Medical Centers Worldwide • Novartis • David Lebwohl • Andrea Kay • Bee-Lian Chen • Andrew Henry • Eric Masson • Schering AG Germany • Andrea Wagner • Christine Gonschorek • Michael Kretschmann • Martina Poethig • Silke Zaun

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