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 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 Fit of PTK/ZK (green) into the ATP binding site 3 VEGF-A VEGF-C VEGF-D VEGF-A VEGF-B PlGF VEGF-C VEGF-D VEGFR-1/Flt-1VEGFR-2/KDRVEGFR-3/Flt-4 PTK/ZK Extracellular Intracellular Angiogenesis Lymphangiogenesis Tumor metastasis PTK/ZK Inhibits All Known Receptors of VEGF Endothelial Cell PTK/ZK 4 Proof of Concept in mCRC Baseline Day 2 PTK/ZK Morgan B, et al. J Clin Oncol. 2003;21: Steward W, et al. ASCO 2004 Baseline Tumor vascularity and permeability decreased rapidly with PTK/ZK and correlated with clinical benefit Subsequent PTK/ZK-FOLFOX combination showed promising activity Patients Stratification Factors: PS: 0, 1-2 LDH: , > 1.5 x ULN FOLFOX 4 + PTK/ZK 1250 mg po qd CONFIRM-1 Trial Design FOLFOX 4 + Placebo Multinational randomized phase III trial in previously untreated mCRC RANDOMIZEDRANDOMIZED 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 Characteristics FOLFOX 4 + PTK/ZK N=585 FOLFOX 4 + Placebo N=583 Median Age (yrs)5961 Male / Female (%)63 / 3760 / 40 WHO PS 0 / 1 / 2 (%)55 / 41 / 454 / 40 / 6 Colon / Rectum (%)71 / 2668 / 30 Liver Metastasis (%)8074 Lung Metastasis (%)2631 Number of Organs Involved (%) > Median LDH at Baseline0.95 x ULN Prior Adjuvant Chemotherapy (%)2628 9 Patient Disposition FOLFOX 4 + PTK/ZK N= 585 (%) FOLFOX 4 + Placebo N=583 (%) Patients ongoing2532 Patients discontinued due to: Progressive disease3342 Adverse event2111 Withdrawal of consent127 Other reasons patients were randomized between February 2003 and May 2004 10 Safety 11 Grade 3/4 NCI Adverse Events in >5% of Patients Adverse Events FOLFOX 4 + PTK/ZK N=579 (%) FOLFOX 4 + Placebo N=574 (%) Grade 3Grade 4Grade 3Grade 4 Neutropenia Thrombocytopenia6