Phase I/II personalized therapy trial for metastatic colorectal cancer using functional pathway mapping: Stratification to imatinib therapy.

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TPS194 Background: Profiling protein signaling pathways in human cancer is critical because proteins represent the targets for new molecular guided therapeutics. Pathway mapping of liver metastasis from patients with stage IV colorectal cancer (CRC) revealed the unexpected activation of the drug targets of imatinib: PDGFR, c-kit and c-abl. Based on these results, we are conducting a trial whereby patients with advanced CRC with WT kras are stratified for imatinib therapy in conjunction with panitumimab, based on the pathway activation status obtained from metastatic tumor biopsies using Reverse Phase Protein Microarray (RPMA) technology. This trial represents the first personalized therapy trial for stage IV CRC patients stratifying patients to targeted therapy based upon functional protein pathway activation of a metastatic lesion. The ability to perform pathway- based stratification in a clinical setting represents an important milestone for future personalized therapy trials. Further patient enrollment will be required to determine the clinical utility of this particular combination therapy for patients with stage IV CRC. Methods: Stage IV CRC patients with WT kras who progressed on prior therapy are eligible. A liver biopsy is taken for functional pathway activation analysis of PDGFR, c-kit and c-abl by RPMA analysis of the laser capture microdissected (LCM) tumor epithelium. A predefined cut-point, based on the activation of these proteins of an independent cohort of colorectal metastases, is used to stratify patients to: Arm 1: 28-day run-in with imatinib monotherapy (300-600 mg/kg/day) followed by a second biopsy and addition of panitumumab (6 mg/kg) or Arm 2: panitumimab alone. Evaluation is per RECIST. Further, comparisons are made with sequential biopsies of the liver metastasis obtained pre and post treatment with imatinib and downstream pathway activation of AKT, ERK and EGFR pathways is analyzed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Theranostics Health Theranostics Health Theranostics Health