Pilot trial of molecular profiling and targeted therapies in advanced thoracic malignancies: Non-small cell lung cancer, small cell lung cancer and thymic malignancies (CUSTOM).

Abstract

TPS7609 Background: For decades, clinical trial design strategies have relied upon the broad classification of tumors into tumor site and histopathology. Several lines of evidence have shown that a molecular approach to patient selection may be better in its capacity to improve patient outcomes. CUSTOM is an innovative clinical trial that allows for the parallel evaluation of multiple targeted therapies in molecularly selected patients with multiple cancer histological subtypes and the prospective evaluation of multiple molecular biomarkers. Methods: All patients with advanced lung cancer and thymic malignancies and a good performance status are eligible independently of previous lines of treatment. The trial begins with tumor biopsy and molecular profiling using a multi-platform approach to identify oncogenic alterations in more than 34 genes for treatment allocation (12 genes) and exploratory purposes. Depending upon the specific biomarker identified, patients are then triaged into 5 experimental arms. Erlotinib for sensitizing EGFR mutations; AZD6244 for KRAS, NRAS, HRAS and BRAF mutations; MK2206 for PIK3CA, AKT and PTEN mutations and PIK3CA amplification; Lapatinib for ERBB2 mutations or amplification; Sunitnib for KIT mutations and PDGFRA mutations and amplification. Patients not eligible for the experimental treatment arms are enrolled into a standard treatment arm. Upon disease progression patients are eligible for repeat biopsy and molecular profiling in order to identify molecular changes and mechanisms of resistance. All patients are followed until death. The primary endpoint is response rate and secondary endpoints include progression-free survival, duration of response and overall survival. With three disease types and five experimental drugs, there are 15 possible treatment arms which will be under active consideration. For each of these, the study will be conducted as an optimal two-stage phase II trial in order to rule out an unacceptably low 10% clinical response rate in favor of a modestly high response rate of 40%. As of January 11, 2012, two hundred and sixteen patients have been enrolled.