Phase I dose escalation study with irinotecan, capecitabine, epirubicin, and granulocyte colony-stimulating factor support for patients with solid malignancies.

OBJECTIVES: Preclinical studies using sequences of topoisomerase I and II inhibitors suggested synergism; preliminary clinical studies, resulting in enhanced antitumor responses, confirm this in selected malignancies. This study determined the maximum-tolerated dose (MTD), toxicity, and pharmacokinetics of irinotecan (CPT-11), capecitabine, and epirubicin in patients with metastatic adenocarcinoma of lung, breast, or gastrointestinal tract. Correlation of topoisomerase IIbeta was also done. METHODS: Eligibility criteria included the following: documented adenocarcinoma of the lung, breast, or gastrointestinal tract, <3 prior chemotherapy regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, age > or =18 years, adequate organ function, and signed informed consent. Irinotecan was administered at 250 mg/m2 intravenously day 1 every 21-day cycle, but was reduced to 180 mg/m2 in cohort 2 due to toxicity. Capecitabine was administered at 750 mg/m2 twice daily days 2 to 14 in cohort 1 but only on days 2 to 7 from cohort 2 due to early neutropenia and to allow for prophylactic granulocyte colony-stimulating factor (GCSF) support. Epirubicin was administered at 40 mg/m2 in cohort 1, but reduced to 30 mg/m2 in cohort 2, then reescalated until the MTD was reached. RESULTS: Toxicity was assessed in 21 patients; response was assessed in 17 patients. The most common grade 3 to 4 toxicities included neutropenia (57.1%) and anemia (28.6%). The MTD of epirubicin was 50 mg/m2. In evaluable patients, there were 2 partial responses (11.8%) and 13 stable disease (76.5%); these correlated well with topoisomerase IIbeta. CONCLUSIONS: The recommended doses for phase II studies: irinotecan 180 mg/m2 day 1, epirubicin 50 mg/m2 day 2, and capecitabine 750 mg/m2 twice daily days 2 to 7 of each 21-day cycle. This combination is reasonably active and warrants evaluation in the phase II setting.

Identification and validation of genes involved in the pathogenesis of colorectal cancer using cDNA microarrays and RNA interference.

PURPOSE: The purpose of this study was to profile gene expression changes in colorectal tumors to identify new targets and strategies for the management of this disease. EXPERIMENTAL DESIGN: cDNA microarray analysis was used to detect differences in gene expression between normal tissue and colon tumors and polyps isolated from 20 patients. To identify genes that are important in regulating the growth properties of colorectal cancer, RNA interference (RNAi) was used to disrupt expression of several of the overexpressed genes in a colon tumor cell line, HCT116, which showed similar patterns of gene expression as many of the patient tumors. RESULTS: Expression changes of > or =2-fold in approximately one-third of the patients were consistently observed for 2632 of a total of 9592 genes (574 up-regulated genes and 2058 down-regulated genes). Subsequent analysis of 13 genes by quantitative real-time PCR confirmed the reliability of this analysis. RNAi-mediated disruption of the expression of one of these genes, survivin, a potent inhibitor of apoptosis, severely reduced tumor growth both in vitro and in an in vivo xenograft model. CONCLUSIONS: The combined use of microarray analysis and RNAi provides an excellent system to define the role of specific genes that are up-regulated in cancer lead to the increased in vitro and in vivo growth of colon tumors.