Phase I dose escalation study with irinotecan, capecitabine, epirubicin, and granulocyte colony-stimulating factor...

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.

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.

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.

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.