Phase I dose escalation study with irinotecan, capecitabine, epirubicin, and granulocyte colony-stimulating factor support for patients with solid malignancies.
OBJECTIVE
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.
Becerra
Carlos R
CR
Translational Oncology Program-Phase I unit, Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA. carlos.becerra@usoncology.com
Verma
Udit N
UN
Tran
Hia T
HT
Tavana
Denise
D
Williams
Noelle S
NS
Frenkel
Eugene P
EP
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000505:Alopecia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069287:Capecitabine; D004264:DNA Topoisomerases, Type I / Q000097:blood; D004250:DNA Topoisomerases, Type II / Q000097:blood; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015251:Epirubicin / Q000008:administration & dosage*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D059005:Topoisomerase II Inhibitors; D016896:Treatment Outcome
D059005:Topoisomerase II Inhibitors; D003841:Deoxycytidine; D016179:Granulocyte Colony-Stimulating Factor; D015251:Epirubicin; D000069287:Capecitabine; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D005472:Fluorouracil; D002166:Camptothecin