Investigational New Drugs

, Volume 25, Issue 3, pp 237–245

Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers

Authors

    • Department of OncologyAlbert Einstein College of Medicine and Cancer Center
    • Department of OncologyMontefiore Medical Center
  • Kavita Desai
    • Department of OncologyAlbert Einstein College of Medicine and Cancer Center
    • Department of OncologyMontefiore Medical Center
  • Sirisha Karri
    • Department of OncologyAlbert Einstein College of Medicine and Cancer Center
    • Department of OncologyMontefiore Medical Center
  • Radharani Gollamudi
    • Department of OncologyAlbert Einstein College of Medicine and Cancer Center
    • Department of OncologyMontefiore Medical Center
  • Imran Chaudhary
    • Department of OncologyAlbert Einstein College of Medicine and Cancer Center
    • Department of OncologyMontefiore Medical Center
  • Anca Bulgaru
    • Department of OncologyAlbert Einstein College of Medicine and Cancer Center
    • Department of OncologyMontefiore Medical Center
  • Andreas Kaubisch
    • Department of OncologyAlbert Einstein College of Medicine and Cancer Center
    • Department of OncologyMontefiore Medical Center
  • Gary Goldberg
    • Department of OncologyAlbert Einstein College of Medicine and Cancer Center
    • Division of Gynecologic OncologyMontefiore Medical Center
  • Mark Einstein
    • Department of OncologyAlbert Einstein College of Medicine and Cancer Center
    • Division of Gynecologic OncologyMontefiore Medical Center
  • Fernando Camacho
    • Department of OncologyMontefiore Medical Center
  • Sharyn Baker
    • Department of OncologyJohns Hopkins University, School of Medicine
  • Sridhar Mani
    • Department of OncologyAlbert Einstein College of Medicine and Cancer Center
    • Department of OncologyMontefiore Medical Center
Phase I Studies

DOI: 10.1007/s10637-006-9028-1

Cite this article as:
Goel, S., Desai, K., Karri, S. et al. Invest New Drugs (2007) 25: 237. doi:10.1007/s10637-006-9028-1

Summary

Background: Capecitabine and irinotecan have demonstrated in vitro synergistic anti-cancer activity, and both are substrates for carboxyl esterases (CES). We conducted a study to identify a safe dose and potential drug-drug interactions of this combination.

Methods: This was an open-label phase I dose escalation trial. Irinotecan was given as a 30 min infusion on days 1 and 8, and capecitabine on days 1–14 of a 21-day cycle. Plasma for pharmacokinetic analyses was drawn on days 1 and 8.

Results: Forty-seven patients with advanced solid tumors received 202 cycles of chemotherapy in 6 dose cohorts. At the highest dose tested, 1 of 3 patients developed fatal neutropenia and gram-negative sepsis. At dose level 5 (100/2000), 2 of 28 patients developed cycle 1 DLT—grade 3 diarrhea/vomiting, and grade 3 diarrhea. Responses were observed in 9 of 35 (5 of 9 ovarian cancer) evaluable patients. The AUC(0-last) of irinotecan, SN-38G, and APC were similar on days 1 and 8. However, SN-38 Tmax was longer on Day 8 (0.88 h vs. 1.23 h, p = 0.012). While SN-38 AUC(0-last) was lower on day 8 by 35%, this was not statistically significant (p = 0.123).

Conclusions: Capecitabine results in a significantly delayed conversion of irinotecan to SN-38, suggesting drug-drug interaction at the level of CES. This suggests caution should be used when irinotecan is combined with substrates of CES, and warrants further study. The combination of irinotecan and capecitabine is safe and well tolerated at 100/2000, and warrants further evaluation in ovarian and breast cancer.

Keywords

PharmacokineticsPhase IIrinotecanCapecitabineSolid tumors

Copyright information

© Springer Science+Business Media, LLC 2006