Investigational New Drugs

, Volume 25, Issue 3, pp 237–245 | Cite as

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

  • Sanjay Goel
  • Kavita Desai
  • Sirisha Karri
  • Radharani Gollamudi
  • Imran Chaudhary
  • Anca Bulgaru
  • Andreas Kaubisch
  • Gary Goldberg
  • Mark Einstein
  • Fernando Camacho
  • Sharyn Baker
  • Sridhar Mani
Phase I Studies

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

Pharmacokinetics Phase I Irinotecan Capecitabine Solid tumors 

Notes

Acknowledgments

This study is supported by a grant from Hoffmann-La Roche Inc and Pfizer Inc. SM is supported by a clinical investigator award from the Damon Runyon Cancer Research Foundation (CI: 15-02). ME is supported by a Clinical Mentored Research Scholar Program Award (K12 RR017672).

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Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Sanjay Goel
    • 1
    • 2
  • Kavita Desai
    • 1
    • 2
  • Sirisha Karri
    • 1
    • 2
  • Radharani Gollamudi
    • 1
    • 2
  • Imran Chaudhary
    • 1
    • 2
  • Anca Bulgaru
    • 1
    • 2
  • Andreas Kaubisch
    • 1
    • 2
  • Gary Goldberg
    • 1
    • 3
  • Mark Einstein
    • 1
    • 3
  • Fernando Camacho
    • 2
  • Sharyn Baker
    • 4
  • Sridhar Mani
    • 1
    • 2
  1. 1.Department of OncologyAlbert Einstein College of Medicine and Cancer CenterBronxUSA
  2. 2.Department of OncologyMontefiore Medical CenterNYUSA
  3. 3.Division of Gynecologic OncologyMontefiore Medical CenterBronxUSA
  4. 4.Department of OncologyJohns Hopkins University, School of MedicineBaltimoreUSA

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