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

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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.

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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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Authors and Affiliations

  1. Department of Oncology, Albert Einstein College of Medicine and Cancer Center, 1825 Eastchester Road, Bronx, NY, 10461, USA

    Sanjay Goel, Kavita Desai, Sirisha Karri, Radharani Gollamudi, Imran Chaudhary, Anca Bulgaru, Andreas Kaubisch, Gary Goldberg, Mark Einstein & Sridhar Mani

  2. Department of Oncology, Montefiore Medical Center, NY, 10461, USA

    Sanjay Goel, Kavita Desai, Sirisha Karri, Radharani Gollamudi, Imran Chaudhary, Anca Bulgaru, Andreas Kaubisch, Fernando Camacho & Sridhar Mani

  3. Division of Gynecologic Oncology, Montefiore Medical Center, Bronx, NY, 10461, USA

    Gary Goldberg & Mark Einstein

  4. Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD, 21231, USA

    Sharyn Baker

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  1. Sanjay Goel
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Correspondence to Sanjay Goel.

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Goel, S., Desai, K., Karri, S. et al. Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers. Invest New Drugs 25, 237–245 (2007). https://doi.org/10.1007/s10637-006-9028-1

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