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UGT1A1 genotype-guided phase I study of irinotecan, oxaliplatin, and capecitabine

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Summary

Purpose We performed a UGT1A1 genotype-guided study to determine the maximum tolerated dose (MTD) and evaluate the toxicities and pharmacokinetics of the combination of capecitabine (CAP), oxaliplatin (OX), and irinotecan (IRIN). Experimental design Patients were screened for UGT1A1 *28 genotype prior to treatment. The starting dose (mg/m2) was IRIN (150), OX (85) and CAP (400), days 2–15. Doses were escalated or de-escalated within each genotype group (*28/*28, *1/*28 and *1/*1). IRIN pharmacokinetics was performed at the MTD. Results 50 patients were evaluable for toxicity [11 (*28/*28); 18 (*1/*28); 21 (*1/*1)]. UGT1A1 *28/*28 patients experienced hematologic dose limiting toxicity (DLT), requiring dose-de-escalation. The UGT1A1 *28/*28 recommended phase 2 dose (RP2D) was IRIN (75), OX (85), and CAP (400). In contrast, both UGT1A1 *1/*28 and *1/*1 tolerated higher doses of IRIN and non-hematologic toxicity was dose limiting for UGT1A1 *1/*1. The RP2D was IRIN (150), OX (85), and CAP (400) for UGT1A1*1/*28 and IRIN (150), OX (100), and CAP (1600) for UGT1A1 *1/*1. UGT1A1 *1/*28 and *1/*1 patients treated with IRIN (150) had similar AUCs for the active irinotecan metabolite, SN38 (366 +/− 278 and 350 +/− 159 ng/ml*hr, respectively). UGT1A1 *28/*28 patients (n = 3) treated with a lower IRIN dose (100) had non-significantly higher mean SN38 exposures (604 +/− 289 ng/ml*hr, p = 0.14). Antitumor activity was observed in all genotype groups. Conclusions UGT1A1 genotype affects the dose and pharmacokinetics of the CAPIRINOX regimen and UGT1A1 genotype-guided dosing of CAPIRINOX is ongoing in a phase II study of small bowel cancer (NCT00433550).

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Acknowledgments

We thank Sacha Nelson and Deb Kaul (Protocol Development Coordinators), Kim Jensen and Janet Lensing (Certified Research Associates), Jill Piens (Research nurse) and the patients who participated in this trial.

Conflicts of interest

The authors have no conflicts of interest to report.

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Authors and Affiliations

  1. Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Matthew P. Goetz, Heidi A. McKean, Joel M. Reid, Mary A. Kuffel, Stephanie L. Safgren, Renee M. McGovern, Axel A. Grothey, Robert McWilliams, Charles Erlichman & Matthew M. Ames

  2. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

    Matthew P. Goetz, Joel M. Reid & Matthew M. Ames

  3. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    Sumithra J. Mandrekar & Angelina D. Tan

  4. Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James), Columbus, OH, USA

    Richard M. Goldberg

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  1. Matthew P. Goetz
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  2. Heidi A. McKean
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  3. Joel M. Reid
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  4. Sumithra J. Mandrekar
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  6. Mary A. Kuffel
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  7. Stephanie L. Safgren
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  10. Axel A. Grothey
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  11. Robert McWilliams
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  13. Matthew M. Ames
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Corresponding author

Correspondence to Matthew P. Goetz.

Additional information

Matthew P. Goetz and Heidi A. McKean contributed equally to this work.

Supported in part by U01 CA69912, RR024150 (from the Mayo Clinic General Clinical Research Center), CA15083 (Mayo Clinic Comprehensive Cancer Center) CA90628-03 (K-12) (MPG) and Commonwealth Foundation for Cancer Research (MPG and MMA).

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Goetz, M.P., McKean, H.A., Reid, J.M. et al. UGT1A1 genotype-guided phase I study of irinotecan, oxaliplatin, and capecitabine. Invest New Drugs 31, 1559–1567 (2013). https://doi.org/10.1007/s10637-013-0034-9

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