Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers
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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.
KeywordsPharmacokinetics Phase I Irinotecan Capecitabine Solid tumors
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).
- 2.Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355:1041–1047PubMedCrossRefGoogle Scholar
- 5.O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R (2002) Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 20:2812–2823PubMedCrossRefGoogle Scholar
- 6.Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P, Xeloda Colorectal Cancer Study Group (2001) Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 19:4097–4106PubMedGoogle Scholar
- 7.Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R (2001) Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19:2282–2292PubMedGoogle Scholar
- 8.Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kroning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schuller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W (2005) Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352:2696–2704PubMedCrossRefGoogle Scholar
- 10.Nishimura G, Fujita H, Ninomiya I, Fushida S, Fujimura T, Ohta T (2006) Evidence of increased effect of thymidine phosphorylase by irinotecan: a proof for the intensified efficacy by combination with irinotecan and capecitabine. In: Proceedings of the 2006 Gastrointestinal Cancers Symposium (abstract # 298)Google Scholar
- 12.Delord JP, Pierga JY, Dieras V, Bertheault-Cvitkovic F, Turpin FL, Lokiec F, Lochon I, Chatelut E, Canal P, Guimbaud R, Mery-Mignard D, Cornen X, Mouri Z, Bugat R (2005) A phase I clinical and pharmacokinetic study of capecitabine (Xeloda) and irinotecan combination therapy (XELIRI) in patients with metastatic gastrointestinal tumours. Br J Cancer 92:820–826PubMedCrossRefGoogle Scholar
- 13.Rea DW, Nortier JW, Ten Bokkel Huinink WW, Falk S, Richel DJ, Maughan T, Groenewegen G, Smit JM, Steven N, Bakker JM, Semiond D, Kerr DJ, Punt CJ (2005) A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer. Ann Oncol 16:1123–1132PubMedCrossRefGoogle Scholar
- 16.Hanna N, Bunn PA Jr, Langer C, Einhorn L, Guthrie T Jr, Beck T, Ansari R, Ellis P, Byrne M, Morrison M, Hariharan S, Wang B, Sandler A (2006) Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24:2038–2043Google Scholar
- 19.Package insert: Irinotecan. http://www.meds.com/colon/camptosar/fullrx.html. Downloaded Aug 7, 2006Google Scholar
- 20.Product Monograph data on file with Hoffman La Roche, Nutley, NJ, 2004Google Scholar
- 21.CTC version 2.0. http://ctep.cancer.gov/forms/CTCManual_v4_10-4-99.pdfGoogle Scholar
- 24.Hamberg P, Donders RC, ten Bokkel Huinink D (2006) Central nervous system toxicity induced by irinotecan. J Natl Cancer Inst 98:219lGoogle Scholar
- 31.Roberts TG Jr, Goulart BH, Squitieri L, Stallings SC, Halpern EF, Chabner BA, Gazelle GS, Finkelstein SN, Clark JW (2004) Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA 292:2130–2140Google Scholar
- 33.Goel S, Bulgaru A, Hochster H, Wadler S, Zamboni W, Egorin M, Ivy P, Leibes L, Muggia F, Lockwood G, Harvey E, Renshaw G, Mani S (2003) Phase I clinical study of infusional 5-fluorouracil with oxaliplatin and gemcitabine (FOG regimen) in patients with solid tumors. Ann Oncol 14:1682–1687PubMedCrossRefGoogle Scholar
- 34.Gold PJ, Godfrey T, Dhami M, Andria M, Fischer D, Chen Y-M, Samid D, Meropol N (2003) Capecitabine and Irinotecan as 1st line therapy for patients with metastatic colorectal cancer. Phase II study preliminary results. In: Proceedings of the 39th annual meeting of the American society of clinical oncology 22:2003 (abstract 1158)Google Scholar
- 35.Grothey K, Jordan O, Kellner C, Constantin G, Dittrich H, Kroening L, Mantovani C, Schlichting H, Forstbauer H-J, (2003) Schmoll Randomized Phase II trial of capecitabine plus irinotecan (capiri) vs capecitabine plus oxaliplatin (capox) as first line therapy of advanced colorectal cancer (ACRC). In: Proceedings of the 39th annual meeting of the American society of clinical oncology 22:2003 (abstract 1022)Google Scholar