Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Investigational New Drugs
Published in: Investigational New Drugs 3/2007

01-06-2007 | Phase I Studies

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

Authors: Sanjay Goel, Kavita Desai, Sirisha Karri, Radharani Gollamudi, Imran Chaudhary, Anca Bulgaru, Andreas Kaubisch, Gary Goldberg, Mark Einstein, Fernando Camacho, Sharyn Baker, Sridhar Mani

Published in: Investigational New Drugs | Issue 3/2007

Login to get access

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.
Literature
1.
Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan study group. N Engl J Med 343:905–914PubMedCrossRef
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 355:1041–1047PubMedCrossRef
3.
Pentheroudakis G, Twelves C (2002) The rational development of capecitabine from the laboratory to the clinic. Anticancer Res 22:3589–3596PubMed
4.
Schuller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, Utoh M, Mori K, Weidekamm E, Reigner B (2000) Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 45:291–297PubMedCrossRef
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 20:2812–2823PubMedCrossRef
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 19:4097–4106PubMed
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 19:2282–2292PubMed
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 352:2696–2704PubMedCrossRef
9.
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)
11.
Cao S, Durrani FA, Rustum YM (2005) Synergistic antitumor activity of capecitabine in combination with irinotecan. Clin Colorectal Cancer 4:336–343PubMedCrossRef
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 92:820–826PubMedCrossRef
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 16:1123–1132PubMedCrossRef
14.
Czejka M, Schueller J, Hauer K, Ostermann E (2005) Pharmacokinetics and metabolism of irinotecan combined with capecitabine in patients with advanced colorectal cancer. Anticancer Res 25:2985–2990PubMed
15.
Sharma R, Rivory L, Beale P, Ong S, Horvath L, Clarke SJ (2006) A phase II study of fixed-dose capecitabine and assessment of predictors of toxicity in patients with advanced/metastatic colorectal cancer. Br J Cancer 94:964–968PubMedCrossRef
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 24:2038–2043
17.
Perry MC (2006) Reponses to Topoisomerase-I inhibitors in extensive small-cell lung cancer: chance or chromosomes? J Clin Oncol 24:1980–1981PubMedCrossRef
18.
19.
Package insert: Irinotecan. http://​www.​meds.​com/​colon/​camptosar/​fullrx.​html.​ Downloaded Aug 7, 2006
20.
Product Monograph data on file with Hoffman La Roche, Nutley, NJ, 2004
21.
CTC version 2.0. http://​ctep.​cancer.​gov/​forms/​CTCManual_​v4_​10-4-99.​pdf
22.
Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214PubMedCrossRef
23.
de Bruijn P, Willems EW, Loos WJ, Verweij J, Sparreboom A (2004) Indirect determination of the irinotecan metabolite 7-ethyl-10-O-glucuronyl-camptothecin in human samples. Anal Biochem 328:84–86PubMedCrossRef
24.
Hamberg P, Donders RC, ten Bokkel Huinink D (2006) Central nervous system toxicity induced by irinotecan. J Natl Cancer Inst 98:219l
25.
Frickhofen N, Beck FJ, Jung B, Fuhr HG, Andrasch H, Sigmund M (2002) Capecitabine can induce acute coronary syndrome similar to 5-fluorouracil. Ann Oncol 13:797–801PubMedCrossRef
26.
Cardinale D, Colombo A, Colombo N (2006) Acute coronary syndrome induced by oral capecitabine. Can J Cardiol 22:251–253PubMed
27.
Goel S, Jhawer M, Rajdev L, Hopkins U, Fehn K, Baker C, Chun HG, Makower D, Landau L, Hoffman A, Wadler S, Mani S (2002) Phase I clinical trial of irinotecan with oral capecitabine in patients with gastrointestinal and other solid malignancies. Am J Clin Oncol 25:528–534PubMedCrossRef
28.
Bodurka DC, Levenback C, Wolf JK, Gano J, Wharton JT, Kavanagh JJ, Gershenson DM (2003) Phase II trial of irinotecan in patients with metastatic epithelial ovarian cancer or peritoneal cancer. J Clin Oncol 21:291–297PubMedCrossRef
29.
Rischin D, Phillips KA, Friedlander M, Harnett P, Quinn M, Richardson G, Martin A (2004) A phase II trial of capecitabine in heavily pre-treated platinum-resistant ovarian cancer. Gynecol Oncol 93:417–421PubMedCrossRef
30.
Horstmann E, McCabe MS, Grochow L, Yamamoto S, Rubinstein L, Budd T, Shoemaker D, Emanuel EJ, Grady C (2005) Risks and benefits of phase 1 oncology trials, 1991 through 2002. N Engl J Med 352:895–904PubMedCrossRef
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 292:2130–2140
32.
Rothenberg ML, Meropol NJ, Poplin EA, Van Cutsem E, Wadler S (2001) Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 19:3801–3807PubMed
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 14:1682–1687PubMedCrossRef
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)
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)
36.
Tabata T, Katoh M, Tokudome S, Nakajima M, Yokoi T (2004) Identification of the cytosolic carboxylesterase catalyzing the 5′-deoxy-5-fluorocytidine formation from capecitabine in human liver. Drug Metab Dispos 32:1103–1110PubMedCrossRef
37.
Sanghani SP, Quinney SK, Fredenburg TB, Sun Z, Davis WI, Murry DJ, Cummings OW, Seitz DE, Bosron WF (2003) Carboxylesterases expressed in human colon tumor tissue and their role in CPT-11 hydrolysis. Clin Cancer Res 9:4983–4991PubMed
Metadata
Title
Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers
Authors
Sanjay Goel
Kavita Desai
Sirisha Karri
Radharani Gollamudi
Imran Chaudhary
Anca Bulgaru
Andreas Kaubisch
Gary Goldberg
Mark Einstein
Fernando Camacho
Sharyn Baker
Sridhar Mani
Publication date
01-06-2007
Published in
Investigational New Drugs / Issue 3/2007
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-006-9028-1

Other articles of this Issue 3/2007

Investigational New Drugs 3/2007 Go to the issue

Phase I Studies

Phase I dose-finding and pharmacokinetic trial of orally administered indibulin (D-24851) to patients with solid tumors

Phase I Studies

Phase I trial of three-weekly Docetaxel, Carboplatin and oral lenalidomide (Revlimid®) in patients with advanced solid tumors

Phase II Studies

Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma

Short Report

Evidence for the involvement of p38 MAP kinase in the action of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)

Erratum

Investigational New Drugs, Volume 25, Number 1

Phase I Studies

A phase I study of oral LY293111 given daily in combination with irinotecan in patients with solid tumours
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits