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01-06-2009 | Original Article

Dose finding study of erlotinib combined to capecitabine and irinotecan in pretreated advanced colorectal cancer patients

Authors: Emilio Bajetta, Maria Di Bartolomeo, Roberto Buzzoni, Erminia Ferrario, Katia F. Dotti, Luigi Mariani, Roberto Bajetta, Arpine Gevorgyan, Paola Venturino, Margherita Galassi

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2009

Abstract

Purpose

This study evaluated the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine in pre-treated metastatic colorectal cancer patients.

Methods

Five dose level combinations with irinotecan (from 180 to 240 mg/m², day 1, q21), capecitabine (1,500–2,000 mg/m² per day, days 2–15, q21) and erlotinib (50–150 mg per day, continuously) were planned. Patients were enrolled in cohorts of three, and evaluated for first cycle acute toxicity.

Results

Twenty-one patients were treated. In the first cohort, no DLT was reported, in the second: one DLT (G4 neutropenic fever associated with G3 cutaneous rash and mucositis); in the third dose level: two DLT (G3 diarrhea and G4 neutropenic fever). To confirm these results, other six patients were additionally included and no DLT was observed.

Conclusions

The results documented that erlotinib at the dose of 100 mg per day, irinotecan 180 mg/m² and capecitabine 1,500 mg/m² per day for 14 days has an acceptable safety profile and appears suitable for further phase II studies.

Jemeal A, Murray T, Ward E et al (2006) Cancer Statistics, 2006. CA Cancer J Clin 56:106–130CrossRef

Colucci G, Gebbia V, Poletti G et al (2005) Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 23:4866–4875PubMedCrossRef

Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342PubMedCrossRef

Cunningam D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 22:337–345CrossRef

Van Cutsem E, Twelves C, Cassidy J et al (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 1:4097–4106

Carmichael J, Popiela T, Radstone D et al (2002) Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3617–3627PubMedCrossRef

Cassidy J, Tabernero J, Twelves C et al (2004) XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22:2084–2091PubMedCrossRef

Bajetta E, Di Bartolomeo M, Mariani L et al (2004) Randomized multicenter Phase II trial of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma. Cancer 100:279–287PubMedCrossRef

Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137PubMedCrossRef

10.

Hidalgo M, Bloedow D (2003) Pharmacokinetics and pharmacodynamics: maximizing the clinical potential of Erlotinib (Tarceva). Semin Oncol 3:25–33

11.

Pollack V, Savage D, Baker D (1999) Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358, 774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 291:739–748PubMed

12.

Ouchi KF, Yanagisawa M, Sekigucki F et al (2006) Antitumor activity of erlotinib in combination with capecitabine in human tumor xenograft models. Cancer Chemother Pharmacol 57:693–702PubMedCrossRef

13.

Chen J, Smith M, Kolinsky K et al (2007) Antitumor activity of HER1/EGFR tyrosine kinase inhibitor erlotinib, alone and in combination with CPT-11 (irinotecan) in human colorectal cancer xenograft models. Cancer Chemother Pharmacol 59:651–659PubMedCrossRef

14.

Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evacuate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216PubMedCrossRef

15.

Patt YZ, Lee FC, Liebman JE et al (2007) Capecitabine plus 3-weekly irinotecan (XELIRI regimen) as first-line chemotherapy for metatstsic colorectal cancer. Phase II trial results. Am J Clin Oncol Aug 30(4):350–357CrossRef

16.

Hidalgo M, Siu L, Nemunaitis J (2001) Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267–3279PubMed

17.

Malik S, Siu L, Rowinsky E (2003) Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients. Clin Cancer Res 9:2478–2486PubMed

18.

Messersmith WA, Laheru DA, Senzer NN et al (2004) Phase I trial of irinotecan, infusional 5-fluorouracil, and leucovorin (FOLFIRI) with erlotinib (OSI-774): early termination due to increased toxicities. Clin Cancer Res 10:6522–6527PubMedCrossRef

19.

Townsley CA, Major P, Siu L (2006) Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer 94:1136–1143PubMedCrossRef

20.

Hanauske A, Cassidy J, Sastre J et al (2007) Phase 1b dose escalation study of erlotinib in combination with infusional 5-Fluorouracil, leucovorin, and oxaliplatin in patients with advanced solid tumors. Clin Cancer Res 13:523–531PubMedCrossRef

21.

Meyerhardt JA, Zhu A, Enzinger P et al (2006) Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol 24:1892–1897PubMedCrossRef

22.

Van Cutsem E, Verslype C, Beale P et al (2008) A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients. Ann Oncol 19:332–339PubMedCrossRef

Title: Dose finding study of erlotinib combined to capecitabine and irinotecan in pretreated advanced colorectal cancer patients
Authors: Emilio Bajetta
Maria Di Bartolomeo
Roberto Buzzoni
Erminia Ferrario
Katia F. Dotti
Luigi Mariani
Roberto Bajetta
Arpine Gevorgyan
Paola Venturino
Margherita Galassi
Publication date: 01-06-2009
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2009
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-008-0852-1

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Purpose

Methods

Results

Conclusions

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