Phase I Trial of Irinotecan, Infusional 5-Fluorouracil, and Leucovorin (FOLFIRI) with Erlotinib (OSI-774)

Messersmith, Wells A.; Laheru, Daniel A.; Senzer, Neil; Donehower, Ross C.; Grouleff, Paula; Rogers, Tamara; Kelley, Sean K.; Ramies, David A.; Lum, Bert L.; Hidalgo, Manuel

doi:10.1158/1078-0432.ccr-04-0746

Cited by 78 publications

(34 citation statements)

References 21 publications

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“…These negative results may be due to a lack of efficacy of small molecules inhibitors of EGFR in combination with Figure 1 Kaplan -Meier plots for progression free survival. Gefitinib and FOLFOX in colorectal cancer S Cascinu et al chemotherapy as in colorectal cancer or to the lack of patient selection Herbst et al, 2004;Messersmith et al, 2004). A recent study by Zampino and co-workers also evaluated the combination FOLFOX-6 and gefitinib in a phase II trial including 56 patients.…”

Section: Discussionmentioning

confidence: 99%

A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

Cascinu

Berardi

Salvagni³

et al. 2007

Br J Cancer

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Interesting activity has been reported by combining chemotherapy with cetuximab. An alternative approach for blocking EGFR function has been the development of small-molecule inhibitors of tyrosine kinase domain such as gefitinib. We designed a multicentre phase II study in advanced colorectal cancer combining gefitinib þ FOLFOX in order to determine the activity and to relate EGFR expression and gene amplification and NF-kB activation to therapeutic results. Patients received FOLFOX-4 regimen plus gefitinib as first-line treatment. Tumour samples were analysed for EGFR protein expression by immunohistochemical analysis and for EGFR gene amplification by fluorescence in situ hybridisation (FISH), chromogenic in situ hybridisation (CISH) and NF-kB activation. Forty-three patients were enrolled into this study; 15 patients experienced a partial response (response rate ¼ 34.9%), whereas other 12 (27.9%) had a stable disease. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 13.9 months. We did not find any relationship with EGFR overexpression, gene amplification, while NF-kB activation was associated with a resistance to therapy. Gefitinib does not seem to increase the activity of FOLFOX in advanced colorectal cancer even in patients overexpressing EGFR or with EGFR amplification. Furthermore, while NF-kB activation seems to predict resistance to chemotherapy as demonstrated 'in vitro' models, gefitinib does not overcome this mechanism of resistance, as reported for cetuximab.

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Section: Discussionmentioning

confidence: 99%

A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

Cascinu

Berardi

Salvagni³

et al. 2007

Br J Cancer

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“…In subsequent studies, trastuzumab, bevacizumab, and IMC-A12 were each used at 1 Ag/mL. Erlotinib was used at 2 Amol/L, in keeping with previously reported clinical steady state plasma concentrations in the range of 2 to 4 Amol/L (44,45). These studies suggest that high HER2 -expressing breast cancer cell lines exhibit greater growth inhibition in response to trastuzumab, erlotinib, or bevacizumab, than the low HER2 -expressing cell lines over a range of concentrations.…”

Section: Her2 Expression In Human Breast Cancer Cell Linesmentioning

confidence: 99%

Response to trastuzumab, erlotinib, and bevacizumab, alone and in combination, is correlated with the level of human epidermal growth factor receptor-2 expression in human breast cancer cell lines

Emlet

Brown

Kociban

et al. 2007

Molecular Cancer Therapeutics

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Human epidermal growth factor receptor-2 (HER2) and epidermal growth factor receptor (EGFR) heterodimerize to activate mitogenic signaling pathways. We have shown previously, using MCF7 subcloned cell lines with graded levels of HER2 expression, that responsiveness to trastuzumab and AG1478 (an anti-EGFR agent), varied directly with levels of HER2 expression. HER2 and EGFR upregulate vascular endothelial growth factor (VEGF), a growth factor that promotes angiogenesis and participates in autocrine growth-stimulatory pathways that might be active in vitro. Here, we show that trastuzumab, erlotinib, and bevacizumab, individually and in combination, inhibit cell proliferation in a panel of unrelated human breast cancer cell lines, in proportion to their levels of HER2 expression. The combination of all three drugs provided a greater suppression of growth than any single drug or twodrug combination in the high HER2 -expressing cell lines (P < 0.001). Combination index analysis suggested that the effects of these drugs in combination were additive. The pretreatment net level of VEGF production in each cell line was correlated with the level of HER2 expression (r = 0.883, P = 0.016). Trastuzumab and erlotinib each reduced total net VEGF production in all cell lines. Multiparameter flow cytometry studies indicated that erlotinib alone and the triple drug combination produced a prolonged but reversible blockade of cells in G 1 , but did not increase apoptosis substantially. These studies suggest that the effects of two and three-drug combinations of trastuzumab, erlotinib, and bevacizumab might offer potential therapeutic advantages in HER2-overexpressing breast cancers, although these effects are of low magnitude, and are likely to be transient. [Mol Cancer Ther 2007;6(10):2664 -74]

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“…We propose that the interaction of irinotecan and gefitinib in our trial is likely to have been pharmacokinetic, resulting in greater than anticipated exposure to irinotecan and its active metabolite. Interestingly, Messersmith et al (2004) have recently reported excessive toxicity requiring early closure of the study in a phase I trial of a combination of erlotinib with reduced doses of irinotecan and infusional 5-FU. A pharmacokinetic interaction between irinotecan, 5-FU, and erlotinib could not explain the toxicity.…”

Section: Discussionmentioning

confidence: 99%

A phase II trial of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer

et al. 2005

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Inhibition of epidermal growth factor receptor (EGFR) signalling contributes to the therapy of colorectal cancer. Gefitinib, an oral EGFR tyrosine kinase inhibitor, shows supra-additive growth inhibition with irinotecan and fluoropyrimidines in xenograft models. We designed a study to determine the tolerability and efficacy of gefitinib in combination with irinotecan, infusional 5-fluorouracil (5-FU) and leucovorin (LV), on a 2-week schedule. Among 13 patients with advanced colorectal cancer, 10 required dose reductions of irinotecan and 5-FU because of dehydration, diarrhoea, and neutropenia, seven of whom required hospitalisation, three with neutropenic fever. One patient achieved partial response and seven had disease stabilisation. The combination of this standard chemotherapy regimen with gefitinib is associated with excessive toxicity, suggesting an interaction at a pharmacokinetic or pharmacodynamic level.

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Phase I Trial of Irinotecan, Infusional 5-Fluorouracil, and Leucovorin (FOLFIRI) with Erlotinib (OSI-774)

Cited by 78 publications

References 21 publications

A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

Response to trastuzumab, erlotinib, and bevacizumab, alone and in combination, is correlated with the level of human epidermal growth factor receptor-2 expression in human breast cancer cell lines

A phase II trial of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer

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