Phase I Studies of Anti–Epidermal Growth Factor Receptor Chimeric Antibody C225 Alone and in Combination With Cisplatin

Baselga, José; Pfister, David G.; Cooper, Michael R.; Cohen, Roger B.; Burtness, Barbara; Bos, Monique M.E.M.; D’Andrea, Gabriella; Seidman, Andrew D.; Norton, Larry; Gunnett, K.; Falcey, John; Anderson, Veanne N.; Waksal, Harlan W.; Mendelsohn, John

doi:10.1200/jco.2000.18.4.904

Cited by 661 publications

(330 citation statements)

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“…This could be explained by an intrinsic activity of ZD1839 as radiosensitiser, as has previously been shown for cetuximab, another EGFR-targeting drug (Ezekiel et al, 1999;Huang et al, 1999;Mendelsohn et al, 1999;Baselga et al, 2000;Huang and Harari, 2000;Milas et al, 2000), and also for trastuzumab (Herceptin TM ), a HER-2-targeting drug (Pegram et al, 1998;Pietras et al, 1999;Pegram and Slamon, 2000). Trastuzumab increased the radiosensitivity of HER-2-overexpressing MCF7 breast cancer cells as measured by in vitro colony-forming assays, and the combination of trastuzumab and radiation showed synergistic tumour reduction in nude mice (Pietras et al, 1999).…”

Section: Discussionmentioning

confidence: 77%

“…The impact of ZD1839 on the effects of the combined drugs was sequence dependent. The highest synergistic effects were obtained when ZD1839 was applied before and during exposure to cytotoxic drugs (Table 4) Baselga et al, 2000;Huang and Harari, 2000;Milas et al, 2000). The mechanisms by which receptor blockade by C225 augments the cytotoxic effect of anti-neoplastic agents was attributed by these authors to cell cycle effects and an enhanced capacity for apoptosis by C225.…”

Section: Discussionmentioning

confidence: 99%

“…EGFR signalling has been found to control not only cell growth, but also angiogenesis and DNA repair (Wheeler et al, 1999;Schlessinger, 2000), and has recently been assessed as an innovative target in cancer therapy and particularly in HNC. To date, clinical studies in this area have involved the administration of cetuximab (C225, a chimeric monoclonal antibody), either alone or in combination with chemotherapy or radiotherapy, to patients with advanced head and neck squamous cell carcinoma (Ezekiel et al, 1999;Huang et al, 1999;Mendelsohn et al, 1999;Baselga et al, 2000;Huang and Harari, 2000;Milas et al, 2000). More recently, a wide range of small-molecule tyrosine kinase inhibitors have been developed, and one of the most advanced in this class of compounds is ZD1839 ('Iressa'), which is a quinazoline derivative.…”

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Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer

et al. 2002

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Elevated levels of epidermal growth factor receptor in head and neck cancer have been extensively reported, and are correlated with poor prognosis. The combination of cisplatin and 5-fluorouracil is a standard treatment regimen for head and neck cancer, with radiation representing another therapeutic option. Six head and neck cancer cell lines were used to study the cytotoxic effects of combining ZD1839 ('Iressa'), a new selective epidermal growth factor receptor tyrosine kinase inhibitor, and radiation. Two of the cell lines were also used to study the combination of ZD1839 and cisplatin/5-fluorouracil. Cytotoxic effects were assessed by the MTT test. The results indicated that ZD1839 applied before radiation gave the best effects (P=0.002); an effect that was strongest in those p53-mutated cell lines that express the highest epidermal growth factor receptor levels. The effects of ZD1839 with cisplatin and/or 5-fluorouracil were sequence dependent (P50

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer

et al. 2002

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“…This activates different downstream signaling cascades. 36,49,50 Ligand-stimulated heterodimerization results in considerably higher tyrosine kinase activity than homodimerization. This is particularly true for ERB-B2, which depends on colocalization of another EGFR family member to form heterodimers with high tyrosine kinase activity.…”

Section: Discussionmentioning

confidence: 99%

Absence of c‐KIT and members of the epidermal growth factor receptor family in refractory germ cell cancer

Kollmannsberger

Mayer

Preßler

et al. 2002

Cancer

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BACKGROUNDGerm cell tumors (GCTs) in adolescent and young males are very sensitive to cisplatin‐based chemotherapy. However, 10–20% of the patients cannot be cured by currently available therapeutic options. Once a tumor does not respond to cisplatin, current therapeutic modalities offer only a chance for short palliation. Recently, new treatment options that interfere with various receptor tyrosine kinases, including c‐KIT and members of the epidermal growth factor receptor (EGFR) family, have been used successfully in chemotherapy‐resistant tumors overexpressing c‐KIT, ERB‐B2, or EGFR.METHODSWe studied the presence of c‐KIT and the four members of the EGFR family by immunohistochemistry, as well as by ERB‐B2 gene amplification using fluorescent in situ hybridization, in a series of 22 patients with cisplatin‐resistant GCTs in search of new treatment targets. The results in these refractory tumors were compared with those of 12 patients with chemosensitive GCTs diagnosed in an advanced metastatic stage.RESULTSThe data obtained in both groups did not differ in any of the investigated biologic markers. c‐KIT was detected in the one case of pure seminoma studied and in the seminomatous components of combined tumors. The presence of EGFR was restricted to trophoblastic giant cells and the syncytiotrophoblastic elements of four nonseminomas including one pure choriocarcinoma and to a secondary non–germ cell malignancy, which had developed most likely from a mature teratoma. ERB‐B2 was moderately positive in the secondary non–germ cell malignancy, in one mature teratoma component of a mixed nonseminoma, and together with EGFR in the syncytiotrophoblastic cells of a pure choriocarcinoma. Of all samples investigated, this latter case was the only one showing an amplification of the ERB‐B2 gene in the syncytiotrophoblasts. ERB‐B3 and ERB‐B4 were detected rarely.CONCLUSIONThe majority of refractory GCTs do not qualify for treatment with new biologic agents targeting the receptor tyrosine kinases EGFR, ERB‐B2, or c‐KIT. The lack of differences between the tumors of refractory and the responsive patients indicates that overexpression of any of these receptor tyrosine kinases does not contribute to a resistant phenotype in GCTs. Cancer 2002;95:301–8. © 2002 American Cancer Society.DOI 10.1002/cncr.10671

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“…5 Cetuximab (Erbitux; Merck KgaA, Darmstadt, Germany) is an immunoglobulin G1 monoclonal antibody that specifically targets EGFR, competitively inhibiting ligand binding and ligand-dependent downstream signaling. 6 Phase 1 clinical trials demonstrated the safety of cetuximab combined with CP 7 and cetuximab combined with radiation therapy 8 in SCCs other than anal carcinoma. Also, in phase 3 clinical trials, adding cetuximab to first-line chemotherapy or RT improves outcomes in various types of cancers.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Olivatto

Vieira

Pereira

et al. 2013

Cancer

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BACKGROUND: This study sought to determine the feasibility and recommended phase 2 dose (RP2D) of the combination of cetuximab with chemoradiotherapy based on 5-fluorouracil (5-FU) and cisplatin (CP) in locally advanced anal canal carcinoma. METHODS: Cetuximab was administered on days 1,8,15, 29, 36, 43, and 50 (400 mg/m 2 initial dose, then 250 mg/m 2 /week) concurrent with total dose radiation of 55 to 59 Gy, both starting on day 1. Escalating doses of 5-FU (96-hour infusion) and CP (2-hour infusion), both on days 1 and 29, were administered according to the following design: starting dose level (0) 5-FU/CP 5 800/60 mg/m 2 /day and up to dose level (12) 5-FU/CP 5 1000/80 mg/m 2 /day. RESULTS: Dose-limiting toxicity (DLT) events (uncontrolled diarrhea or febrile neutropenia) occurred in 3 of 14 assessable patients receiving escalated dose of 5-FU/CP, with 1 in dose level (0) and 2 in dose level (12). The RP2D was 5-FU/CP 5 800/80 mg/m 2 /day. Because of unexpected non-DLT treatment-related grade 3 (G3) adverse events (AEs) such as thrombosis/embolism, syncope, and infection occurring in 20% of patients, a safety expansion cohort with an additional 9 patients was investigated with the RP2D. The most frequent G3/G4 AEs evaluated in 23 patients were radiation dermatitis (12 patients), diarrhea (10 patients), thrombosis/embolism (6 patients), and infection (5 patients). The study was closed due to these severe AEs, although no G5 AEs occurred. Twenty of 21 patients (95%) achieved pathological complete response at primary tumor. With a median follow-up of 43.4 months, the 3-year locoregional control rate was 64.2%. CONCLUSIONS: Cetuximab could not be integrated with chemoradiotherapy-cisplatin-based therapy due to the high toxicity rate. However, efficacy is encouraging and further investigation of an epidermal growth factor receptor-targeted agent (other than cetuximab) concurrent with chemoradiation should be pursued. Cancer 2013;119:2973-80.

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Phase I Studies of Anti–Epidermal Growth Factor Receptor Chimeric Antibody C225 Alone and in Combination With Cisplatin

Abstract: C225 has dose-dependent pharmacokinetics, and doses that achieve saturation of systemic clearance are well tolerated. C225 given in combination with cisplatin has biologic activity at pharmacologically relevant doses.

Cited by 661 publications

References 20 publications

Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer

Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer

Absence of c‐KIT and members of the epidermal growth factor receptor family in refractory germ cell cancer

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

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