Top

Cancer Chemotherapy and Pharmacology

Published in:

01-01-2012 | Clinical Trial Report

Safety and pharmacokinetics of high-dose gefitinib in patients with solid tumors: results of a phase I study

Authors: Mitchell E. Gross, Lawrence Leichman, Elizabeth S. Lowe, Alan Swaisland, David B. Agus

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2012

Abstract

Purpose

Previous studies established the safety of continuous gefitinib 250 or 500 mg daily. It was postulated that a higher dose may have increased efficacy by inhibiting signaling in both the mitogen-activated protein kinase and AKT pathways. This study investigated the tolerability, pharmacokinetics, and antitumor activity of high-dose gefitinib in patients with refractory solid malignancies.

Methods

Sequential cohorts received oral gefitinib once or twice-weekly, with dose escalation from 1,500 to 3,500 mg.

Results

Twenty-three patients received gefitinib at seven dose levels (1,500, 2,000, 2,500, 3,000, and 3,500 mg once-weekly; 1,500 and 2,000 mg twice-weekly). Gefitinib was well tolerated, with no dose-limiting toxicities. The maximum tolerated dose was not reached. The most common gefitinib-related adverse events were nausea and diarrhea, vomiting, and rash. Pharmacokinetic data demonstrated no consistent increase in exposure to gefitinib with increasing dose across cohorts. Consequently, the study was stopped early and gefitinib 2,000 mg twice-weekly was the highest dose administered. One of eight patients with non-small-cell lung cancer achieved a partial response.

Conclusions

Exposure to gefitinib did not increase consistently with increasing dose beyond gefitinib 1,500 mg once-weekly or twice-weekly. These data do not support further evaluation of gefitinib at high-dose schedules.

Available only for authorised users

Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard J-Y, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong R-P, Baselga J (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237–2246PubMedCrossRef

Kim ES, Hirsch V, Mok T, Socinski MA, Gervais R, Wu Y-L, Li L-Y, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao M-L, Østerlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard J-Y (2008) Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372:1809–1818PubMedCrossRef

Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer. A randomized trial. JAMA 290:2149–2158PubMedCrossRef

Thatcher N, Chang A, Parikh P, Rodrigues PJ, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K (2005) Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa survival evaluation in lung cancer). Lancet 366:1527–1537PubMedCrossRef

Bell DW, Lynch TJ, Haserlat SM, Harris PL, Okimoto RA, Brannigan BW, Sgroi DC, Muir B, Riemenschneider MJ, Iacona RB, Krebs AD, Johnson DH, Giaccone G, Herbst RS, Manegold C, Fukuoka M, Kris MG, Baselaga J, Ochs JS, Haber DA (2005) Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 23:8081–8092PubMedCrossRef

Douillard J-Y, Shepherd FA, Hirsh V, Mok T, Socinski MA, Gervais R, Liao ML, Bischoff H, Reck M, Sellers MV, Watkins CL, Speake G, Armour AA, Kim ES (2010) Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 28:744–752PubMedCrossRef

Hirsch FR, Varella-Garcia M, Bunn PA Jr, Franklin WA, Dziadziuszko R, Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Watkins C, Flannery A, Ellison G, Donald E, Knight L, Parums D, Botwood N, Holloway B (2006) Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24:5034–5042PubMedCrossRef

Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139PubMedCrossRef

Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500PubMedCrossRef

10.

Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101:13306–13311PubMedCrossRef

11.

Mok TS, Wu Y-L, Thongprasert S, Yang C-H, Chu D-T, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang J–J, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957PubMedCrossRef

12.

Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T, The North-East Japan Study Group (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388PubMedCrossRef

13.

Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M, The West Japan Oncology Group (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11:121–128PubMedCrossRef

14.

Anido J, Matar P, Albanell J, Guzmán M, Rojo F, Arribas J, Averbuch S, Baselga J (2003) ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. Clin Cancer Res 9:1274–1283PubMed

15.

Janmaat ML, Kruyt FAE, Rodriguez JA, Giaccone G (2003) Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin Cancer Res 9:2316–2326PubMed

16.

Albanell J, Rojo F, Averbuch S, Feyereislova A, Mascaro JM, Herbst R, LoRusso P, Rischin D, Sauleda S, Gee J, Nicholson RI, Baselga J (2002) Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 20:110–124PubMedCrossRef

17.

Moasser MM, Basso A, Averbuch SD, Rosen N (2001) The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 61:7184–7188PubMed

18.

Ono M, Kuwano M (2006) Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res 12:7242–7251PubMedCrossRef

19.

Jones HK, Stafford LE, Swaisland HC, Payne R (2002) A sensitive assay for ZD1839 (‘Iressa’) in human plasma by liquid–liquid extraction and high performance liquid chromatography with mass spectrometric detection: validation and use in phase I clinical trials. J Pharm Biomed Anal 29:221–228PubMedCrossRef

20.

Ranson M, Hammond LA, Ferry D, Kris M, Tullo A, Murray PI, Miller V, Averbuch S, Ochs J, Morris C, Feyereislova A, Swaisland H, Rowinsky EK (2002) ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 20:2240–2250PubMedCrossRef

21.

Rukazenkov Y, Speake G, Marshall G, Anderton J, Davies BR, Wilkinson RW, Hickinson DM, Swaisland A (2009) Epidermal growth factor receptor tyrosine kinase inhibitors: similar but different? Anticancer Drugs 20:856–866PubMedCrossRef

22.

Fury MG, Solit DB, Su YB, Rosen N, Sirotnak FM, Smith RP, Azzoli CG, Gomez JE, Miller VA, Kris MG, Pizzo BA, Henry R, Pfister DG, Rizvi NA (2007) A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 59:467–475PubMedCrossRef

Title: Safety and pharmacokinetics of high-dose gefitinib in patients with solid tumors: results of a phase I study
Authors: Mitchell E. Gross
Lawrence Leichman
Elizabeth S. Lowe
Alan Swaisland
David B. Agus
Publication date: 01-01-2012
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1757-y

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2012

Preclinical anti-angiogenesis and anti-tumor activity of SIM010603, an oral, multi-targets receptor tyrosine kinases inhibitor

Population pharmacokinetics of PM00104 (Zalypsis®) in cancer patients

The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates

A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects

Modification of uptake and subcellular distribution of doxorubicin by N-acylhydrazone residues as visualised by intrinsic fluorescence

A phase I trial of oral metronomic vinorelbine plus capecitabine in patients with metastatic breast cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer