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Phase I Safety, Pharmacokinetic, and Pharmacodynamic Trial of ZD1839, a Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Five Selected Solid Tumor Types

From Vall d’Hebron University Hospital, Barcelona, Spain; Peter MacCallum Institute, Melbourne, Australia; Christie Hospital National Health Service Trust, Manchester, Northern Centre for Cancer Treatment, Newcastle-upon-Tyne, The Royal Marsden Hospital, Sutton, Churchill Hospital, Oxford, and AstraZeneca, Alderley Park, United Kingdom; Institut Gustave Roussy, Villejuif, France; Maastricht University Medical Center, Maastricht, the Netherlands; Istituto Nazionale Tumori, Milan, Italy; Universitetssjukhuset, Malmö, Sweden; and AstraZeneca, Wilmington, DE.

Address reprint requests to José Baselga, MD, Department of Oncology, Vall d’Hebron University Hospital, Paseo Vall d’Hebron 119-129, 08035 Barcelona, Spain; email: baselga{at}hg.vhebron.es

PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types.

PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non–small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited.

RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for 3 months; seven of these patients remained on study drug for 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway.

CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.

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				F. R. Luo, Z. Yang, H. Dong, A. Camuso, K. McGlinchey, K. Fager, C. Flefleh, D. Kan, I. Inigo, S. Castaneda, et al. Prediction of Active Drug Plasma Concentrations Achieved in Cancer Patients by Pharmacodynamic Biomarkers Identified from the Geo Human Colon Carcinoma Xenograft Model Clin. Cancer Res., August 1, 2005; 11(15): 5558 - 5565. [Abstract] [Full Text] [PDF]

				D. S. Krause and R. A. Van Etten Tyrosine Kinases as Targets for Cancer Therapy N. Engl. J. Med., July 14, 2005; 353(2): 172 - 187. [Full Text] [PDF]

				A Agrawal, E Gutteridge, J M W Gee, R I Nicholson, and J F R Robertson Overview of tyrosine kinase inhibitors in clinical breast cancer Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S135 - S144. [Abstract] [Full Text] [PDF]

				H E Jones, J M W Gee, K M Taylor, D Barrow, H D Williams, M Rubini, and R I Nicholson Development of strategies for the use of anti-growth factor treatments Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S173 - S182. [Abstract] [Full Text] [PDF]

				E. F. Petricoin III, V. E. Bichsel, V. S. Calvert, V. Espina, M. Winters, L. Young, C. Belluco, B. J. Trock, M. Lippman, D. A. Fishman, et al. Mapping Molecular Networks Using Proteomics: A Vision for Patient-Tailored Combination Therapy J. Clin. Oncol., May 20, 2005; 23(15): 3614 - 3621. [Abstract] [Full Text] [PDF]

				J. Nemunaitis, I. Eiseman, C. Cunningham, N. Senzer, A. Williams, P. F. Lenehan, S. C. Olson, P. Bycott, M. Schlicht, R. Zentgraff, et al. Phase 1 Clinical and Pharmacokinetics Evaluation of Oral CI-1033 in Patients with Refractory Cancer Clin. Cancer Res., May 15, 2005; 11(10): 3846 - 3853. [Abstract] [Full Text] [PDF]

				R. Perez-Soler, J. P. Delord, A. Halpern, K. Kelly, J. Krueger, B. M. Sureda, J. von Pawel, J. Temel, S. Siena, D. Soulieres, et al. HER1/EGFR Inhibitor-Associated Rash: Future Directions for Management and Investigation Outcomes from the HER1/EGFR Inhibitor Rash Management Forum Oncologist, May 1, 2005; 10(5): 345 - 356. [Abstract] [Full Text] [PDF]

				Y. Marie, A. F. Carpentier, A.M.P. Omuro, M. Sanson, J. Thillet, K. Hoang-Xuan, and J. -Y. Delattre EGFR tyrosine kinase domain mutations in human gliomas Neurology, April 26, 2005; 64(8): 1444 - 1445. [Abstract] [Full Text] [PDF]

				D. B. Agus, M. S. Gordon, C. Taylor, R. B. Natale, B. Karlan, D. S. Mendelson, M. F. Press, D. E. Allison, M. X. Sliwkowski, G. Lieberman, et al. Phase I Clinical Study of Pertuzumab, a Novel HER Dimerization Inhibitor, in Patients With Advanced Cancer J. Clin. Oncol., April 10, 2005; 23(11): 2534 - 2543. [Abstract] [Full Text] [PDF]

				J. Baselga and C. L. Arteaga Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer J. Clin. Oncol., April 10, 2005; 23(11): 2445 - 2459. [Abstract] [Full Text] [PDF]

				W. Pao and V. A. Miller Epidermal Growth Factor Receptor Mutations, Small-Molecule Kinase Inhibitors, and Non-Small-Cell Lung Cancer: Current Knowledge and Future Directions J. Clin. Oncol., April 10, 2005; 23(11): 2556 - 2568. [Abstract] [Full Text] [PDF]

				G. Giaccone HER1/EGFR-targeted agents: predicting the future for patients with unpredictable outcomes to therapy Ann. Onc., April 1, 2005; 16(4): 538 - 548. [Abstract] [Full Text] [PDF]

				R. A. Messmann Patient Selection for Early Phase Clinical Trials Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 294 - 296. [Full Text] [PDF]

				N. J. Meropol Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer: It's Time to Get Back on Target J. Clin. Oncol., March 20, 2005; 23(9): 1791 - 1793. [Full Text] [PDF]

				R. Govindan, R. A. Kratzke, J. E. Herndon II, G. A. Niehans, R. Vollmer, D. Watson, M. R. Green, H. L. Kindler, and on behalf of the Cancer and Leukemia Group B Gefitinib in Patients with Malignant Mesothelioma: A Phase II Study by the Cancer and Leukemia Group B Clin. Cancer Res., March 15, 2005; 11(6): 2300 - 2304. [Abstract] [Full Text] [PDF]

				J. A. Engelman, P. A. Janne, C. Mermel, J. Pearlberg, T. Mukohara, C. Fleet, K. Cichowski, B. E. Johnson, and L. C. Cantley ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines PNAS, March 8, 2005; 102(10): 3788 - 3793. [Abstract] [Full Text] [PDF]

				Y. W. Park, M. N. Younes, S. A. Jasser, O. G. Yigitbasi, G. Zhou, C. D. Bucana, B. N. Bekele, and J. N. Myers AEE788, a Dual Tyrosine Kinase Receptor Inhibitor, Induces Endothelial Cell Apoptosis in Human Cutaneous Squamous Cell Carcinoma Xenografts in Nude Mice Clin. Cancer Res., March 1, 2005; 11(5): 1963 - 1973. [Abstract] [Full Text] [PDF]

				C.M. Canil, M.J. Moore, E. Winquist, T. Baetz, M. Pollak, K.N. Chi, S. Berry, D.S. Ernst, L. Douglas, M. Brundage, et al. Randomized Phase II Study of Two Doses of Gefitinib in Hormone-Refractory Prostate Cancer: A Trial of the National Cancer Institute of Canada-Clinical Trials Group J. Clin. Oncol., January 20, 2005; 23(3): 455 - 460. [Abstract] [Full Text] [PDF]

				A. J. Dannenberg, S. M. Lippman, J. R. Mann, K. Subbaramaiah, and R. N. DuBois Cyclooxygenase-2 and Epidermal Growth Factor Receptor: Pharmacologic Targets for Chemoprevention J. Clin. Oncol., January 10, 2005; 23(2): 254 - 266. [Abstract] [Full Text] [PDF]

				R. BENEZRA, E. HENKE, A. CIARROCCHI, M. RUZINOVA, D. SOLIT, N. ROSEN, D. NOLAN, V. MITTAL, and P. DE CANDIA Induction of Complete Regressions of Oncogene-induced Breast Tumors in Mice Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 375 - 381. [Abstract] [PDF]

				N. T. Shah, M. G. Kris, W. Pao, L. B. Tyson, B. M. Pizzo, M.-H. Heinemann, L. Ben-Porat, D. L. Sachs, R. T. Heelan, and V. A. Miller Practical Management of Patients With Non-Small-Cell Lung Cancer Treated With Gefitinib J. Clin. Oncol., January 1, 2005; 23(1): 165 - 174. [Abstract] [Full Text] [PDF]

				K. Mimori, K. Yamashita, M. Ohta, K. Yoshinaga, K. Ishikawa, H. Ishii, T. Utsunomiya, G. F. Barnard, H. Inoue, and M. Mori Coexpression of Matrix Metalloproteinase-7 (MMP-7) and Epidermal Growth Factor (EGF) Receptor in Colorectal Cancer: An EGF Receptor Tyrosine Kinase Inhibitor Is Effective against MMP-7-Expressing Cancer Cells Clin. Cancer Res., December 15, 2004; 10(24): 8243 - 8249. [Abstract] [Full Text] [PDF]

				B. Shuch, M. Mikhail, J. Satagopan, P. Lee, H. Yee, C. Chang, C. Cordon-Cardo, S. S. Taneja, and I. Osman Racial Disparity of Epidermal Growth Factor Receptor Expression in Prostate Cancer J. Clin. Oncol., December 1, 2004; 22(23): 4725 - 4729. [Abstract] [Full Text] [PDF]

				S. L. Matheson, J. P. McNamee, T. Wang, M. A. Alaoui-Jamali, A. M. Tari, and B. J. Jean-Claude The Combi-Targeting Concept: Dissection of the Binary Mechanism of Action of the Combi-Triazene SMA41 in Vitro and Antitumor Activity in Vivo J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 1163 - 1170. [Abstract] [Full Text] [PDF]