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Epidermal Growth Factor Receptor Inhibitors in Clinical Trials Published on Physicians Practice (http://www.physicianspractice.com) Epidermal Growth Factor Receptor Inhibitors in Clinical Trials Review Article [1] | June 01, 2001 By Janet E. Dancey, MD [2] With the understanding of the mechanism of malignant transformation has come the knowledge that oncogene products are frequently growth factors, growth factor receptors, or elements of growth factor signal-transduction pathways. Overexpression ith the understanding of the mechanism of malignant transformation has come the knowledge that oncogene products are frequently growth factors, growth factor receptors, or elements of growth factor signal-transduction pathways. Overexpression of the components of these signal-transduction pathways can lead to the development and propagation of malignancies. In addition, human cells exhibit complex responses to DNA damage, including activation of genes involved in cell-cycle arrest, DNA repair, and apoptosis. Recent findings suggest that the cellular response to DNA damage is markedly impaired by deprivation of essential growth factors or by blockage of growth-factor receptors, which suggests that these pathways contribute to the ineffectiveness of chemotherapy and radiation.[1,2] Thus, specific blockade of these pathways in tumor cells may be attractive targets for new cancer therapies, since inhibiting these pathways may induce tumor stasis and/or regression and increase the cytotoxic effects of chemotherapy and radiation. W Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community. It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).* We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study. This month’s installment of Clinical Trials Referral Resource is devoted to studies regarding epidermal growth factor receptor inhibitors. For patient entry information, see the individual trials. * PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, Internet access is available at http://cancernet.nci.nih.gov/pdqfull.html, or contact the Cancer Information Service offices (1-800-4-CANCER). The ErbB family of growth-factor receptors is well characterized and has generated significant interest as a target for cancer therapeutics. The family consists of epidermal growth factor receptor (EGFR), HER2, HER3, and HER4, and at least 10 ligands that bind and activate family members.[3] Ligand-receptor binding results in receptor dimerization with the same or different family member, autophosphorylation, kinase activation, and the generation of binding sites for downstream adaptor molecules and second messengers. Because family members can be activated by multiple ligands and ligand-receptor expression determines homo/heterodimerization between receptors as well as rate of receptor internalization Page 1 of 7 Epidermal Growth Factor Receptor Inhibitors in Clinical Trials Published on Physicians Practice (http://www.physicianspractice.com) and degradation, the efficiency and diversity of signal transduction through these receptor complexes is remarkable. Activation of this family of growth-factor receptors influences cell proliferation, survival, motility, adhesion, invasion, and angiogenesis.[3] Preclinical and clinical data support the involvement of the ligands’ transforming growth factor-alpha and epidermal growth factor and EGFR in the formation and progression of human cancers. Hyperactive receptor signaling promotes deregulated cell growth and subsequent development of malignancy. EGFR is overexpressed in a significant proportion of human cancers such as breast, lung, and head and neck carcinomas, and glioblastomas.[4,5] In addition, several studies suggest a correlation between receptor and/or ligand expression and poor prognosis. In some studies, EGFR overexpression was associated with poorer prognosis in bladder, head and neck, esophageal, non-small-cell lung, and breast cancer patients.[6-10] Most importantly, EGFR inhibition in EGFR-expressing cancer cells leads to cell cycle arrest, apoptosis, tumor stasis, and even tumor regression in preclinical models.[3,11] Inhibitors of EGFR appear to work additively and/or synergistically with standard cytotoxic agents and radiotherapy.[12] A number of modalities are being developed to target the ErbB family. These include antibodies to the extracellular domain of the receptors, small molecules that reversibly or irreversibly inhibit receptor autophosphorylation by inhibiting ATP binding, and antisense oligonucleotides. Among these pharmacologic strategies, both antibodies and small molecules directed toward EGFR are currently in clinical development (Table 1). However, only the small molecule ZD1839 (Iressa) and the antibody C225 are presently in phase III trials (see trials). Given the success of trastuzumab (Herceptin), a humanized, anti-HER2 murine monoclonal antibody, directed against the extracellular domain of HER2, it is not surprising that a similar approach targeting EGFR is underway. C225, a human/mouse chimeric antibody, binds to the EGFR extracellular domain blocking EGF-ligand binding. In vitro, this antibody blocks ligand-dependent proliferation of tumor cell lines and can induce tumor regression in xenografts. C225 potentiates the effects of ionizing radiation[13] and, similar to trastuzumab, enhances the activity of doxorubicin and taxanes.[14] Phase I trials of C225 evaluating single-dose and multi-dose schedules have been reported.[15] In neither study was the maximum tolerated dose reached. In the single dose schedule, patients with various EGFR-overexpressing tumors received 5 to 100 mg/m2 intravenously over 30 minutes. Toxicities included fever, chills, fatigue, hepatic transaminase elevation, nausea, and acneiform skin rash. Receptor-saturating levels were obtained for 7 days. Two patients with head and neck cancer had minor responses. No serious toxicities were seen in patients receiving C225 weekly and antibody doses in the range of 200 to 400 mg/m2 were associated with complete saturation of systemic clearance. Coadministration of cisplatin at 60 mg/m2 once every 4 weeks with C225 doses of 5 to 400 mg/m2 did not alter C225 clearance. Antibodies against C225 were detected in only one patient, and C225-associated toxicity was minimal. Of 13 patients treated with antibody doses of ≥ 50 mg/m2 with cisplatin, 9 completed 12 weeks of therapy, and two partial responses were observed.[15] Concurrent treatment with C225 and radiation in patients with head and neck carcinoma did not enhance radiation-induced toxicity, and all the patients in this phase I study achieved a response.[16] Currently, a phase III study to determine the additional benefit of C225 to radiation is being evaluated in this patient population. Antibodies can exert a therapeutic effect by hindering receptor-ligand binding or receptor-receptor dimerization. They may also induce antibody-mediated cellular cytotoxicity. However, there are potential disadvantages to the use of antibodies as therapeutic modalities. Antibodies are bulky, which may result in inefficient treatment delivery in the setting of central nervous system malignancies. They bind to the extracellular domain of the receptor and therefore will be inactive against the truncated forms of the molecule that may be present in some percentage of tumors. Finally, antibodies have the potential for generating an immunologic response that may hinder repeated treatment. Despite these theoretical disadvantages, the anti-EGFR antibody C225 has been well tolerated and has shown promising results in early clinical trials. Small molecule inhibitors of the intracellular tyrosine kinase domain of EGFR are also under clinical evaluation.[3,17,18] Currently available EGFR inhibitors belong to three chemical series: Page 2 of 7 Epidermal Growth Factor Receptor Inhibitors in Clinical Trials Published on Physicians Practice (http://www.physicianspractice.com) 4-anilinoquinazolines, 4-[ar(alk)ylamino] pyridopyrimidines, and 4-phenylaminopyrrolo-pyrimidines. Two quinazolines that have shown promising antitumor activity in early clinical trials are ZD1839 and OSI-774 (formerly CP-358, 774). These small molecules competitively inhibit ATP binding to EGFR, hindering autophosphorylation, and induce tumor stasis and even tumor regression in some tumor xenograft models. In addition to their shared mechanism of action, these agents are also administered orally on chronic schedules and have a similar spectrum of toxicity, with diarrhea and skin rash being most common. More recently, potent, irreversible inhibitors of EGFR kinases have been developed such as CI-1033, which inhibits all four EGFR family members. This compound covalently binds to a cysteine residue near the ATP binding site. Whether irreversible inhibition will result in an improved therapeutic index or will remove the need for continuous dosing will require further clinical study. ZD1839 is an anilinoquinazoline that acts as a potent and specific inhibitor of EGFR tyrosine kinase activity by competing with adenosine triphosphate for its binding site on the intracellular domain of the receptor. The IC50 of ZD1839 using enzyme extracted from A431 human squamous vulval cell line was 0.023 to 0.079 mM.[19] It is approximately 100-fold less active against ErbB2 kinase and has little or no enzyme inhibitory activity against several other tyrosine and serine-threonine kinases tested. ZD1839 has antitumor activity in a broad range of human tumor xenografts with both tumor stasis and regression seen in xenograft models. However, rapid regrowth of tumors was generally observed when the drug was discontinued, suggesting the need for chronic administration. Two trials are assessing escalating doses of ZD1839 administered on a continuous daily schedule. Dose-limiting toxicity has not been reached at dose levels of 600 and 800 mg/d.[20] The most frequent adverse events were grade 1 or 2 skin rash, diarrhea, nausea, and vomiting. Grade 3 adverse events included diarrhea, skin rash, increased hepatic transaminases, nausea, and vomiting. Skin toxicity consisted primarily of grade 1 or 2 pustular or acne-like lesions with occasional erythema, or dry skin. The rash was usually located on the face, with involvement of the upper torso at higher doses, and resolved rapidly after discontinuation of the drug. Nausea and/or emesis occurred infrequently and was mild to moderate in severity. Oral doses of 250 and 500 mg/d in combination with standard chemotherapy are being evaluated in ongoing phase III placebo-controlled studies in patients with locally advanced non-small-cell lung cancer. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) is currently sponsoring clinical trials of ZD1839 in glioblastoma, squamous cell carcinoma of the head and neck, renal cell carcinoma, transitional cell carcinoma, colorectal carcinoma, and locally advanced non-small-cell lung carcinoma. Other studies are planned in ovarian carcinoma, endometrial carcinoma, and mesothelioma. Research goals include defining optimal combinations with conventional chemotherapeutic agents and with radiation therapy, determining the best therapy candidates, and expanding clinical trials to other tumor types. Details of these trials can be found through the National Cancer Institute’s PDQ Clinical Trials Database (http://cancernet.nci.nih.gov/trialsrch.shtml) available on the Internet through CancerNet, an NCI website that features interactive tools for online searching. Phase III Title: Phase III Randomized Study of Cisplatin With or Without Monoclonal Antibody C225 in Patients with Metastatic and/or Recurrent Squamous Cell Cancer of the Head and Neck (active) Protocol Number: E5397 Participating Institutions: Eastern Cooperative Oncology Group Protocol Status: In review Contact: Jean McDonald, (617) 632-3610 Title: Phase III Randomized Study of Cisplatin, Etoposide, Radiotherapy, and Docetaxel With or Without ZD 1839 in Patients With Unresectable Stage III Non-Small Cell Lung Cancer Protocol Number: SWOG-S0023 Participating Institutions: Southwest Oncology Group; North Central Cancer Treatment Group, National Cancer Institute of Canada, Clinical Trials Support Unit Page 3 of 7 Epidermal Growth Factor Receptor Inhibitors in Clinical Trials Published on Physicians Practice (http://www.physicianspractice.com) Protocol Status: Active Contact: Karen Kelly, Southwest Oncology Group, (303) 315-8801; for a complete listing of study contacts, click here Latest Information: http://cancernet.nci.nih.gov/ Phase II Title: Phase II Study of ZD 1839 in Patients With Metastatic Renal Cell Cancer Protocol Number: NCI-1373 Participating Institutions: Memorial Sloan-Kettering Cancer Center Protocol Status: Active Contact: Robert J. Motzer, Memorial Sloan-Kettering Cancer Center, (212) 639-6667 Latest Information: http://cancernet.nci.nih.gov/ Title: Phase II Study of ZD 1839 in Patients With Advanced Transitional Cell Carcinoma of the Urothelium Protocol Number: SWOG-S0031 Participating Institutions: Southwest Oncology Group Protocol Status: Active Contact: Daniel P. Petrylak, Southwest Oncology Group, (212) 305-1731; for a complete listing of study contacts, click here Latest Information: http://cancernet.nci.nih.gov/ Title: Phase II Study of ZD 1839 in Patients With Glioblastoma Multiforme Protocol Number: NCCTG-N0074 Participating Institutions: North Central Cancer Treatment Group Protocol Status: Active Contact: Joon H. Uhm, North Central Cancer Treatment Group, (507) 284-3559; for a complete listing of study contacts, click here Latest Information: http://cancernet.nci.nih.gov/ Title: Phase II Study of ZD 1839 in Patients With Progressive Stage IV or Recurrent Renal Cell Cancer Protocol Number: NCI-1639 Participating Institutions: Marlene & Stewart Greenebaum Cancer Center, University of Maryland Cancer Center Protocol Status: Active Contact: Nancy Ann Dawson, Marlene & Stewart Greenebaum Cancer Center, University of Maryland, (410) 328-2565 Latest Information: http://cancernet.nci.nih.gov/ Title: Phase II Study of ZD 1839 in Patients With Metastatic or Recurrent Squamous Cell Carcinoma of the Head and Neck Protocol Number: NCI-1721 Participating Institutions: University of Chicago Protocol Status: Active Contact: Fred R. Rosen, University of Chicago Cancer Research Center, (312) 996-7975; for a complete listing of study contacts, click here Latest Information: http://cancernet.nci.nih.gov/ Title: Phase II Study of ZD 1839 in Patients With Glioblastoma Multiforme in First Relapse Protocol Number: NCI-1253 Participating Institutions: Duke University Medical Center Protocol Status: Active Contact: Henry S. Friedman, Duke Comprehensive Cancer Center, (919) 684-5301 Latest Information: http://cancernet.nci.nih.gov/ Title: Phase II Study of ZD1839 in Recurrent/Metastatic Squamous Cell Cancer of Head & Neck (in review) Page 4 of 7 Epidermal Growth Factor Receptor Inhibitors in Clinical Trials Published on Physicians Practice (http://www.physicianspractice.com) Protocol Number: 1701 Participating Institutions: University of Utah Protocol Status: In review Contact: Richard H. Wheeler, MD, (801) 585-0100 Title: A Phase II Clinical, Biological and Pharmacological Study of ZD1839 in Patients With Advanced Colorectal Carcinoma Refractory to Fluorouracil (5-FU) and Irinotecan Chemotherapy (in review) Protocol Number: 3753 Participating Institutions: University of Texas Health Science Center Protocol Status: In review Contact: Manuel Hidalgo, MD, PhD, (210) 567-7000 Title: A Phase I/Randomized Phase II Trial of Oxaliplatin (NSC# 266046) With or Without ZD1839 (NSC# 715055) in Patients With Advanced Colorectal Carcinoma (in review) Protocol Number: 3857 Participating Institutions: University of Chicago Protocol Status: In review Contact: Hedy Lee Kindler, MD, (773) 702-0360 Title: A Phase II Trial of ZD1839 (Iressa) (NSC #715055) in Persistent or Recurrent Epithelial Ovarian or Primary Peritoneal Carcinoma (in review) Protocol Number: GOG-0170-C Participating Institutions: Gynecologic Oncology Group Protocol Status: In review Contact: Russell J. Schilder, MD, (888) 369-2427 Title: ZD1839 for Treatment of Recurrent or Progressive Malignant Astrocytoma or Glioblastoma and Recurrent or Progressive Meningioma: A Phase II Study With a Phase I Component for Patients Receiving EIAEDs (in review) Protocol Number: NABTC-00-01 Participating Institutions: North American Brain Tumor Consortium; University of Pittsburgh, University of California at San Francisco, Dana-Farber Cancer Center, University of Michigan Medical Center, National Institutes of Health, M. D. Anderson Cancer Center, University of Texas Southwestern Medical Center, University of Wisconsin, University of California at Los Angeles, Memorial Sloan-Kettering Cancer Center, University of Texas Health Science Center Protocol Status: In review Contact: Frank S. Lieberman, MD, (412) 692-2600 Phase I/II Title: A Phase I/II Study of ZD1839 in Combination With Radiation in Locally Advanced Squamous Cell Carcinoma of the Head and Neck (in review) Protocol Number: 4551 Participating Institutions: University of Colorado Protocol Status: In review Contact: David Raben, MD, (800) 473-2288 Title: A Phase I/II Trial of Herceptin and ZD1839 (Iressa) in Patients With Metastatic Breast Cancer That Overexpresses HER2/neu (Erb-2) (in review) Protocol Number: E1100 Participating Institutions: Eastern Cooperative Oncology Group; Vanderbilt University, Rush-Presbyterian-St. Luke’s Medical Center, Indiana University Medical Center, Johns Hopkins University Protocol Status: In review Contact: Jean McDonald, (617) 632-3610 Phase I Page 5 of 7 Epidermal Growth Factor Receptor Inhibitors in Clinical Trials Published on Physicians Practice (http://www.physicianspractice.com) Title: A Phase I Study of ZD1839 (Iressa) in Combination With Irinotecan, Leucovorin, and 5-Fluorouracil in Previously Untreated, Stage IV Colorectal Cancer (in review) Protocol Number: 3792 Participating Institutions: Dana-Farber Cancer Center Protocol Status: In review Contact: Charles S. Fuchs, MD, MPH, (800) 320-0022 Title: A Phase I Study of ZD1839 (Iressa) in Combination With Oxaliplatin, 5-Fluorouracil (5-FU) and Leucovorin (LV) in Advanced Solid Malignancies (in review) Protocol Number: 4370 Participating Institutions: Stanford University School of Medicine Protocol Status: In review Contact: Branimir I. Sikic, MD, (650) 725-6427 References: 1. Kastan MB, Canman CE, Leonard CJ, et al: P53, cell cycle control and apoptosis: Implications for cancer. Cancer Metastasis Rev 14:3-15, 1995. 2. Lichter AS, Lawrence TS: Recent advances in radiation oncology. N Engl J Med 332:371-379, 1995. 3. Woodburn JR:The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 82(2-3):241-250, 1999. 4. Pegram MD, Pauletti G, Slamon DJ, et al: HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res Treat 52:65-77, 1998. 5. Salomon DS, Brandt R, Ciardiello F, et al: Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183-232, 1995. 6. Diedrich U, Lucius J, Baron E, et al: Distribution of epidermal growth factor receptor gene amplification in brain tumours and correlation to prognosis. J Neurol 242:683-688, 1995. 7. Giatromanolaki A, Koukourakis MI, O’Byrne K, et al: Non-small cell lung cancer: c-ErbB-2 overexpression correlates with low angiogenesis and poor prognosis. Anticancer Res 16:3819-3825, 1996. 8. Maurizi M, Almadori G, Ferrandina G, et al: Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma. Br J Cancer 74:1253-1257, 1996. 9. Dong M, Nio Y, Guo KJ, et al: Epidermal growth factor and its receptor as prognostic indicators in Chinese patients with pancreatic cancer. Anticancer Res 18:4613-4619, 1998. 10. Ohsaki Y, Tanno S, Fujita Y, et al: Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. Oncol Rep 7:603-607, 2000. 11. Gibbs JB: Anticancer drug targets: Growth factors and growth factor signaling. J Clin Invest 105:9-13, 2000. 12. Fortunato C, Caputo R, et al: Potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an EGFR-selective tyrosine kinase inhibitor. Proc Ann Meet Am Assoc Cancer Res 41:A3075, 2000. 13. Huang SM, Bock JM, Harari PM, et al: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59:1935-1940, 1999. Page 6 of 7 Epidermal Growth Factor Receptor Inhibitors in Clinical Trials Published on Physicians Practice (http://www.physicianspractice.com) 14. Prewett M, Rockwell P, Rockwell RF, et al: The biologic effects of C225, a chimeric monoclonal antibody to the EGFR, on human prostate carcinoma. J Immunother Emphasis Tumor Immunol 19:419-27, 1996. 15. Baselga J, Pfister D, Cooper MR, et al: Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 18:904-914, 2000. 16. Bonner JA, Ezekiel MP, Robert F, et al: Continued response following treatment with IMC-C225, an EGFR MoAb, combined with RT in advanced head and neck malignancies (abstract 5F). Proc Am Soc Clin Oncol 19:4a, 2000. 17. Fry DW: Inhibition of the epidermal growth factor receptor family of tyrosine kinases as an approach to cancer chemotherapy: progression from reversible to irreversible inhibitors. Pharmacol Ther 82(2-3):207-218, 1999. 18. Traxler P, Furet P: Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol Ther 82(2-3):195-206, 1999. 19. Woodburn JR, Barker AJ, et al: ZD1839, an epidermal growth factor tyrosinde kinase inhibitor selected for clinical development (meeting abstract). Proc Ann Meet Am Assoc Cancer Res 38:A4251, 1997. 20. Baselga J, LoRusso P, et al: A pharmacokinetic/pharmacodynamic trial of ZD1839 (Iressa), a novel oral epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor, in patients with 5 selected tumor types (a phase I/II trial of continuous once-daily treatment) (meeting abstract A29). Proceedings of the 1999 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Washington, DC, 1999. Source URL: http://www.physicianspractice.com/review-article/epidermal-growth-factor-receptor-inhibitors-clinical -trials Links: [1] http://www.physicianspractice.com/review-article [2] http://www.physicianspractice.com/authors/janet-e-dancey-md Page 7 of 7