Epidermal Growth Factor Receptor Inhibitors in Clinical Trials

June 1, 2001

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

With the understanding of the mechanism ofmalignant transformation has come the knowledge that oncogene products arefrequently growth factors, growth factor receptors, or elements of growth factorsignal-transduction pathways. Overexpression of the components of thesesignal-transduction pathways can lead to the development and propagation ofmalignancies. In addition, human cells exhibit complex responses to DNA damage,including activation of genes involved in cell-cycle arrest, DNA repair, andapoptosis. Recent findings suggest that the cellular response to DNA damage ismarkedly impaired by deprivation of essential growth factors or by blockage ofgrowth-factor receptors, which suggests that these pathways contribute to theineffectiveness of chemotherapy and radiation.[1,2] Thus, specific blockade ofthese pathways in tumor cells may be attractive targets for new cancertherapies, since inhibiting these pathways may induce tumor stasis and/orregression and increase the cytotoxic effects of chemotherapy and radiation.

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 characterizedand has generated significant interest as a target for cancer therapeutics. Thefamily consists of epidermal growth factor receptor (EGFR), HER2, HER3, andHER4, and at least 10 ligands that bind and activate family members.[3]Ligand-receptor binding results in receptor dimerization with the sameor different family member, autophosphorylation, kinase activation, and thegeneration of binding sites for downstream adaptor molecules and secondmessengers.

Because family members can be activated by multiple ligands andligand-receptor expression determines homo/heterodimerization between receptorsas well as rate of receptor internalization and degradation, the efficiency anddiversity of signal transduction through these receptor complexes is remarkable.Activation of this family of growth-factor receptors influences cellproliferation, 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 theformation and progression of human cancers. Hyperactive receptor signalingpromotes deregulated cell growth and subsequent development of malignancy.

EGFR is overexpressed in a significant proportion of humancancers such as breast, lung, and head and neck carcinomas, andglioblastomas.[4,5] In addition, several studies suggest a correlation betweenreceptor and/or ligand expression and poor prognosis. In some studies, EGFRoverexpression was associated with poorer prognosis in bladder, head and neck,esophageal, non-small-cell lung, and breast cancer patients.[6-10] Mostimportantly, EGFR inhibition in EGFR-expressing cancer cells leads to cell cyclearrest, apoptosis, tumor stasis, and even tumor regression in preclinicalmodels.[3,11] Inhibitors of EGFR appear to work additively and/orsynergistically with standard cytotoxic agents and radiotherapy.[12]

A number of modalities are being developed to target the ErbBfamily. These include antibodies to the extracellular domain of the receptors,small molecules that reversibly or irreversibly inhibit receptorautophosphorylation by inhibiting ATP binding, and antisense oligonucleotides.Among these pharmacologic strategies, both antibodies and small moleculesdirected toward EGFR are currently in clinical development (Table1). However, only the small molecule ZD1839 (Iressa) and the antibody C225are presently in phase III trials (see trials).

Given the success of trastuzumab (Herceptin), a humanized,anti-HER2 murine monoclonal antibody, directed against the extracellular domainof HER2, it is not surprising that a similar approach targeting EGFR isunderway. C225, a human/mouse chimeric antibody, binds to the EGFR extracellulardomain blocking EGF-ligand binding. In vitro, this antibody blocksligand-dependent proliferation of tumor cell lines and can induce tumorregression in xenografts. C225 potentiates the effects of ionizing radiation[13]and, similar to trastuzumab, enhances the activity of doxorubicin andtaxanes.[14]

Phase I trials of C225 evaluating single-dose and multi-doseschedules have been reported.[15] In neither study was the maximum tolerateddose reached. In the single dose schedule, patients with variousEGFR-overexpressing tumors received 5 to 100 mg/m2 intravenously over30 minutes. Toxicities included fever, chills, fatigue, hepatic transaminaseelevation, nausea, and acneiform skin rash. Receptor-saturating levels wereobtained for 7 days. Two patients with head and neck cancer had minor responses.No serious toxicities were seen in patients receiving C225 weekly and antibodydoses in the range of 200 to 400 mg/m2 were associated with completesaturation of systemic clearance. Coadministration of cisplatin at 60 mg/m2once every 4 weeks with C225 doses of 5 to 400 mg/m2 did not alterC225 clearance. Antibodies against C225 were detected in only one patient, andC225-associated toxicity was minimal. Of 13 patients treated with antibody dosesof ³ 50 mg/m2 with cisplatin, 9 completed12 weeks of therapy, and two partial responses were observed.[15] Concurrenttreatment with C225 and radiation in patients with head and neck carcinoma didnot enhance radiation-induced toxicity, and all the patients in this phase Istudy achieved a response.[16] Currently, a phase III study to determine theadditional benefit of C225 to radiation is being evaluated in this patientpopulation.

Antibodies can exert a therapeutic effect by hinderingreceptor-ligand binding or receptor-receptor dimerization. They may also induceantibody-mediated cellular cytotoxicity. However, there are potentialdisadvantages to the use of antibodies as therapeutic modalities. Antibodies arebulky, which may result in inefficient treatment delivery in the setting ofcentral nervous system malignancies. They bind to the extracellular domain ofthe receptor and therefore will be inactive against the truncated forms of themolecule that may be present in some percentage of tumors. Finally, antibodieshave the potential for generating an immunologic response that may hinderrepeated treatment. Despite these theoretical disadvantages, the anti-EGFRantibody C225 has been well tolerated and has shown promising results in earlyclinical trials.

Small molecule inhibitors of the intracellular tyrosine kinasedomain of EGFR are also under clinical evaluation.[3,17,18] Currently availableEGFR inhibitors belong to three chemical series: 4-anilinoquinazolines,4-[ar(alk)ylamino] pyridopyrimidines, and 4-phenylaminopyrrolo-pyrimidines. Twoquinazolines that have shown promising antitumor activity in early clinicaltrials are ZD1839 and OSI-774 (formerly CP-358, 774). These small moleculescompetitively inhibit ATP binding to EGFR, hindering autophosphorylation, andinduce tumor stasis and even tumor regression in some tumor xenograft models.

In addition to their shared mechanism of action, these agentsare also administered orally on chronic schedules and have a similar spectrum oftoxicity, 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 acysteine residue near the ATP binding site. Whether irreversible inhibition willresult in an improved therapeutic index or will remove the need for continuousdosing will require further clinical study.

ZD1839 is an anilinoquinazoline that acts as a potent andspecific inhibitor of EGFR tyrosine kinase activity by competing with adenosinetriphosphate for its binding site on the intracellular domain of the receptor.The IC50 of ZD1839 using enzyme extracted from A431 human squamous vulval cellline was 0.023 to 0.079 mM.[19] It is approximately 100-fold less activeagainst ErbB2 kinase and has little or no enzyme inhibitory activity againstseveral other tyrosine and serine-threonine kinases tested. ZD1839 has antitumoractivity in a broad range of human tumor xenografts with both tumor stasis andregression seen in xenograft models. However, rapid regrowth of tumors wasgenerally observed when the drug was discontinued, suggesting the need forchronic administration.

Two trials are assessing escalating doses of ZD1839 administeredon a continuous daily schedule. Dose-limiting toxicity has not been reached atdose levels of 600 and 800 mg/d.[20] The most frequent adverse events were grade1 or 2 skin rash, diarrhea, nausea, and vomiting. Grade 3 adverse eventsincluded diarrhea, skin rash, increased hepatic transaminases, nausea, andvomiting. Skin toxicity consisted primarily of grade 1 or 2 pustular oracne-like lesions with occasional erythema, or dry skin. The rash was usuallylocated on the face, with involvement of the upper torso at higher doses, andresolved rapidly after discontinuation of the drug. Nausea and/or emesisoccurred infrequently and was mild to moderate in severity. Oral doses of 250and 500 mg/d in combination with standard chemotherapy are being evaluated inongoing phase III placebo-controlled studies in patients with locally advancednon-small-cell lung cancer.

The Cancer Therapy Evaluation Program (CTEP) of the NationalCancer Institute (NCI) is currently sponsoring clinical trials of ZD1839 inglioblastoma, squamous cell carcinoma of the head and neck, renal cellcarcinoma, transitional cell carcinoma, colorectal carcinoma, and locallyadvanced non-small-cell lung carcinoma. Other studies are planned in ovariancarcinoma, endometrial carcinoma, and mesothelioma. Research goals includedefining optimal combinations with conventional chemotherapeutic agents and withradiation therapy, determining the best therapy candidates, and expandingclinical trials to other tumor types. Details of these trials can be foundthrough 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 featuresinteractive tools for online searching.

Phase III

Title: Phase III Randomized Study of Cisplatin With orWithout Monoclonal Antibody C225 in Patients with Metastatic and/or RecurrentSquamous 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 WithUnresectable Stage III Non-Small Cell Lung Cancer
Protocol Number:
SWOG-S0023
Participating Institutions:
Southwest Oncology Group; North Central CancerTreatment Group, National Cancer Institute of Canada, Clinical Trials SupportUnit
Protocol Status: Active
Contact:
Karen Kelly, Southwest Oncology Group, (303) 315-8801; for acomplete listing of study contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Phase II

Title: Phase II Study of ZD 1839 in Patients WithMetastatic 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 WithAdvanced 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; fora complete listing of study contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase II Study of ZD 1839 in Patients WithGlioblastoma 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 hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase II Study of ZD 1839 in Patients WithProgressive Stage IV or Recurrent Renal Cell Cancer
Protocol Number: NCI-1639
Participating Institutions: Marlene & Stewart Greenebaum CancerCenter, 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 WithMetastatic 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 hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase II Study of ZD 1839 in Patients WithGlioblastoma 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/MetastaticSquamous Cell Cancer of Head & Neck (in review)
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 andPharmacological Study of ZD1839 in Patients With Advanced Colorectal CarcinomaRefractory 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 AdvancedColorectal 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 ProgressiveMalignant Astrocytoma or Glioblastoma and Recurrent or Progressive Meningioma: APhase II Study With a Phase I Component for Patients Receiving EIAEDs (inreview)
Protocol Number: NABTC-00-01
Participating Institutions: North American Brain Tumor Consortium;University of Pittsburgh, University of California at San Francisco, Dana-FarberCancer Center, University of Michigan Medical Center, National Institutes ofHealth, M. D. Anderson Cancer Center, University of Texas Southwestern MedicalCenter, University of Wisconsin, University of California at Los Angeles,Memorial Sloan-Kettering Cancer Center, University of Texas Health ScienceCenter
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 WithRadiation in Locally Advanced Squamous Cell Carcinoma of the Head and Neck (inreview)
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 OncologyGroup; 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

Title: A Phase I Study of ZD1839 (Iressa) in CombinationWith Irinotecan, Leucovorin, and 5-Fluorouracil in Previously Untreated, StageIV 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 CombinationWith Oxaliplatin, 5-Fluorouracil (5-FU) and Leucovorin (LV) in Advanced SolidMalignancies (in review)
Protocol Number: 4370
Participating Institutions: Stanford University School ofMedicine
Protocol Status: In review
Contact:
Branimir I. Sikic, MD, (650) 725-6427

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13. Huang SM, Bock JM, Harari PM, et al: Epidermal growth factorreceptor blockade with C225 modulates proliferation, apoptosis, andradiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res59:1935-1940, 1999.

14. Prewett M, Rockwell P, Rockwell RF, et al: The biologiceffects of C225, a chimeric monoclonal antibody to the EGFR, on human prostatecarcinoma. J Immunother Emphasis Tumor Immunol 19:419-27, 1996.

15. Baselga J, Pfister D, Cooper MR, et al: Phase I studies ofanti-epidermal growth factor receptor chimeric antibody C225 alone and incombination with cisplatin. J Clin Oncol 18:904-914, 2000.

16. Bonner JA, Ezekiel MP, Robert F, et al: Continued responsefollowing treatment with IMC-C225, an EGFR MoAb, combined with RT in advancedhead and neck malignancies (abstract 5F). Proc Am Soc Clin Oncol 19:4a, 2000.

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18. Traxler P, Furet P: Strategies toward the design of noveland selective protein tyrosine kinase inhibitors. Pharmacol Ther82(2-3):195-206, 1999.

19. Woodburn JR, Barker AJ, et al: ZD1839, an epidermal growthfactor tyrosinde kinase inhibitor selected for clinical development (meetingabstract). Proc Ann Meet Am Assoc Cancer Res 38:A4251, 1997.

20. Baselga J, LoRusso P, et al: Apharmacokinetic/pharmacodynamic trial of ZD1839 (Iressa), a novel oral epidermalgrowth factor receptor tyrosine kinase (EGFR-TK) inhibitor, in patients with 5selected tumor types (a phase I/II trial of continuous once-daily treatment)(meeting abstract A29). Proceedings of the 1999 AACR-NCI-EORTC InternationalConference on Molecular Targets and Cancer Therapeutics. Washington, DC, 1999.