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Epidermal Growth Factor Receptor Inhibitors in Clinical Trials
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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
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Epidermal Growth Factor Receptor Inhibitors in Clinical Trials
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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:
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Epidermal Growth Factor Receptor Inhibitors in Clinical Trials
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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
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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)
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Epidermal Growth Factor Receptor Inhibitors in Clinical Trials
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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
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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
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Epidermal Growth Factor Receptor Inhibitors in Clinical Trials
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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.
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