V O L U M E 2 3 䡠 N U M B E R 3 䡠 J A N U A R Y 2 0 2 0 0 5
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`From the Princess Margaret Hospital,
`University Health Network; and
`Toronto-Sunnybrook Regional Cancer
`Centre, Toronto; London Regional
`Cancer Centre, London; McGill-Jewish
`General Hospital, Montreal; The
`Prostate Centre, Vancouver General
`Hospital, Vancouver; Tom Baker Cancer
`Centre, Calgary; and National Cancer
`Institute of Canada-Clinical Trials Group,
`Kingston, Canada.
`
`Submitted February 20, 2004; accepted
`October 12, 2004.
`
`Supported by AstraZeneca Pharmaceu-
`ticals and the National Cancer Institute
`of Canada.
`
`Presented at 27th European Society for
`Medical Oncology Congress, Nice,
`France, October 18-22, 2002.
`
`Authors’ disclosures of potential con-
`flicts of interest are found at the end of
`this article.
`
`Address reprint requests to Malcolm J.
`Moore, MD, Department of Medical
`Oncology and Hematology, Princess
`Margaret Hospital, University Health
`Network, 610 University Ave, Toronto,
`Ontario, M5G 2M9, Canada; e-mail:
`malcolm.moore@uhn.on.ca.
`
`© 2005 by American Society of Clinical
`Oncology
`
`0732-183X/05/2303-455/$20.00
`
`DOI: 10.1200/JCO.2005.02.129
`
`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
`C.M. Canil, M.J. Moore, E. Winquist, T. Baetz, M. Pollak, K.N. Chi, S. Berry, D.S. Ernst, L. Douglas,
`M. Brundage, B. Fisher, A. McKenna, and L. Seymour
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`Overexpression of the epidermal growth factor receptor has been demonstrated in advanced
`prostate cancer and is associated with a poor outcome. A multi-institutional, randomized,
`phase II study was undertaken by the National Cancer Institute of Canada-Clinical Trials
`Group to evaluate the efficacy and toxicity of two doses of oral gefitinib in patients with
`minimally symptomatic, hormone-refractory prostate cancer (HRPC).
`Patients and Methods
`Between July and November 2001, 40 patients with HRPC and increasing prostate-specific
`antigen (PSA) or progression in measurable disease who had not received prior chemother-
`apy were randomly assigned to 250 mg (n ⫽ 19) or 500 mg (n ⫽ 21) oral gefitinib daily
`continuously. The primary end points were PSA response rate and objective measurable
`response. Functional Assessment of Cancer Therapy Prostate Cancer Subscale (FACT-P)
`quality-of-life questionnaires were completed at baseline and during treatment.
`Results
`None of the patients demonstrated a PSA or objective measurable response. Five (14.3%) of
`35 assessable patients had stable PSA (one patient at 250 mg and four patients at 500 mg),
`and five patients (14.3%) had a best response of stable disease (duration, 2.5 to 16.8
`months). No significant effect on the rate of increase in PSA was seen. The most common
`drug-related nonhematologic toxicities observed were grade 1 to 2 diarrhea (250 mg, 65%;
`500 mg, 56%), fatigue (250 mg, 29%; 500 mg, 33%), and grade 1 to 2 skin rash (250 mg,
`24%; 500 mg, 39%). FACT-P scores decreased during treatment, indicating worsening of
`symptoms compared with baseline.
`Conclusion
`Gefitinib did not result in any responses in PSA or objective measurable disease at either
`dose level. Gefitinib has minimal single-agent activity in HRPC.
`
`J Clin Oncol 23:455-460. © 2005 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Prostate cancer is the most common male
`cancer and the second leading cause of can-
`cer death in men, accounting for an esti-
`mated 33,000 deaths in North America
`annually.1,2 Patients with advanced or met-
`astatic disease are incurable. Androgen abla-
`
`tion is standard first-line therapy for these
`patients, and although 80% will initially re-
`spond to androgen withdrawal, the median
`duration of response is approximately 18
`months. Once a patient develops metastatic
`hormone-resistant disease, the median sur-
`vival is 9 to 18 months. Subsequent thera-
`peutic options are limited, and treatment
`
`Downloaded from jco.ascopubs.org on June 14, 2016. For personal use only. No other uses without permission.
`Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
`
`455
`
`AVENTIS EXHIBIT 2104
`Mylan v. Aventis, IPR2016-00712
`
`

`
`Canil et al
`
`goals focus on palliation of symptoms such as fatigue, bone
`pain, and weight loss. Although chemotherapy has been
`shown to improve quality of life and pain control, no im-
`provement in survival has yet been demonstrated.3 With
`the earlier use of androgen ablation and frequent use of
`prostate-specific antigen (PSA) for monitoring, patients
`with hormone-refractory prostate cancer (HRPC) are now
`more commonly identified at an earlier stage by an increas-
`ing PSA rather than by new or worsening symptoms as in
`the past. These patients are often asymptomatic when
`initially seen, although progression to symptomatic dis-
`ease usually occurs within 6 to 12 months. Because con-
`ventional chemotherapy has not been shown to benefit
`these patients, they are an appropriate group in which to
`test new approaches to therapy. In addition, these clini-
`cally stable patients can tolerate the 2- to 3-week time
`period often required to achieve therapeutic steady-state
`and allow for an assessment of any potential cytostatic
`activity associated with many of the novel oral agents
`currently under investigation.
`In vitro proliferation of prostate epithelial cells cannot
`be induced by androgens alone but requires costimulation
`by a number of growth factors, including epidermal growth
`factor (EGF).4,5 EGF binds to its receptor, inducing confor-
`mational changes within the receptor and increasing the
`activity of associated tyrosine kinases. This results in in-
`creased biologic activity, including cell proliferation and/or
`differentiation. Abnormal EGF receptor (EGFR) expres-
`sion, either mutation or overexpression, has been demon-
`strated in many malignancies including prostate cancer.6-10
`EGFR is an ideal molecular target for inhibition because it is
`overexpressed in many tumor cells, yet it is strictly con-
`trolled in normal cells. Several inhibitors of the EGFR are in
`clinical testing. The two major categories of inhibitors are
`antibodies to the external epitope and small molecule in-
`hibitors of the receptor tyrosine kinase.
`Gefitinib (4-[3-chloro-4-fluorophenylamino]-7-methoxy-
`6-[3-{4-morpholinyl}propoxy]quinazoline, Iressa, ZD1839;
`AstraZeneca Pharmaceuticals, Mississauga, Canada) is an
`orally administered quinazoline-based molecule that inhibits
`EGFR tyrosine kinase. In preclinical models and early clini-
`cal studies, inhibition of EGFR has resulted in antitumor
`activity.11 Growth inhibition and tumor regression has been
`seen in human xenograft models in lung, prostate, breast, and
`colorectal cancers.12-15
`More than 250 patients with advanced solid tumor,
`including prostate cancer, were enrolled onto phase I stud-
`ies of gefitinib16-21 The maximum-tolerated dose was deter-
`mined to be 700 to 1,000 mg/d, with diarrhea as the dose-
`limiting toxicity. Serial skin biopsies have confirmed
`inhibition of EGFR tyrosine kinase in cancer patients.16
`Responses and stable disease were observed in some pa-
`tients, particularly in non–small-cell lung cancer and head
`and neck cancer, with some activity reported against pros-
`
`tate cancer. Once-daily oral doses of 250 mg and 500 mg,
`which are below the maximum-tolerated dose but have
`plasma concentrations above those required to maximally
`inhibit EGFR, were selected for further clinical investiga-
`tion.21 The US Food and Drug Administration has ap-
`proved gefitinib (ZD1893) as monotherapy treatment for
`patients with locally advanced or metastatic non–small-cell
`lung cancer after failure of both platinum-based and do-
`cetaxel chemotherapies on the basis of phase II studies
`showing response in refractory patients.22-26 In other phase
`II studies of gefitinib, activity has been seen in head and
`neck cancer, although results in renal and bladder cancer
`have been disappointing.27,28
`Given the high expression of EGFR in prostate cancer,
`the preclinical activity and responses in phase I, and the
`urgent need for new approaches for HRPC, a phase II trial
`of two doses of oral gefitinib was initiated by the National
`Cancer Institute of Canada-Clinical Trials Group.
`
`PATIENTS AND METHODS
`
`Patient Eligibility
`Patients with histologic or cytologic evidence of adenocarci-
`noma of the prostate, increasing PSA ⱖ 20 ng/mL, or increasing
`measurable disease while receiving androgen-ablative therapy
`were eligible. Androgen-ablative therapy was defined as surgical or
`medical castration, with testosterone level ⱕ 50 ng/mL. Patients
`were required to have discontinued peripheral antiandrogen ther-
`apy for ⱖ 4 weeks (ⱖ 6 weeks for bicalutamide) before study entry,
`but luteinizing hormone-releasing hormone agonist was contin-
`ued; if discontinued, it was restarted. Increasing PSA was defined
`as ⱖ 25% increase in reference value of PSA (absolute value of
`increase, ⱖ 5 ng/mL) a minimum of 1 week from the reference
`value and confirmed by a second increase in PSA at least 1 week
`later. To be considered measurable, a lesion must have measured
`at least 20 mm in one dimension with conventional techniques
`(physical examination, computed tomography, x-ray, or magnetic
`resonance imaging) or at least 10 mm with spiral computed to-
`mography according to Response Evaluation Criteria in Solid
`Tumors.29 An assessment of EGFR expression was not mandated
`initially but would have been performed if gefitinib demonstrated
`sufficient activity to proceed to the second stage of the study.
`The institutional review boards at all participating sites ap-
`proved the study protocol, and written informed consent was
`obtained before study. Other eligibility criteria included Eastern
`Cooperative Oncology Group performance status of 0 or 1, no
`prior chemotherapy, and no prior investigational agents. Radia-
`tion was permitted if ⱖ 4 weeks had elapsed since treatment, and
`corticosteroids were permitted provided that no increase in dose
`was planned or had occurred within 4 weeks before random-
`ization. Patients who required large amounts of narcotic ther-
`apy to control pain (eg, morphine equivalent dose of ⬎ 60
`mg/d) were excluded. If capable, patients must have been will-
`ing to complete quality-of-life assessments (Functional Assess-
`ment of Cancer Therapy Prostate Cancer Subscale [FACT-P])
`in either English or French.30
`Requirements for organ function were absolute granulocytes
`ⱖ 1.5 ⫻ 109/L, platelets ⱖ 100 ⫻ 109/L, serum creatinine and
`
`456
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Downloaded from jco.ascopubs.org on June 14, 2016. For personal use only. No other uses without permission.
`Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
`
`

`
`Gefitinib in HRPC
`
`bilirubin ⱕ 2 ⫻ upper normal limits, and AST and ALT ⱕ 2.5 ⫻
`upper normal limits (ⱕ 5 ⫻ upper normal limit if liver metastases
`were present). Patients were excluded if they had any prior malig-
`nancy within the last 5 years, were receiving ketoconazole, or had
`any other serious medical condition or illness that would not
`permit the patient to be managed according to the protocol.
`Study Design and Treatment
`This was a multi-institutional study conducted by the Na-
`tional Cancer Institute of Canada-Clinical Trials Group at six
`participating centers (Princess Margaret Hospital; Toronto-
`Sunnybrook Regional Cancer Centre; London Regional Cancer
`Centre; McGill-Jewish General Hospital; Vancouver Prostate
`Centre; and Tom Baker Cancer Centre, Calgary). AstraZeneca
`Pharamaceuticals supplied gefitinib and provided some financial
`support for this study. Patients were randomly assigned to either
`250 mg or 500 mg of gefitinib taken orally on a daily basis for a
`28-day cycle. Hematology was examined weekly for two cycles and
`then on days 1 and 15 of subsequent cycles. Biochemistry,
`including PSA, was evaluated on day 1 of each cycle. Imaging of
`measurable disease was repeated on day 1 of every second cycle.
`Toxicity was assessed continuously and graded using the Na-
`tional Cancer Institute Common Toxicity Criteria version 2.0.
`Patients completed the quality-of-life questionnaire (FACT-P)
`on day 1 of each cycle.
`Therapy was continued until treatment failure, unacceptable
`toxicity, intercurrent illness interfering with protocol treatment
`and/or assessment, patient request, or investigator discretion. Any
`patient who experienced grade 4 toxicity attributable to therapy
`was withdrawn from study. For patients with grade 3 toxicity or
`grade 2 renal or ocular toxicity, treatment was discontinued until
`toxicity resolved to ⱕ grade 1. All patients, regardless of whether
`they had initially received 250 mg or 500 mg per day, were then
`rechallenged at 250 mg per day. If toxicity returned, they were
`removed from the study.
`Response Assessment
`All patients who received any gefitinib were assessable for
`toxicity. All patients who received at least one cycle of therapy or
`had objective progression or treatment failure in cycle 1 were
`considered assessable for response. Treatment failure was defined
`as new or worsening disease symptoms requiring change in man-
`agement, a decrease in Eastern Cooperative Oncology Group per-
`formance status by two levels, new or objective progression in
`measurable disease, or a 25% increase over the baseline or nadir
`PSA value (whichever was lower), with an increase of at least 5
`ng/mL, that is confirmed by a second measurement (a modifica-
`tion to Bubley et al).31 PSA response was defined as a 50% decrease
`in PSA from baseline confirmed by a second PSA value ⱖ 4 weeks
`later. Objective measurable response was evaluated using Re-
`sponse Evaluation Criteria in Solid Tumors criteria. Stable disease
`was defined as not meeting the criteria for complete response,
`partial response, or progressive disease.
`Statistical Considerations
`The primary end point of this study was response as deter-
`mined by PSA and/or measurable disease (if present). A two-stage
`design based on both response and progression was used to allow
`for early closure if the drug was inactive.32 The first stage was
`designed to accrue 15 patients in each arm. If two or fewer patients
`responded and there were nine or more early failures (within two
`cycles), the arm would be closed, and the regimen would be
`considered inactive. If these criteria were not fulfilled, an addi-
`
`tional 15 patients would be accrued to that arm for a final set of 30
`assessable patients per arm.
`In addition to the planned analyses, an exploratory analysis
`was performed to determine doubling times of patient PSA levels
`before and during treatment with gefitinib. To be assessable for
`PSA doubling time, a minimum of three PSA levels (minimum of
`5 days to a maximum of 5 months) were required before entry
`onto study. PSA values before and on study were plotted, linear
`regression analysis was performed, and a best-fit curve was gener-
`ated for each graph before and during gefitinib. From the slope of
`the best fit curves, PSA doubling times were calculated using the
`following formula: doubling time ⫽ ln2/b. The percentage change
`in PSA doubling time on study was compared with PSA doubling
`time before study for each patient.
`
`RESULTS
`
`Patient Characteristics
`The first patient was randomized in July 2001. In No-
`vember 2001, after 40 patients had been enrolled, accrual
`was held pending assessment of response of the first cohort.
`When the criteria for closure were met at both dose levels,
`the study was then permanently closed. Five patients were
`not assessable; one patient was not treated, and four pa-
`tients were deemed ineligible (two patients had prior che-
`motherapy with estramustine, one patient had a decreasing
`PSA when starting treatment, and one patient first started a
`luteinizing hormone-releasing hormone agonist just before
`study entry). Table 1 lists the demographics and clinical
`characteristics of the 35 assessable patients.
`Seventeen and 18 assessable patients were randomly
`assigned to 250 mg and 500 mg of daily gefitinib, respec-
`tively. The median number of cycles administered was two
`(range, one to five cycles on 250 mg; and one to six cycles on
`500 mg). All patients receiving 250 mg and 72% of patients
`on 500 mg of gefitinib received ⱖ 90% of the planned dose.
`Two patients on 250 mg were taken off study because of
`toxicity (nausea and diarrhea; and fatigue and blurred vi-
`sion), and two patients on 500 mg required a dose reduction
`because of rash, stomatitis, and edema. The most com-
`mon toxicity was grade 1 to 2 diarrhea (65% on 250 mg
`and 56% on 500 mg), followed by fatigue (29% on 250
`mg and 33% on 500 mg). Table 2 lists the drug-related
`adverse events that occurred in more than 10% of pa-
`tients in either dose group.
`
`Response to Treatment
`In 35 assessable patients, there were no PSA responses
`seen; five patients had stable disease for 2 months or greater,
`23 had progression within two cycles, and seven did not
`have sufficient values performed to define a response. Of 21
`patients with measurable disease, there were no responses
`seen. In patients with nonprogression, the duration of dis-
`ease stability ranged from 2.5 to 16.8 months. Twenty-six
`patients (74%) had sufficient prestudy and on-study PSA
`
`www.jco.org
`
`457
`
`Downloaded from jco.ascopubs.org on June 14, 2016. For personal use only. No other uses without permission.
`Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
`
`

`
`Canil et al
`
`Table 1. Baseline Patient Characteristics
`
`Table 2. Drug-Related Adverse Events
`
`Gefitinib Dose (N ⫽ 35)
`
`250 mg/d
`(n ⫽ 17)
`
`500 mg/d
`(n ⫽ 18)
`
`Characteristic
`
`No. of
`Patients
`
`%
`
`No. of
`Patients
`
`%
`
`Age, years
`Median
`Range
`ECOG performance status
`0
`1
`Baseline PSA
`Median
`Range
`Prior therapy
`Adjuvant hormone
`therapy
`Hormones for metastatic
`disease
`Radiotherapy
`Other therapy
`Measurable disease
`Sites of disease
`PSA elevated only
`Bone
`Liver
`Lung
`Lymph nodes
`Locoregional
`No. of sites of disease
`No lesions
`1
`2
`3
`
`70
`56-83
`
`74
`60-86
`
`10
`7
`
`10
`
`15
`
`12
`1
`11
`
`0
`12
`0
`1
`10
`3
`
`0
`10
`4
`3
`
`58.8
`41.2
`
`93
`13-882
`
`58.8
`
`88.2
`
`70.6
`5.9
`64.7
`
`0
`70.6
`0
`5.9
`58.8
`17.7
`
`0
`58.8
`23.5
`17.7
`
`7
`11
`
`13
`
`8
`
`9
`1
`10
`
`1
`15
`1
`0
`12
`0
`
`1
`7
`9
`1
`
`38.9
`61.1
`
`129
`28-421
`
`72.2
`
`44.4
`
`50.0
`5.6
`55.6
`
`5.6
`83.3
`5.6
`0
`66.7
`0
`
`5.6
`38.9
`50.0
`5.6
`
`Abbreviations: ECOG, Eastern Cooperative Oncology Group; PSA,
`prostate-specific antigen.
`
`values to be eligible for an analysis of PSA doubling times.
`The median PSA doubling time was 71 days (range, 23 to
`315 days) before study entry and 68 days (range, 22 to 315
`days) while on study. Fifteen patients (58%) exhibited an
`increase in their PSA doubling time while on study, whereas
`11 patients (42%) exhibited a decrease (Fig 1). There were
`eight patients who exhibited a greater than 50% increase in
`PSA doubling time. There was no apparent difference be-
`tween patients receiving 250 mg or 500 mg of gefitinib.
`FACT-P quality-of-life questionnaires were completed
`by 33 patients at baseline (94.3%), and conclusions are
`limited because of small sample size. The compliance rates
`were 71% (25 of 35 evaluable patients) and 63% (17 of 27
`evaluable patients) at the beginning of cycles 2 and 3
`during treatment, and 32% (10 of 31 evaluable patients)
`at the first 4-week assessment after off treatment. Little
`difference was seen between arms. In most cases, patient
`scores decreased during treatment, indicating worsening
`of symptoms compared with baseline scores.
`
`Gefitinib Dose
`
`250 mg/d
`(n ⫽ 17)
`
`500 mg/d
`(n ⫽ 18)
`
`Range of
`CTC Grade
`
`No. of
`Patients %
`
`No. of
`Patients %
`
`1-3
`1-2
`1-2
`1-2
`1-2
`1-2
`2
`1
`1
`1-2
`1
`
`5
`4
`11
`5
`1
`1
`2
`2
`2
`4
`0
`
`29
`24
`65
`29
`6
`6
`12
`12
`12
`24
`0
`
`6
`3
`10
`3
`2
`4
`0
`0
`6
`7
`2
`
`33
`17
`56
`17
`11
`22
`0
`0
`33
`39
`11
`
`Toxicity
`
`Fatigue
`Anorexia
`Diarrhea
`Nausea
`Stomatitis
`Taste disturbance
`Vomiting
`Alopecia
`Dry skin
`Rash/desquamation
`Bruising
`
`NOTE. Adverse events were not observed at CTC grades higher than
`those presented. Only events that occurred in more than 10% of patients
`in either dose group are reported.
`Abbreviation: CTC, Common Toxicity Criteria.
`
`DISCUSSION
`
`Overexpression of EGFR in prostate cancer cells has led to
`development of novel therapeutic approaches targeting
`EGFR and its signal transduction cascade. Such approaches
`may include monoclonal antibodies directed against the
`extracellular ligand– binding domain of the receptor, anti-
`sense oligonucleotides directed against the expression of
`EGFR ligands or the receptor itself, low molecular weight
`inhibitors of the receptor tyrosine kinase activity, or low
`molecular weight compounds directed against the down-
`stream components of the signal transduction pathway
`such as ras.4 In addition to gefitinib, clinical investiga-
`tions are underway to assess the activity of cetuximab, a
`
`Fig 1. The effect of gefitinib on prostate-specific antigen (PSA) bdoubling
`times (n ⫽ 26).
`
`458
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Downloaded from jco.ascopubs.org on June 14, 2016. For personal use only. No other uses without permission.
`Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
`
`

`
`Gefitinib in HRPC
`
`monoclonal antibody against the external ligand-binding
`domain of EGFR, in patients with HRPC.
`Our study did not demonstrate any activity for gefitinib
`as a monotherapy in HRPC at either 250 mg or 500 mg daily
`using conventional response criteria. An analysis of PSA
`doubling time did not show any significant effects on the
`rate of increase in PSA at either dose level. Another study of
`gefitinib (500 mg/d) in a similar patient population was
`recently presented in abstract form and similarly showed
`minimal activity.33
`The results of this study were disappointing. It is im-
`probable that the negative results seen were a result of poor
`compliance with therapy because these men were highly
`motivated to take their medications, and the toxicity seen
`was that expected. The effects were comparable at both dose
`levels, and there is no evidence from any tumor type that a
`higher dose than what was used in this study has a greater
`benefit. We did not biopsy the tumors before study entry
`to phenotype the tumors. This is difficult to do in pa-
`tients with limited-volume advanced prostate cancer,
`
`and studies in other tumors where EGFR inhibitors have
`activity have not shown a clear correlation between
`EGFR expression and response.
`The EGF signaling pathway remains an attractive target
`for cancer therapy. We need to understand more about
`interactions with other cell growth and signaling pathways
`and how to define when EGFR is a critical component of
`cancer proliferation. It is clear that a single targeted ap-
`proach of inhibition of the EGFR pathway is inadequate to
`control tumor growth in HRPC, despite the frequent over-
`expression of EGFR that has been reported. Further assess-
`ment of EGFR inhibitors in prostate cancer need to focus on
`earlier stages of the disease or the use of EGFR inhibitors as
`a component of a multimodal strategy in combination with
`other targeted agents.
`
`■ ■ ■
`
`Authors’ Disclosures of Potential
`Conflicts of Interest
`The authors indicated no potential conflicts of interest.
`
`REFERENCES
`
`1. American Cancer Society: Prostate cancer
`statistics. http://www.cancer.org/docroot/home/
`index.asp
`2. National Cancer Institute of Canada: Cana-
`dian Cancer Statistics, 2003. Toronto, Canada,
`National Cancer Institute of Canada, 2003
`3. Tannock IF, Osoba D, Stockler MR, et al:
`Chemotherapy with mitoxantrone plus pred-
`nisone or prednisone alone for symptomatic
`hormone-refractory prostate cancer: A Canadian
`randomized trial with palliative endpoints. J Clin
`Oncol 14:1756-1764, 1996
`4. Barton J, Blackledge G, Wakeling A:
`Growth factors and their receptors: New targets
`for prostate cancer therapy. Urology 58:S115-
`S122, 2001
`5. McKeehan WL, Adams PS, Rosser MP:
`Direct mitogenic effects of insulin epidermal
`growth factor, glucocorticoid, cholera toxin, un-
`known pituitary factors and possibly prolactin but
`not androgen on normal rat prostate epithelial
`cells in serum free primary cell culture. Cancer
`Res 44:1998-2010, 1984
`6. Cerny T, Barnes DM, Hasleton P, et al:
`Expression of epidermal growth factor receptor
`(EGF-R) in human lung tumours. Br J Cancer
`54:265-269, 1986
`7. Bradley SJ, Garfinkle E, Walker R, et al:
`Increased expression of the epidermal growth
`factor receptor on human colon carcinoma cells.
`Arch Surg 121:1242-1247, 1986
`8. Mendelsohn J, Baselga J: Status of epi-
`dermal growth factor receptor antagonists in the
`biology and treatment of cancer. J Clin Oncol
`21:2787-2799, 2003
`9. Tillotson JK, Rose DP: Density-dependent
`regulation of epidermal growth factor receptor
`expression in DU 145 prostate cancer cells.
`Prostate 19:53-61, 1991
`10. Weichselbaum TT, Dunphy EJ, Beckett
`MA, et al: Epidermal growth factor receptor gene
`
`amplification and expression in head and neck
`cancer cell lines. Head Neck 11:437-442, 1989
`11. Brady LW, Miyamoto C, Woo DV, et al:
`Malignant astrocytomas treated with iodine-125
`labeled monoclonal antibody 425 against epider-
`mal growth factor receptor: A phase II trial. Int J
`Radiat Oncol Biol Phys 22:225-230, 1992
`12. Chan KC, Knox WF, Woodburn JR, et al:
`ZD1839 (Iressa), an epidermal growth factor
`receptor (EGFR) tyrosine kinase inhibitor, re-
`stricts proliferation in normal and preinvasive
`breast epithelia. Clin Cancer Res 5:3735S, 1999
`(abstr 27, suppl)
`13. Woodburn JR, Morris CQ, Kelly H, et al:
`EGF receptor tyrosine kinase inhibitors as anti-
`cancer agents: Preclinical and early clinical profile
`of ZD1839. Cell Mol Biol Lett 3:348-349, 1998
`14. Sirotnak FM, Zakowski MF, Miller VA, et
`al: Efficacy of cytotoxic agents against human
`tumour xenographs is markedly enhanced by
`co-administration of ZD1839 (Iressa), an inhibitor
`of EGF receptor tyrosine kinase. Clin Cancer Res
`6:4885-4892, 2000
`15. Sirotnak FM, She Y, Lee F, et al: Studies
`with CWR22 xenografts in nude mice suggest that
`ZD1839 may have a role in the treatment of both
`androgen-dependent and androgen-independent
`human prostate cancer. Clin Cancer Res 8:3870-
`3876, 2002
`16. Goss G, Stewart DJ, Hirte H, et al: Initial
`results of part 2 of a phase I/II pharmacokinetics
`(PK), pharmacodynamic (PD) and biological activ-
`ity study of ZD1839 (Iressa): NCIC-CTG IND. 122.
`Proc Am Soc Clin Oncol 21:16a, 2002 (abstr 59)
`17. Baselga J, Rischin D, Ranson M, et al:
`Phase I safety, pharmacokinetic, and pharmaco-
`dynamic trial of ZD1839, a selective oral epider-
`mal growth factor
`receptor
`tyrosine kinase
`inhibitor,
`in patients with five selected solid
`tumor types. J Clin Oncol 20:4292-4302, 2002
`18. Ranson M, Hammond LA, Ferry D, et al:
`ZD1839, a selective oral epidermal growth factor
`receptor-tyrosine kinase inhibitor, is well toler-
`
`ated and active in patients with solid, malignant
`tumors: Results of a phase I trial. J Clin Oncol
`20:2240-2250, 2002
`19. Nakagawa K, Tamura T, Negoro S, et al:
`Phase I pharmacokinetic trial of the selective oral
`epidermal growth factor receptor tyrosine kinase
`inhibitor gefitinib (Iressa, ZD1839) in Japanese
`patients with solid malignant tumors. Ann Oncol
`14:922-930, 2003
`20. Herbst RS, Maddox AM, Rothernberg ML,
`et al: Selective oral epidermal growth factor
`receptor tyrosine kinase inhibitor ZD1839 is gen-
`erally well-tolerated and has activity in non–
`small-cell
`lung cancer and other solid tumors:
`Results of a phase I trial. J Clin Oncol 20:3815-
`3825, 2002
`21. Lorusso PM: Phase I studies of ZD1839 in
`patients with common solid tumors. Semin On-
`col 30:21-29, 2003
`22. Fukuoka M, Yano S, Giaccone G, et al:
`Multi-institutional randomized phase II trial of
`gefitinib for previously treated patients with ad-
`vanced non–small-cell lung cancer. J Clin Oncol
`21:2237-2246, 2003
`23. Kris MG, Natale RB, Herbst RS, et al:
`Efficacy of gefitinib, an inhibitor of the epidermal
`growth factor receptor tyrosine kinase, in symp-
`tomatic patients with non-small cell lung cancer:
`A randomized trial. JAMA 290:2149-2158, 2003
`24. Giaccone G, Hohnson DH, Manegold C, et
`al: A phase III clinical trial of ZD1839 (Iressa) in
`combination with gemcitabine and cisplatin in
`chemotherapy-naive patients with advanced
`non-small cell lung cancer (INTACT-1). Ann Oncol
`13:S2, 2002 (suppl)
`25. Johnson DH, Herbst R, Giaccone G, et
`al: ZD1839 (Iressa) in combination with pacli-
`taxel and carboplatin in chemotherapy-naive
`patients with advanced non-small cell
`lung
`cancer (NSCLC): Initial results from a phase III
`trial
`(INTACT 2). Ann Oncol 13:S127, 2002
`(suppl)
`
`www.jco.org
`
`459
`
`Downloaded from jco.ascopubs.org on June 14, 2016. For personal use only. No other uses without permission.
`Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
`
`

`
`Canil et al
`
`26. Cohen MH, Williams GA, Sridhara R, et al:
`FDA drug approval summary: Gefitinib (ZD1839)
`(Iressa) tablets. Oncologist 8:303-306, 2003
`27. Drucker BJ, Bacik J, Ginsberg M, et al:
`Phase II trial of ZD1839 (IRESSA) in patients with
`advanced renal cell carcinoma.
`Invest New
`Drugs 21:341-345, 2003
`28. Petrylak D, Faulkner JR, Van Veldhuizen
`PJ, et al: Evaluation of ZD1839 for advanced
`transitional cell carcinoma (TCC) of the urothe-
`lium: A Southwest Oncology Group Trial. Proc
`Am Soc Clin Oncol 22:403, 2003 (abstr 1619)
`
`29. Therasse P, Arbuck SG, Eisenhauer EA, et
`al: New guidelines to evaluate the response to
`treatment in solid tumors (RECIST guidelines).
`J Natl Cancer Inst 92:205-216, 2000
`30. Esper P, Mo F, Chodak G, et al: Measuring
`quality of life in men with prostate cancer using
`the functional assessment of cancer therapy-
`prostate instrument. Urology 50:920-928, 1997
`31. Bubley GJ, Carducci M, Dahut W, et al:
`Eligibility and response guidelines for phase II
`clinical trials in androgen-independent prostate
`cancer: Recommendations from the Prostate-
`
`Specific Antigen Working Group. J Clin Oncol
`17:3461-3467, 1999
`32. Zee B, Melnychuk D, Dancey J, et al:
`Design of phase II clinical trials incorporating
`response and early progression. Control Clin
`Trials 12:S85, 1996 (abstr 80)
`33. Rosenthal M, Toner GC, Gurney H, et al:
`Inhibition of the epidermal growth factor recep-
`tor (EGFR) in hormone refractory prostate cancer
`(HRPC): Initial results of a phase II trial of ge-
`fitinib. Proc Am Soc Clin Oncol 21:416, 2003
`(abstr 1671)
`
`460
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Downloaded from jco.ascopubs.org on June 14, 2016. For personal use only. No other uses without permission.
`Copyright © 2005 American Society of Clinical Oncology. All rights reserved.