Randomized Phase II Study of Two Doses of Gefitinib in Hormone-Refractory Prostate Cancer: A Trial of the National Cancer Institute of Canad
http://www.100md.com
《临床肿瘤学》
the Princess Margaret Hospital, University Health Network
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
National Cancer Institute of Canada-Clinical Trials Group, Kingston, Canada
ABSTRACT
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 chemotherapy 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.
INTRODUCTION
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 conformational changes within the receptor and increasing the activity of associated tyrosine kinases. This results in increased biologic activity, including cell proliferation and/or differentiation. Abnormal EGF receptor (EGFR) expression, either mutation or overexpression, has been demonstrated 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 controlled 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 inhibitors 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 clinical 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 studies of gefitinib16-21 The maximum-tolerated dose was determined 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 patients, particularly in non–small-cell lung cancer and head and neck cancer, with some activity reported against prostate 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 investigation.21 The US Food and Drug Administration has approved gefitinib (ZD1893) as monotherapy treatment for patients with locally advanced or metastatic non–small-cell lung cancer after failure of both platinum-based and docetaxel 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
The institutional review boards at all participating sites approved 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. Radiation was permitted if ≥ 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 randomization. Patients who required large amounts of narcotic therapy to control pain (eg, morphine equivalent dose of > 60 mg/d) were excluded. If capable, patients must have been willing to complete quality-of-life assessments (Functional Assessment of Cancer Therapy Prostate Cancer Subscale [FACT-P]) in either English or French.30
Requirements for organ function were absolute granulocytes ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, serum creatinine and bilirubin ≤ 2 x upper normal limits, and AST and ALT ≤ 2.5 x upper normal limits (≤ 5 x upper normal limit if liver metastases were present). Patients were excluded if they had any prior malignancy 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 National 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 National 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 ≤ 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 management, a decrease in Eastern Cooperative Oncology Group performance 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 modification to Bubley et al).31 PSA response was defined as a 50% decrease in PSA from baseline confirmed by a second PSA value ≥ 4 weeks later. Objective measurable response was evaluated using Response 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 determined 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 additional 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 generated 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
Seventeen and 18 assessable patients were randomly assigned to 250 mg and 500 mg of daily gefitinib, respectively. 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 ≥ 90% of the planned dose. Two patients on 250 mg were taken off study because of toxicity (nausea and diarrhea; and fatigue and blurred vision), and two patients on 500 mg required a dose reduction because of rash, stomatitis, and edema. The most common 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 patients 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 disease stability ranged from 2.5 to 16.8 months. Twenty-six patients (74%) had sufficient prestudy and on-study PSA 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 between 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.
DISCUSSION
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 improbable 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 patients 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 approach of inhibition of the EGFR pathway is inadequate to control tumor growth in HRPC, despite the frequent overexpression of EGFR that has been reported. Further assessment 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
NOTES
Supported by AstraZeneca Pharmaceuticals 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 conflicts of interest are found at the end of this article.
REFERENCES
1. American Cancer Society: Prostate cancer statistics. http://www.cancer.org/docroot/home/index.asp
2. National Cancer Institute of Canada: Canadian Cancer Statistics, 2003. Toronto, Canada, National Cancer Institute of Canada, 2003
3. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone 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, unknown 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 epidermal 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 epidermal 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, restricts 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 activity 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 pharmacodynamic trial of ZD1839, a selective oral epidermal 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 tolerated 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 generally 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 Oncol 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 advanced 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 symptomatic 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 paclitaxel 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)
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 urothelium: 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 receptor (EGFR) in hormone refractory prostate cancer (HRPC): Initial results of a phase II trial of gefitinib. Proc Am Soc Clin Oncol 21:416, 2003 (abstr 1671)(C.M. Canil, M.J. Moore, E)
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
National Cancer Institute of Canada-Clinical Trials Group, Kingston, Canada
ABSTRACT
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 chemotherapy 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.
INTRODUCTION
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 conformational changes within the receptor and increasing the activity of associated tyrosine kinases. This results in increased biologic activity, including cell proliferation and/or differentiation. Abnormal EGF receptor (EGFR) expression, either mutation or overexpression, has been demonstrated 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 controlled 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 inhibitors 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 clinical 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 studies of gefitinib16-21 The maximum-tolerated dose was determined 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 patients, particularly in non–small-cell lung cancer and head and neck cancer, with some activity reported against prostate 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 investigation.21 The US Food and Drug Administration has approved gefitinib (ZD1893) as monotherapy treatment for patients with locally advanced or metastatic non–small-cell lung cancer after failure of both platinum-based and docetaxel 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
The institutional review boards at all participating sites approved 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. Radiation was permitted if ≥ 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 randomization. Patients who required large amounts of narcotic therapy to control pain (eg, morphine equivalent dose of > 60 mg/d) were excluded. If capable, patients must have been willing to complete quality-of-life assessments (Functional Assessment of Cancer Therapy Prostate Cancer Subscale [FACT-P]) in either English or French.30
Requirements for organ function were absolute granulocytes ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, serum creatinine and bilirubin ≤ 2 x upper normal limits, and AST and ALT ≤ 2.5 x upper normal limits (≤ 5 x upper normal limit if liver metastases were present). Patients were excluded if they had any prior malignancy 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 National 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 National 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 ≤ 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 management, a decrease in Eastern Cooperative Oncology Group performance 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 modification to Bubley et al).31 PSA response was defined as a 50% decrease in PSA from baseline confirmed by a second PSA value ≥ 4 weeks later. Objective measurable response was evaluated using Response 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 determined 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 additional 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 generated 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
Seventeen and 18 assessable patients were randomly assigned to 250 mg and 500 mg of daily gefitinib, respectively. 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 ≥ 90% of the planned dose. Two patients on 250 mg were taken off study because of toxicity (nausea and diarrhea; and fatigue and blurred vision), and two patients on 500 mg required a dose reduction because of rash, stomatitis, and edema. The most common 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 patients 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 disease stability ranged from 2.5 to 16.8 months. Twenty-six patients (74%) had sufficient prestudy and on-study PSA 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 between 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.
DISCUSSION
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 improbable 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 patients 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 approach of inhibition of the EGFR pathway is inadequate to control tumor growth in HRPC, despite the frequent overexpression of EGFR that has been reported. Further assessment 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
NOTES
Supported by AstraZeneca Pharmaceuticals 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 conflicts of interest are found at the end of this article.
REFERENCES
1. American Cancer Society: Prostate cancer statistics. http://www.cancer.org/docroot/home/index.asp
2. National Cancer Institute of Canada: Canadian Cancer Statistics, 2003. Toronto, Canada, National Cancer Institute of Canada, 2003
3. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone 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
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