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© 2002 American Society for Clinical Oncology Prospective, Randomized, Double-Blind, Placebo-Controlled Trial of Marimastat After Response to First-Line Chemotherapy in Patients With Small-Cell Lung Cancer: A Trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of CancerByFrom the National Cancer Institute of Canada-Clinical Trials Group; the Princess Margaret Hospital and the University of Toronto, Toronto, Ontario Canada; and the European Organization for Research and Treatment of Cancer, Brussels, Belgium. Address reprint requests to Frances A. Shepherd, MD, Princess Margaret Hospital, 610 University Ave, 5-104, Toronto, Ontario, M5G 2M9, Canada; email: frances.shepherd{at}uhn.on.ca
PURPOSE: Increased expression of metalloproteinases is associated with poor prognosis in small-cell lung cancer (SCLC). This trial was undertaken to determine whether adjuvant treatment with the metalloproteinase inhibitor marimastat could prolong survival in responding patients with SCLC after chemotherapy. PATIENTS AND METHODS: SCLC patients in complete or partial remission were eligible. They were stratified by radiotherapy (early, late, or none), stage (extensive or limited), response (complete or partial), and cooperative group (National Cancer Institute of Canada-Clinical Trials Group or European Organization for Research and Treatment of Cancer). They were randomized to receive marimastat 10 mg or placebo orally bid for up to 2 years. RESULTS: There were 532 eligible patients (266 marimastat and 266 placebo). Stage was limited for 279 patients (52%) and extensive for 253 (48%). Best response to induction therapy was complete remission for 176 patients (33%), partial remission for 341 (64%), and 15 patients (3%) had undergone surgical resection. The median time to progression for marimastat patients was 4.3 months compared with 4.4 months for placebo patients (P = .81). Median survivals for marimastat and placebo patients were 9.3 months and 9.7 months, respectively (P = .90) Toxicity was generally limited to musculoskeletal symptoms (18% grade 3/4 for marimastat). Dose modifications for musculoskeletal toxicity were required in 90 patients (33%) on the marimastat arm, and 87 (32%) permanently stopped marimastat because of toxicity. Patients on marimastat had significantly poorer quality of life at 3 and 6 months. CONCLUSION: Treatment with marimastat after induction therapy for SCLC did not result in improved survival and had a negative impact on quality of life.
LUNG CANCER IS the most common cause of cancer-related mortality in both men and women in North America, and collectively accounts for more deaths than breast, colon, and prostate cancers combined.1,2 Approximately 25% of lung cancers are small-cell lung cancer (SCLC).3,4 Combination chemotherapy is the mainstay of treatment for SCLC, with radiation reserved mainly for patients with limited-stage disease.5-7 Although overall response rates to chemotherapy are 80% to 90% for patients of all stages,5,6 most patients relapse after discontinuing treatment, and cure remains an elusive goal. The matrix metalloproteinases (MMPs) are a family of secreted proteins that are capable of digesting extracellular matrix and basement membrane components under physiologic and pathologic conditions.8 To date, almost 30 MMPs have been identified, and traditionally, they have been categorized based on their substrate specificity. However, these distinctions are somewhat arbitrary as substrates for individual enzymes are still a matter of debate, and many of the MMPs have overlapping specificities. MMP expression is frequently detected in tumors in both the malignant and surrounding stromal cells.9,10 The number of MMPs and the relative level of individual MMPs that can be detected in a tumor tends to increase with increasing tumor stage.9,10 MMPs have been found to be elevated in both non-SCLC and SCLC.11-16 In SCLC, high-level expression in tumor cells has been reported for several MMPs.2,3,7,9,11,14 Elevated MMP expression has also been identified as an independent negative predictor of survival in SCLC.16 Preclinical studies in animal models of malignancy showed that MMP inhibitors (MMPI) could restrict the growth and regional spread of solid tumors.17,18 Marimastat, a synthetic inhibitor of MMPs was the first of the second-generation MMPIs that demonstrated sufficient absorption after oral administration to justify clinical trials. Based on the spectrum of MMP expression in SCLC and the preclinical models suggesting that MMPIs could inhibit growth of solid tumors, we initiated our study of adjuvant marimastat after first-line therapy. We felt that SCLC offered a unique opportunity to evaluate the ability of a tumoristatic agent to inhibit tumor cell invasion and metastasis because a high proportion of patients respond to chemotherapy, yet most relapse shortly after discontinuing treatment, and the median survival, even for limited-stage patients, is less than 2 years. We report here the results of our National Cancer Institute of Canada-Clinical Trials Group (NCIC-CTG) and European Organization for Research and Treatment of Cancer (EORTC) study.
Patients 18 years of age or older were eligible if they had histologic or cytologic proof of SCLC. They must have received at least four cycles of first-line combination chemotherapy and must have achieved complete or partial remission. The choice of chemotherapy regimen and the decision to use radiation as part of the induction regimen were left to the discretion of the investigator. Determination of response was according to individual institutional standards.
Patients had to have an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, life expectancy
Within 14 days before randomization, all patients underwent a complete history and physical examination, routine hematology and biochemistry, chest radiograph, toxicity evaluation, and a quality-of-life assessment. All x-rays performed before initiation of induction therapy that had been abnormal had to be repeated within 21 days before randomization. An increase in liver or bone enzyme values of
Treatment Patients were randomized to receive marimastat 10 mg orally bid or matched placebo one capsule orally bid with breakfast and the evening meal. Placebo or marimistat (blinded) was dispensed every 3 months in kits that contained a 3-month supply (168 capsules). Capsules were packaged in blister packs that contained 56 capsules per pack.
For patients experiencing Patients in both arms were observed every 6 weeks for 6 months after randomization and then every 3 months until 2 years. Investigations at these visits included history and physical examination, routine hematology and biochemistry, and a chest radiograph. Scans or other investigations were undertaken as clinically indicated. Patients were to continue treatment until disease progression, unacceptable toxicity, or a maximum of 2 years. Treatment was double-blinded and patients were to be unblinded only if knowledge of the investigational agent was essential for the management of toxicity.
Quality of Life
Statistical Considerations The study was designed initially to have 80% chance of detecting a 50% improvement in median survival from 12 to 18 months (hazard ratio [HR], 1.50) using a two-sided 5% level test. It was estimated that 240 patients would be accrued in 1 year. Therefore, 360 patients were required to observe a total of 197 events after 1.5 years accrual and 0.7 years additional follow-up. Recognizing that the survival difference of 6 months may have been an unrealistic goal, the protocol was amended on December 15, 1998 to increase the sample size to 540 patients to observe 388 events during 2.4 years of accrual and 0.8 months follow-up. This gave the study 80% power to detect a 33% improvement in survival from 12 months to 16 months (HR, 1.33) using a 2-sided 5% level test.
The primary study end point was overall survival. Secondary end points included progression-free survival, quality of life, and toxicity. The database for this analysis was locked January 15, 2001. Both survival time and time to progression were measured from the date of randomization. Time to progression was defined as the time from randomization to the time of relapse or progression. Patients who died of disease or complications of treatment were considered to have had events in the progression-free analysis. Deaths due to causes unrelated to disease or treatment and those who were free of progression at the time of analysis were considered censored. Survival was defined as the time from randomization to the time of death from any cause or censored at last follow-up if patients were alive or lost to follow-up at the time of analysis. A log-rank test was used to compare time-to-event end points. A Cox proportional hazards model was used to assess prognostic factors. The treatment effect was assessed after controlling for important prognostic variables in the Cox model.19 Toxicities between the arms were compared using Pearson’s
Patient Characteristics The study opened in the NCIC-CTG in January, 1997, and in the EORTC in May, 1997. Accrual was suspended for administrative reasons in the EORTC in December, 1999, and accrual of 555 patients was completed by the NCIC-CTG on April 30, 2000. Twenty-three patients were considered ineligible because of less than partial response (n = 6), incomplete baseline investigations (n = 6), non–small-cell or mixed histology (n = 5), and other reasons (n = 6). The baseline characteristics for the 532 eligible patients (266 patients in each arm) are listed in Table 1. There were 405 patients from the NCIC-CTG and 127 from EORTC centers. Fifty-five percent of patients were male; 88% had a performance status of 0 or 1; 52% had limited-stage disease, and 33% had achieved complete remission.
Survival All eligible randomized patients were included in intent-to-treat analyses, irrespective of whether they received protocol therapy. At the time of analysis, there were 207 progressions on the marimastat arm and 211 on the placebo arm. Progression-free survival for marimastat patients was 4.3 months compared with 4.4 months for patients on placebo (P = .81; HR = 0.977; 95% confidence interval, 0.807 to 1.184). With 194 deaths and 197 deaths, respectively, median survival for patients on marimastat was 9.3 months compared with 9.7 months for placebo patients (P = .90; HR = 1.013; 95% confidence interval, 0.831 to 1.235). Progression-free and overall survivals are demonstrated graphically in Figs 1 and 2. An exploratory analysis did not detect a significant difference in survival in limited-disease patients.
For the intent-to-treat population, the following variables were found significant at the 0.1 level: sex, performance status, response to induction chemotherapy, degree of response to induction chemotherapy, early thoracic radiation, and disease extent. The interactions between treatment and these covariates were tested by including these significant variables and interaction terms into a new Cox model. None of the interaction terms was found significant at the 0.1 level. Therefore, the final Cox model was fitted with all the variables that had been found significant from the initial model and a treatment variable (Table 2). From this final Cox model, the following variables were significant prognostic factors at the 0.05 level: sex (HR of female to male = 0.69, P = .003), performance status (HR for higher performance status = 1.32, P = .001), response to initial induction chemotherapy (HR for partial response to complete response = 3.6, P = .012), and disease extent at diagnosis (HR for extensive to limited stage = 2.17, P = .0001). The effect of treatment with marimistat was not significant after controlling the significant covariates (HR = 1.03, P = .78).
Toxicity All patients who received protocol therapy were included in the safety analyses (n = 551). Toxicity is summarized in Table 3. There was no significant hematologic toxicity other than a single reversible grade 4 thrombocytopenia in a patient receiving marimastat. Apart from musculoskeletal syndromes, other grade 3 or 4 toxicities were infrequent and equal in both study arms. Dose modifications for musculoskeletal toxicity were required more frequently in the marimastat arm (33% v 9%, P  .001). More patients stopped protocol therapy because of toxicity in the marimastat arm (32% v 7%, P .001). Other toxicities that were seen more frequently with marimastat included lethargy, anorexia, and nausea and vomiting. One patient died with massive liver necrosis 8 days after starting marimastat. Although he was receiving concomitant ketoconazole, in the absence of hepatic tumor or identifiable sepsis, fatal liver toxicity from marimastat could not be excluded. Toxicity resulted in significantly poorer compliance and drug delivery in the marimastat arm (Table 4).
Quality of Life Mean change scores from baseline measured at months 3 and 6 are shown in Table 5. Compliance was excellent in both arms of the trial, with 85% or more forms completed at each time period. The absolute number of questionnaires collected decreased over time because patients either progressed or died, and thus were not expected to have quality of life assessed. At 3 months, pain scores were significantly worse for patients in the marimastat arm, as were overall social and emotional domains. At 6 months, pain scores remained significantly worse as did fatigue and the global quality-of-life score.
In the 1970s, several studies showed that malignant tumors contained proteolytic activity capable of degrading collagen in vitro.20,21 Specific enzymes responsible for this activity were identified, and early work focused on the family of collagenases.22,23 Since then, almost 30 MMPs have been identified. Once they are over-expressed and activated, MMPs break down the extracellular matrix, thus enabling the primary tumor to expand locally.8-10 They also break down basement membranes, allowing entrance to proximal blood vessels and spread to distant sites where tumor cell invasion again requires MMP action. Expression of MMP by tumors and the surrounding stroma has been studied extensively. The emerging pattern of MMP expression is complicated, with many MMPs showing expression in a variety of tumor types including in lung cancer.11-15 Furthermore, most authors have shown that MMP expression increases as tumors become less well differentiated and in tumors that have metastasized to regional lymph nodes or to distant sites.11-15 There have been few studies of MMPs in SCLC. In a Japanese study of 15 patients with SCLC,15 high-level expression was noted in tumor cells for MMP-2 (42%) and MMP-7 (13%). MMP-9, MMP-11, and MMP-14 have also been detected in SCLC tissues by other investigators.24,25 In none of these studies was there any attempt to correlate MMP expression with clinical outcome. The largest study of MMP expression in SCLC is our own study reported by Michael et al.16 Using immunohistochemical techniques, we studied of a broad range of MMPs in tissue samples from 46 patients with SCLC. Positive staining was seen for MMP-1 and MMP-9 in 60% to 70% of tumor cells, and for MMP-11, MMP-13, and MMP-14 in 70% to 100% of specimens. After accounting for the most important clinical variables of stage and weight loss, increased expression of MMP-14 (P = .019) and MMP-11 (P = .031) were independent predictors of survival, and MMP-3 was of borderline significance (P = .077). Marimastat is the first MMPI to be studied in randomized clinical trials in SCLC. It is a broad spectrum MMPI with activity against collagenases, gelatinases, and stromelysins17,18 and demonstrates sufficient absorption from the gastrointestinal tract to reach the 50% inhibitory concentration levels necessary to inhibit these enzymes. Using animal cancer models, marimastat was shown to inhibit both tumor growth and metastasis.17 Despite strong evidence implicating MMPs in cancer growth, invasion, and metastasis, and the encouraging preclinical activity of marimastat seen in animal models, our study of adjuvant therapy in patients with SCLC was negative. Progression-free and overall survival were not prolonged by the addition of marimastat to chemotherapy and radiotherapy, and our exploratory analyses of patients with limited disease and those in complete clinical remission failed to suggest a benefit from treatment. Furthermore, treatment with marimastat was accompanied by significant musculoskeletal toxicity that resulted in discontinuation of therapy in almost 20% of patients and had a significant negative impact on several quality-of-life parameters. Marimastat has been evaluated in other malignancies. In a randomized placebo-controlled study in advanced gastric cancer, an updated analysis showed that both progression-free survival and overall survival were significantly better for patients treated with marimastat compared with the placebo group.26 Musculoskeletal toxicities predominated, but only 10% of patients discontinued therapy for this toxicity compared with 19% in our study. Studies in other tumor types, including malignant brain tumors27 and pancreatic cancer,28 have not demonstrated a survival advantage for treatment with marimastat. In a pancreatic cancer trial that compared gemcitabine chemotherapy to treatment with one of three doses of marimastat,28 there was a suggestion that treatment with marimastat at the highest dose level of 25 mg twice daily might be equivalent to treatment with gemcitabine. This observation led to a subsequent study in pancreatic cancer in which all patients received gemcitabine and randomization was to marimastat or placebo. No survival advantage was observed for the marimastat group in this second trial. (P. Brown, personal communication, September 2001). Another MMPI, BAY12-9566, has also been evaluated in SCLC in a study that was similar in design to that of our trial. At the first interim analysis when 264 of the planned 750 patients had been randomized, survival was found to be shorter in the BAY12-9566 group compared with the placebo group and so the study was closed (P.A. Cyrus, personal communication, January 2001). BAY12-9566 was also compared in a randomized trial with single-agent gemcitabine in patients with advanced pancreatic cancer.29 At the interim analysis, treatment with BAY12-9566 was found to be associated with significantly shorter survival than treatment with gemcitabine (3.2 months v 6.4 months, respectively, P = .0001). The study was closed, and further evaluation and development of the compound was halted. Prinomastat (AG3340) is a more targeted MMPI with activity mainly against MMP-2 and MMP-9. It has not been evaluated in SCLC, but two large trials of chemotherapy with or without prinomastat have been performed in non-SCLC30,31 and one in prostate cancer.32 Neither lung cancer trial showed a survival advantage when prinomastat was added to paclitaxel and carboplatin or gemcitabine and cisplatin chemotherapy,30,31 and the prostate cancer study was also negative.32 With the exception of one study of marimastat in advanced gastric cancer, the randomized trials of MMPI therapy, including our own, have all been negative. It has been suggested that MMPIs are not likely to contribute significantly to the treatment of advanced cancer and that they might be expected to have their greatest effect in the adjuvant setting where they might have the potential to prevent metastasis. Against this theory is the absence of any trend toward improvement in time to progression or survival in our exploratory analysis of patients with limited disease in complete remission. Furthermore, the toxicity of the second generation MMPIs prevents the long-term administration that would be necessary for adjuvant treatment. More than 50% of our patients required dose modifications, and one third discontinued treatment as a result of toxicity. In a pilot trial of adjuvant marimastat in patients with breast cancer, Miller et al33 also reported frequent dose interruptions and re-ductions that resulted in trough plasma levels that were often below the level required for biologic activity. We did not measure marimastat levels in our study, but it is likely that we would have identified similar fluctuations in trough levels had we done so. Third and fourth generation MMPIs, such as BMS-275291, that do not appear to be associated with dose-limiting musculoskeletal effects34 may overcome this problem. Finally, it is possible that our thinking about the metalloprotein enzyme system and its relation to cancer treatment has been somewhat naïve. Control of the extracellular matrix is clearly very complex, with almost 30 enzymes identified to date. As suggested by the results of virtually all of the trials of MMPIs, it is unlikely that inhibition of only a small number of the enzymes will have a significant impact on tumor growth and spread, particularly in the advanced disease setting. To date, however, the results of the studies in advanced cancer do not provide sufficient justification for the evaluation of MMPIs in earlier stages of disease.
APPENDIX
National Cancer Institute of Canada-Clinical Trials Group
European Organization for Research and Treatment of Cancer The appendix listing institutions and investigators who contributed patients to this study is available online at www.jco.org.
This trial was supported in part by a grant to the National Cancer Institute of Canada-Clinical Trials Group from British Biotech Pharmaceuticals Ltd, Oxford, United Kingdom, and in part by grant nos. 5U10 CA11488-27, 2U10 CA11488-28, and 5U10 CA11488-29 from the National Cancer Institute, Bethesda, MD, to the European Organization for Research and Treatment of Cancer.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
1. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics 2000. CA Cancer J Clin 50: 7-33, 2000[Abstract] 2. National Cancer Institute of Canada: Canadian Cancer Statistics. Toronto Canada, Canadian Cancer Society, 2000, pp 11–15 3. Travis WD, Linder J, Mackay B: Classification, histology, cytology and electron microscopy, in Pass HI, Mitchell JB, Johnston DH, et al (eds): Lung Cancer, Principles and Practice ( ed 2 ). Philadelphia PA, Lippincott Williams & Wilkins, 2000, pp 453-495 4. Feld R, Sagman U, LeBlanc M: Staging and prognostic factors for small cell lung cancer, in Pass HI, Mitchell JB, Johnston DH, et al (eds): Lung Cancer, Principles and Practice ( ed 2 ). Philadelphia PA, Lippincott Williams & Wilkins, 2000, pp 612-627 5. Carney DN, Shepherd FA: Treatment of small cell lung cancer: Chemotherapy, in Hansen HH (ed): The International Association for the Study of Lung Cancer Textbook of Lung Cancer. London United Kingdom, Martin Dunitz Publishers, 2000, pp 261-272 6. Shepherd FA: The role of chemotherapy in the treatment of small cell lung cancer. Chest Surg Clinics of North America 7: 113-133, 1997 7. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small cell lung cancer. N Engl J Med 327: 1618-1624, 1992[Abstract] 8. Ennis BW, Matrisian LM: Matrix degrading metalloproteinases. J Neuro-Oncol 18: 105-109, 1994[CrossRef][Medline]
9. Chambers AF, Matrisian LM: Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89: 1260-1270, 1997 10. Khokha R, Denhardt DT: Matrix metalloproteinases and tissue inhibitor of metalloproteinases: A review of their role in tumorigenesis and tissue invasion. Invasion Metastasis 9: 391-405, 1989[Medline] 11. Kodate M, Kasai T, Ghashimoto H, et al: Expression of matrix metalloproteinase (gelatinase) in T1 adenocarcinoma of the lung. Pathol International 47: 461-469, 1997 12. Thomas P, Liu N, Khokha R, et al: Expression of matrix metalloproteinases and their tissue inhibitors in non-small cell lung cancer. J Pathol 190: 150-156, 2000[CrossRef][Medline]
13. Karameris A, Panagou P, Tsilalis T, et al: Association of expression of metalloproteinases and their inhibitors with the metastatic potential of squamous-cell lung carcinomas: A molecular and immunohistochemical study. Am J Resp Crit Care Med 156: 1930-1936, 1997 14. Gonzalez-Avila G, Iturria C, Vadillo F, et al: 72-kD (MMP2) and 92 kD (MMP9) type IV collagenase production and activity in different histologic types of lung cancer cells. Pathobiol 66: 5-16, 1998 15. Kawano N, Osawa H, Ito T, et al: Expression of gelatinase A, tissue inhibitor of metalloproteinase-2, matrilysin and trypsinogen in lung neoplasms: An immunohistochemical study. Hum Pathol 28: 613-622, 1997[CrossRef][Medline]
16. Michael M, Babic B, Khokha R, et al: Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer. J Clin Oncol 17: 1802-1808, 1999
17. Brown PD, Giavazzi R: Matrix metalloproteinase inhibition: A review of anti-tumour activity. Ann Oncol 6: 967-974, 1995 18. Brown PD: Matrix metalloproteinase inhibitors: A novel class of anti-cancer agents. Advan Enzyme Regul 35: 293-301, 1995[CrossRef][Medline] 19. Cox DR: Regression models and life table (with discussion). J Royal Stat Soc B 74: 187-220, 1972 20. Liotta LA, Kleinerman J, Catanzaro P, et al: Degradation of basement membrane by murine tumor cells. J Natl Cancer Inst 58: 1427-1431, 1997 21. Liotta LA, Tryggvason K, Garbisa S, et al: Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 287: 67-68, 1980 22. Salo T, Liotta LA, Keski-Oja J, et al: Secretion of basement membrane collagen degrading enzyme and plasminogen activation by transformed cells: Role in metastasis. Int J Cancer 30: 669-673, 1982[Medline] 23. Brunner N, Pyke C, Hansen CH, et al: Urokinase plasminogen activator (uPA) and its type 1 inhibitor (pa1-1): Regulators of proteolysis during cancer invasion and prognostic parameters in breast cancer. Cancer Treat Res 71: 299-309, 1994[Medline] 24. Urbanski SJ, Edwards JR, Maitland A, et al: Expression of metalloproteinases and their inhibitors in primary pulmonary carcinoma. Br J Cancer 66: 1188-1194, 1992[Medline] 25. Tokuraku M, Sato H, Murakami S, et al: Activation of precursor of gelatinase A/72 kDa type IV collagenase/MMP 2 in lung carcinomas correlates with the expression of membrane-type matrix metalloproteinase [MT-MMP] and with lymph node metastasis. Int J Cancer 64: 355-359, 1995[Medline] 26. Fielding J, Scholefield J, Stuart R, et al: A randomized double-blind placebo-controlled study of marimastat in patients with inoperable gastric adenocarcinoma. Proc Am Soc Clin Oncol 19: 240a, 2000 (abstr 929) 27. Phuphanich S, Levin V, Yung W, et al: A multicenter, randomized, double-blind, placebo-controlled (PB) trial of marimastat (MT) in patients with glioblastoma multiforme or gliosarcoma following completion of conventional first-line treatment. Proc Am Soc Clin Oncol 20: 52a, 2001 (abstr 205)
28. Bramhall S, Rosemurgy A, Brown PD, et al: Marimastat as first-line therapy for patients with unresectable pancreatic cancer: A randomized trial. J Clin Oncol 19: 3447-3455, 2001 29. Moore M, Hamm J, Eisenberg P, et al: A comparison between gemcitabine (GEM) and the matrix metalloproteinase (MMP) inhibitor BAY12-9566 in patients with advanced pancreatic cancer. Proc Am Soc Clin Oncol 19: 240a, 2000 (abstr 930) 30. Smylie M, Mercier R, Aboulafia D, et al: Phase III study of the matrix metalloprotease (MMP) inhibitor prinomastat in patients having advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 20: 307a, 2001 (abstr 1226) 31. Bissett D, O’Byrne K, von Pawel J, et al: Phase III study of the matrix metalloproteinase inhibitor prinomastat in combination with gemcitabine and cisplatin in non-small cell lung cancer. Proc Am Soc Clin Oncol 21: 296a, 2002 (abstr 1183) 32. Ahmann F, Saad F, Mercier R, et al: Interim results of a phase III study of the matrix metalloproteinase inhibitor prinomastat in patients having metastatic hormone refractory prostate cancer. Proc Am Soc Clin Oncol 20: 174a, 2001 (abstr 692) 33. Miller KD, Gradishar WJ, Schuchter LM, et al: A randomized phase II pilot trial of adjuvant marimastat in patients with early breast cancer. Proc Am Soc Clin Oncol 19: 96a, 2000 (abstr 369) 34. Douillard J, Petersen V, Shepherd F, et al: Randomized phase II study of BMS-275291 versus placebo in patients with stage IIIB or IV non-small cell lung cancer receiving paclitaxel + carboplatin. National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Eur J Cancer 37: S19, 2001 (suppl 6, abstr 63) Submitted February 21, 2002; accepted July 22, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
12 weeks, and adequate hematology and biochemistry. They were ineligible if they had had brain metastases or a history of breast cancer, melanoma, or hypernephroma at any time, or other malignancy within the preceding 5 years, if they had active peptic ulceration, or if they were receiving coumarin anticoagulants. Patients with grade 3 or 4 musculoskeletal disorders were also excluded. The protocol was approved by an ethics review board at each institution, and all patients provided written informed consent. 
2 test with Yates’ continuity correction or Fisher’s exact test. Two interim analyses were planned after 96 and 256 events, respectively, to allow for early stopping in the event of extreme results. Significance levels were based on the O’Brien and Flemming type error spending function to maintain the overall significance level at 5%. 
