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Journal of Clinical Oncology, Vol 23, No 4 (February 1), 2005: pp. 842-849 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.170 Phase III Study of Matrix Metalloproteinase Inhibitor Prinomastat in Non–Small-Cell Lung CancerFrom the Aberdeen Royal Infirmary, Aberdeen; Leicester Royal Infirmary, Leicester; University of Edinburgh, Edinburgh, United Kingdom; Asklepios Fachkliniken, München-Gauting; Krankenhaus Grosshansdorf, Grosshansdorf, Germany; Marshfield Clinic, Marshfield, WI; Pfizer Global Research and Development, La Jolla, CA; and Princess Margaret Hospital, Toronto, Ontario, Canada Address reprint requests to Donald Bissett, MD, Department of Clinical Oncology, Clinic D, Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, United Kingdom; e-mail: d.bissett{at}arh.grampian.scot.nhs.uk
PURPOSE: Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non–small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. PATIENTS AND METHODS: Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. RESULTS: Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients. CONCLUSION: Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC.
Non–small-cell lung cancer (NSCLC) remains the most common cause of cancer-related mortality in both Europe and North America.1 Approximately 30% to 40% of patients present with stage IIIB or IV advanced disease, and the prognosis remains poor for these patients despite advances in chemotherapy and radiation therapy. Platinum-based chemotherapy affords a modest survival benefit compared with best supportive care.2 Older cisplatin-based combinations containing agents such as mitomycin, etoposide, and ifosfamide resulted in 1-year survival rates of 25%.3 These have now been replaced by third-generation platinum doublet combinations with either gemcitabine, vinorelbine, irinotecan, or a taxane, which have resulted in 1-year survival rates in excess of 30% in good performance status patients.4 The matrix metalloproteinases (MMPs) are key enzymes in the remodeling of the extracellular matrix and are known to participate in both the growth and the spread of cancers.5 Prinomastat, a novel MMP inhibitor (MMPI) of selected MMPs, was designed on the basis of the x-ray crystal structure of recombinant human MMPs. The relative selectivity of this MMPI for gelatinase A, stromelysin-1, and collagenase-36 suggested that it would inhibit tumor growth, invasion, metastasis, and angiogenesis through inhibition of these MMPs. It was also expected that much of the toxicity associated with less selective MMP inhibitors would not be seen with prinomastat.7 Preclinical studies of prinomastat have demonstrated reduction in the rate of primary tumor growth and in the number and size of distant metastases in animal tumor models.8 Furthermore, when prinomastat was administered in combination with a variety of cytotoxic chemotherapeutic agents in these models, antitumor effects were enhanced without an increase in chemotherapy-related toxicity.9,10 Early clinical trials with prinomastat identified a safety profile suitable for phase II and III studies, although in the phase I trials, dose- and time-dependent musculoskeletal complaints were observed. These typically consisted of arthralgia, stiffness, joint swelling, and limited range of movements, most often affecting the shoulders and hands.11,12 Doses less than 25 mg twice daily were chosen for study in phase III trials. Given the experimental results that indicate that MMPs play a central role in the growth and spread of lung cancer11 and the preclinical evidence of antitumor activity of prinomastat, we initiated an international, multicenter, randomized, double-blind, placebo-controlled, phase III trial to assess the benefit, if any, of prinomastat in patients with advanced NSCLC treated with gemcitabine and cisplatin. The primary end point of the trial was overall survival, and the secondary end points were progression-free survival, response rate, duration of response, 1-year survival, and the safety profile of prinomastat in combination with gemcitabine and cisplatin.
Patient Selection Patients were required to have histologic or cytologic proof of stage IIIB or IV or recurrent NSCLC. Patients could have measurable or assessable disease but could not have received prior chemotherapy for NSCLC. Prior radiotherapy was allowed, but patients had to be at least 2 weeks from completion of radiotherapy and at least 3 weeks from any surgery. The study was limited to patients with good performance status (WHO performance status of 0 to 1), a life expectancy of 12 weeks or greater, and adequate organ function defined as an absolute neutrophil count  1,500/µL, platelets 100,000/µL, creatinine  1.5 mg/dL, bilirubin 1.5 x institutional upper normal limit, and AST 2.5 x institutional upper normal limit. Patients were ineligible if they had brain metastases or a history of prior malignancy, other than basal cell carcinoma or carcinoma-in-situ of the cervix. All patients were required to give written informed consent. The study was conducted with the approval of the appropriate ethical review boards and according to guidelines for good clinical practice. The recommendations of the Declaration of Helsinki for biomedical research involving human subjects were also followed.
Treatment and Treatment Modifications
All patients received gemcitabine 1,250 mg/m2 days 1 and 8 and cisplatin 75 mg/m2 (with appropriate hydration and antiemetics) day 1 of a 21-day cycle. In subsequent cycles, day 1 chemotherapy was delayed until neutrophils were
Baseline and Treatment Evaluations Before each chemotherapy cycle, patients underwent toxicity assessment (using National Cancer Institute Common Toxicity Criteria), physical examination, chest radiography, CBC, and blood chemistry. Before every other cycle, patients underwent radiologic imaging studies to assess disease status. Objective tumor response was evaluated by WHO criteria and required confirmatory imaging a minimum of 4 weeks after the initial response. After completion of chemotherapy, all patients were reviewed at a minimum of 6-week intervals until disease progression. Responding patients had repeat radiologic imaging every other cycle (every 6 weeks) to allow measurement of the duration of response, which was measured from the date the response was first documented to the date of disease progression.
Study Design and Sample Size
Statistical Analysis
Patient Characteristics Between April 1999 and July 2001, a total of 362 patients were randomized from 75 institutions; 181 were assigned to prinomastat, and 181 were assigned to placebo. One patient with stage IIIA disease was randomized in error. Nine patients did not receive treatment on study because of intervening events. The baseline characteristics for all patients are listed in Table 1. Patient demographics and disease characteristics were well balanced between the two arms. Recruitment ceased before the planned interim analysis after release of data from a parallel study.13
Response and Time-to-Event Measures Tumor response data are listed in Table 2. Ninety percent of patients had measurable disease. There was no difference in the overall response rate between prinomastat and placebo patients (27% v 26%, respectively; P = .81). The overall tumor response rate for patients with locoregional disease was 47% for prinomastat patients and 33% for placebo patients (P = .08); and for patients with metastatic disease, the overall tumor response rate was 17% for prinomastat patients and 22% for placebo patients (P = .33). Efficacy outcomes for time-to-event measures are listed in Table 3. Median follow-up times for prinomastat and placebo for these measures were 9.3 and 9.5 months, respectively. There were no differences in overall survival, progression-free survival, or 1-year survival between the two treatment arms. Figure 1 shows Kaplan-Meier curves by treatment arms for overall survival. The median overall survival times were 11.5 and 10.8 months (P = .82), and 1-year survival rates were 43% and 38% (P = .45) for prinomastat and placebo patients, respectively. At the time of analysis, 228 patients (108 prinomastat and 120 placebo patients) had died, giving censoring rates for survival of 40% for prinomastat and 34% for placebo. Figure 2 shows the Kaplan-Meier curves for progression-free survival by treatment arm. The median progression-free survival times were 6.1 and 5.5 months for prinomastat and placebo (P = .11), respectively. At the time of analysis, 306 patients (143 prinomastat and 163 placebo patients) had experienced progression, giving censoring rates for progression of 21% for prinomastat and 10% for placebo.
Subgroup analyses of progression-free and overall survival times were conducted, comparing the two treatment arms according to stage, sex, and pathology. No specific group demonstrated significant improvement in outcome with prinomastat (data not shown). Figure 3 shows the Kaplan-Meier curves for overall survival for patients with only locoregional disease and with metastatic disease according to treatment.
Treatment Administration and Toxicity All patients who received protocol therapy were included in the analysis of toxicity (n = 353). The number of chemotherapy cycles received was similar; the median number of prinomastat cycles was four (range, one to 12 cycles), and the median number of placebo cycles was four (range, one to 11 cycles). A total of 140 patients (71 prinomastat and 69 placebo patients) completed six cycles of chemotherapy treatment. Grade 3 or higher toxicities, including hematologic changes, nausea and vomiting, and neuropathy, are listed in Table 4. Grade 3 or 4 toxicities were infrequent and similar in both arms. Chemotherapy dose reductions were required in 10 patients receiving prinomastat and in eight patients receiving placebo.
Musculoskeletal complaints attributed to study tablets are listed in Table 5. These led to study drug interruption more frequently in the prinomastat arm than in the placebo arm (37% v 12%, respectively; P = .001), although the duration of study drug exposure was similar in the two arms.
Chemotherapy After Study Treatment At the time of progression, implementation of alternative chemotherapy regimens was permitted with continued administration of prinomastat or placebo. Regimens subsequent to gemcitabine and cisplatin were administered to 45 prinomastat patients and 61 placebo patients.
The family of MMPs is now recognized to comprise more than 20 enzymes.5 The physiologic activity of these enzymes is balanced by local production of tissue inhibitors of metalloproteinases. Overexpression of MMPs has been demonstrated in a number of malignancies and their surrounding stroma. These enzymes are responsible for the degradation of the extracellular matrix and basement membrane, thus allowing local growth and invasion of the primary cancer. This also provides tumor access to blood vessels and lymphatics to facilitate spread to distant organs, where MMPs are required for migration out of the vascular space to establish metastases. Recent evidence suggests that these enzymes are also involved in angiogenesis.12 Expression of MMPs has been demonstrated in NSCLC14,15 and small-cell lung cancer,16 and there seems to be an association between MMP expression and advancing stage of disease, in particular expression gelatinase A.17 Prinomastat is a potent inhibitor of gelatinase A (MMP-2), stromelysin-1 (MMP-3), and collagenase-3 (MMP-13) at concentrations that are achievable in plasma in patients taking 15 mg bid orally. Furthermore, in preclinical models, the combination of prinomastat with several chemotherapeutic agents was shown to result in additive effects. Despite this supporting evidence, our trial of prinomastat plus chemotherapy in advanced NSCLC was negative. Neither overall survival nor progression-free survival was prolonged by the addition of prinomastat to gemcitabine and cisplatin chemotherapy. A parallel study of similar design found no benefit when prinomastat was administered in addition to paclitaxel and carboplatin in patients with advanced NSCLC.13 Another trial of this MMPI was conducted in men receiving mitoxantrone chemotherapy for hormone-refractory metastatic prostate cancer, and this trial was also negative.18 In each of these studies, treatment with prinomastat was associated with musculoskeletal toxicity in a significant proportion of patients. In addition, review of the pooled data from the NSCLC trials has shown that prinomastat increases the risk of venous thromboembolic disease in patients receiving combination chemotherapy for NSCLC.19 Marimastat, a nonselective MMPI, has also been tested in a number of malignancies, including lung, breast, gastric, and pancreatic cancers, and in all but one trial in advanced gastric cancer, the results were negative.7,20-22 Musculoskeletal toxicity was a significant problem in all studies and led to abandonment of an adjuvant trial in breast cancer.22 In the National Cancer Institute of Canada trial of marimastat in small-cell lung cancer patients, musculoskeletal toxicity had a significant negative impact on quality of life when measured at 3 and 6 months.7 Another selective MMPI, BAY 12-9566, has been evaluated in several disease settings, but after disappointing results in studies of small-cell lung cancer and pancreatic cancer, its development has been suspended. Although it was ambitious to expect a 40% improvement in overall survival through the addition of prinomastat to gemcitabine and cisplatin chemotherapy, the negative results of our study are entirely in keeping with the lack of clinical benefit observed in other MMPI trials to date. It has been suggested that these disappointing results may be a result of the advanced stage of the disease in which MMPIs have been tested, where metastatic disease is already established. Against this hypothesis, however, are the observations from the National Cancer Institute of Canada trial that showed no benefit from the adjuvant administration of marimastat, even in limited-stage small-cell lung cancer patients who had achieved complete remission.7 A further possible reason why MMPIs are unsuccessful in the therapeutic arena is the observation in a recent phase I study that MMPI treatment results in significant dose-response increases in MMP-2 and tissue inhibitors of metalloproteinase-1.23 It may have been naive to expect that inhibition of only a few members of such a complex system could have resulted in a major clinical benefit. Our study produced better than expected survival results for the control arm, with a 1-year survival rate of 38% in advanced NSCLC. This can be attributed to both the good performance status of the patients and inclusion of a group of patients with T4 tumors, some of which were suitable for radical radiotherapy after chemotherapy. To determine whether prinomastat might have benefit for these patients who had only locoregional disease, data for patients with T4 tumors from this study and the parallel paclitaxel carboplatin study were combined and analyzed. However, prinomastat failed to produce significant improvement in overall survival or progression-free survival even in this more favorable subgroup. The future of MMPIs in cancer therapy is currently unclear. It is hoped that the development of novel assays of MMP activity might allow smaller proof of principle studies using surrogate end points to define the tumor types and patient subgroups who are most likely to derive benefit from this approach. It remains uncertain whether selective rather than broad-spectrum inhibition of MMPs will be successful.
The following investigators participated in the study: David Aboulafia, MD, Virginia Mason Medical Center, Seattle, WA; Andrea Ardizzoni, MD, Instituto Nazionale per la Ricerca sul Cancro, Oncologica Medica 1, Genova, Italy; David Bell, MD, Royal North Shore Hospital, St Leonards, New South Wales, Australia; Joaquin Belon, MD, Complejo Hospitario, Granada, Spain; Donald Bissett, MD, Aberdeen Royal Infirmary, Aberdeen, United Kingdom; Jacob Bitran, MD, Lutheran General Hospital, Park Ridge, IL; Peter Boasberg, MD, John Wayne Cancer Institute, Santa Monica, CA; Philip Bonomi, MD, Rush Presbyterian Medical Center, Chicago, IL; Leon Bosquee, MD, Centre Hospitalier Regional La Citadelle, Liege, Belgium; Joseph Bozzino, MD, Newcastle General Hospital, Newcastle-on-Tyne, United Kingdom; Jean-Luc Breau, MD, Hopital Avicenne, Bobigny, France ; Ronald Burkes, MD, Mount Sinai Hospital, Toronto, Ontario, Canada; Philipe Chahanian, MD, Mount Sinai Medical Center, New York, NY; Victor Chang, MD, East Orange Veterans Affairs Medical Center, East Orange, NY; Ram Chillar, MD, King/Drew Medical Center, Los Angeles, CA; Stephen Clarke, MD, Concard Repatriation General Hospital, Concord, New South Wales, Australia; John Cole, MD, Ochsner Clinic, New Orleans, LA; Yvon Cormier, MD, Hopital Laval, Ste Foy, Quebec, Canada; Arkadiusz Dudeg, MD, University of Minnesota, Minneapolis, MN; David Dunlop, MD, St Mungo Institute, Royal Infirmary, Glasgow, United Kingdom; Paul Ellis, MD, St Thomas Hospital, London, United Kingdom; John Fiore, MD, Stony Brook University Hospital, Stony Brook, NY; Ulrich Gatzemeier, MD, Krankenhaus Grosshansdorf, Grosshansdorf, Germany; Jack Goldberg, MD, Cooper Cancer Institute, Vorhees, NJ; Michael Green, MD, Royal Melbourne Hospital, Parkville, Victoria, Australia; Richard Gregg, Kingston Regional Cancer Center, Kingston, Ontario, Canada; John Hamm, MD, Norton Health Care, Louisville, KY; John Hudson, MD, Augusta Oncology Associates, Augusta, GA; David Irwin, MD, Alta Bates Comprehensive Cancer Center, Berkeley, CA; David Jablons, MD, Mount Zion Medical Center, University of California, San Francisco, CA; Allison Jones, MD, Royal Free Hospital, London, United Kingdom; Daniel Karp, MD, Beth Israel Deaconess Medical Center, Boston, MA; Kaye Kawahara, MD, Queens Medical Center, Honolulu, HI; Ali Khojasteh, MD, Capitol Comprehensive Cancer Clinic, Jefferson City, MO; Michael Kosty, MD, Green Cancer Center at Scripps Clinic, La Jolla, CA; Jean Latreille, MD, Hopital Charles LeMoyne, Green Field Park, Quebec, Canada; William Lawler, MD, Virginia K. Crosson Cancer Center, Fullerton, CA; Craig Lewis, MD, Oncology Day Centre, Rindwick, New South Wales, Australia; Mark Lewis, MD, Memorial Regional Cancer Center, Hollywood, FL; Jose Lizon, MD, Hospital Universitario, San Juan de Alicante, San Juan Alicante, Spain; John Loscalzo, MD, North Shore University Hospital, Manhasset, NY; Christian Manegold, MD, Thorax Clinic, Heidelberg, Germany; Janine Mansi, MD, St Georges Hospital, London, United Kingdom; Bartolome Massutti, MD, Hospital General de Alicante, Alicante, Spain; Richard Mercier, MD, Marshfield Medical Research Foundation, Marshfield, WI; Robert Milroy, MD, Stobhill National Health Service Trust, Glasgow, United Kingdom; Paul Mitchell, MD, Repatriation Campus, West Heidelberg, Victoria, Australia; Frank Mott, MD, Scott & White Memorial Hospital and Clinic, Temple, TX; Mary O’Brien, MD, Royal Marsden National Health Service Trust, Surrey, United Kingdom; Kenneth O’Byrne, MD, Leicester Royal Infirmary, Leicester, United Kingdom; Antti Ojala, MD, Tampereen Yliopistossa Raala, Pikonlinna, Irmeli Uotila, Pikonlanna, Finland; Ravi Patel, Comprehensive Blood and Cancer Center, Bakersfield, CA; Allan Price, MD, University of Edinburgh, Edinburgh, United Kingdom; Michel Poudenx, MD, Centre Antoine Lacassagne, Nice, France; Edna Rapp, MD, Tom Baker Cancer Centre, Calgary, Alberta, Canada; Danny Rischin, MD, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia; Eira Ritanen, MD, Kuopio University Hospital, Kuopio, Finland; Daniel Oscar Rodenstein, MD, Cliniques Universitaire St Luc, Bruxelles, Belgium; Larry Schlabach, MD, University Oncology & Hematology Associates, Chattanooga, TN; Lloyd Shabazz, MD, Cancer Treatment Centers of America, Portsmouth, VA; Frances Shepherd, MD, Princess Margaret Hospital, Toronto, Ontario, Canada; Ray Snyder, MD, St Vincent’s Hospital, Fitzroy, Victoria, Australia; Nick Thatcher, MD, Christie Hospital and Holt Radium Institute, Manchester, United Kingdom; Robert Tucker, MD, Wake Forest University School of Medicine, Winston-Salem, NC; Patrice Viens, MD, Institut Paoli Calmettes, Marseille, France; Nuria Vinolas, MD, Hospital Clinic I Provincial, Barcelona, Spain; J. Von Pawel, MD, Asklepios Fachlinik Gauting, Gaunting, Germany; Israel Wiznitzer, MD, Midwest Cancer Research Group, Inc, Northfield, IL; Penella Woll, MD, Clinical Research Center Academic Unit, Nottingham City Hospital, Nottingham, United Kingdom; Albert Wood, MD, Corpus Christi Cancer Center, Corpus Christi, TX; Paul Wooley, MD, University of Pittsburgh Medical Centre, Lee Regional Medical Center, Johnstown, PA; Furhan Yunus, MD, The Boston Cancer Group, Memphis, TN; and Gerand Zalcman, MD, Institute Curie, Paris, France.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Min H. Zhang, Pfizer; Mary A. Collier, Pfizer. Consultant/Advisory Role: Frances A. Shepherd, Eli Lilly; Ulrich Gatzemeier, AstraZeneca, Eli Lilly, Roche. Stock Ownership: Frances A. Shepherd, Eli Lilly; Min H. Zhang, Pfizer. Honoraria: Marianne Nicolson, Lilly Oncology; Frances A. Shepherd, Eli Lilly; Ulrich Gatzemeier, AstraZeneca, Eli Lilly, Pierre Fabre; Elva Mazabel, Pfizer. Research Funding: Frances A. Shepherd, Eli Lilly; Ulrich Gatzemeier, CTJ, Merck. Expert Testimony: Frances A. Shepherd, Eli Lilly. Other Remuneration: Marianne Nicolson, Lilly Oncology. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
Supported by a project grant from Pfizer Pharmaceuticals. Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= .048, power = 80%). Assuming the median survival in the control arm to be 9 months, accrual to the study to complete within 12 months, and follow-up to continue until 12 months after recruitment of the last patient, the sample size was 420 patients. The expected number of deaths to be included in the final analysis was approximately 281. An interim analysis of efficacy was to be performed when 140 deaths occurred. Randomization was performed centrally and was stratified by geographic region (North America v Europe and Australia). 
