Phase III Study of Matrix Metalloproteinase Inhibitor Prinomastat in Non–Small-Cell Lung Cancer
http://www.100md.com
《临床肿瘤学》
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
Princess Margaret Hospital, Toronto, Ontario, Canada
ABSTRACT
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.
INTRODUCTION
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.
PATIENTS AND METHODS
Treatment and Treatment Modifications
Eligible patients were randomly assigned to receive either prinomastat 15 mg bid or placebo orally, which was started on day 1 of chemotherapy and continued until termination of treatment was judged by the investigator to be in the patient’s best interest. During chemotherapy, the study medication was continued regardless of chemotherapy toxicity, delays in chemotherapy, and response to chemotherapy. The study medication was discontinued for 3 to 4 weeks if patients experienced grade 2 musculoskeletal toxicity (moderate pain interfering with function but not activities of daily living) of at least 3 weeks in duration or grade 3 symptoms (severe pain interfering with activities of daily living) of at least 7 days in duration. After the treatment break, the study medication could be restarted if musculoskeletal toxicity resolved to grade 0 or 1 (none, or mild pain not interfering with function), with treatment allocation remaining blinded but reduction in the prinomastat dose to 5 mg bid. If further musculoskeletal toxicity occurred, a second treatment rest was given, and a second dose reduction to prinomastat 2.5 mg bid was allowed. These dose adjustments were supported by early clinical experience with prinomastat, including pharmacokinetic data with doses of 1 to 2 mg bid showing trough plasma levels predicted to inhibit MMP-2 and MMP-9.12 The study medication was continued after chemotherapy, with the option to take the drug after disease progression and in combination with subsequent therapy.
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 ≥ 1,500/μL, platelets were ≥ 100,000/μL, creatinine was ≤ 2.0 mg/dL, and neurotoxicity was grade 2 or less. The doses of chemotherapy were modified based on the maximum grade of toxicity experienced in the previous course. The doses of both gemcitabine and cisplatin were reduced by 25% if febrile neutropenia, grade 4 thrombocytopenia, or grade 3 nonhematologic toxicity occurred. The dose of day 8 gemcitabine was reduced by 25% if neutrophils were 500 to 999/μL or platelets were 50,000 to 99,000/μL, and day 8 gemcitabine was withheld if neutrophils were less than 500/μL or platelets were less than 50,000/μL. Chemotherapy was discontinued in patients who experienced progressive disease or unacceptable toxicity.
Baseline and Treatment Evaluations
Before entering the study, patients underwent a medical history and physical examination, tumor measurement of palpable lesions, chest radiograph, full blood count, serum chemistry, ECG, vital signs, and calculated creatinine clearance. Additional prestudy assessments included tumor measurement by computed tomography scan or magnetic resonance imaging. The same assessment methods used to determine disease status at baseline were used consistently for efficacy evaluations throughout the study.
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
The study was powered to detect a 40% improvement in survival (two-sided test, {alpha} = .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).
Statistical Analysis
Intent-to-treat analyses were performed on data from all patients who were randomized to the study and received treatment. Estimates of time-to-event end points were calculated using the Kaplan-Meier method and compared using the log-rank test, stratified by region. Disease response rates for the populations having measurable disease in the two treatment arms were compared using a Cochrane-Mantel-Haenszel test, stratified by region.
RESULTS
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.
DISCUSSION
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.
Appendix
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
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.
REFERENCES
1. Jemal A, Thomas A, Murray T, et al: Cancer statistics, 2002. CA Cancer J Clin 52:23-47, 2002
2. Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311:899-909, 1995
3. Cullen MH, Billingham LJ, Woodroffe CM, et al: Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: Effects on survival and quality of life. J Clin Oncol 17:3188-3194, 1999
4. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002
5. Nelson AR, Fingleton B, Rothenberg ML, et al: Matrix metalloproteinases: Biologic activity and clinical implications. J Clin Oncol 18:1135-1149, 2000
6. Scatena R: Prinomastat, a hydroxamate-based matrix metalloproteinase inhibitor: A novel pharmacological approach for tissue remodelling-related diseases. Expert Opin Investig Drugs 9:2159-2165, 2000
7. Shepherd FA, Giaccone G, Seymour L, et al: 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 Cancer. J Clin Oncol 20:4434-4439, 2002
8. Price A, Shi Q, Morris D, et al: Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340. Clin Cancer Res 5:845-854, 1999
9. Shalinsky DR, Brekken J, Zou H, et al: Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. Ann N Y Acad Sci 878:236-270, 1999
10. Shalinsky DR, Brekken J, Zou H, et al: Marked antiangiogenic and antitumor efficacy of AG3340 in chemoresistant human non-small cell lung cancer tumors: Single agent and combination chemotherapy studies. Clin Cancer Res 5:1905-1917, 1999
11. Bonomi P: Matrix metalloproteinases and matrix metalloproteinase inhibitors in lung cancer. Semin Oncol 29:78-86, 2002
12. Chambers AF, Matrisian LM: Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89:1260-1270, 1997
13. 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)
14. Pritchard SC, Nicolson MC, Lloret C, et al: Expression of matrix metalloproteinases 1, 2, 9 and their tissue inhibitors in stage II non-small cell lung cancer: Implications for MMP inhibition therapy. Oncol Rep 8:421-424, 2001
15. Thomas P, Khokha R, Shepherd FA, et al: Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer. J Pathol 190:150-156, 2000
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. Cox G, Jones JL, O’Byrne KJ: Matrix metalloproteinase 9 and the epidermal growth factor signal pathway in operable non-small cell lung cancer. Clin Cancer Res 6:2349-2355, 2000
18. 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)
19. Behrendt CE, Ruiz RB: Venous thromboembolism among patients with advanced lung cancer randomized to prinomastat or placebo, plus chemotherapy. Thromb Haemost 90:734-737, 2003
20. Bramhall SR, Schulz J, Nemunaitis J, et al: A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 87:161-167, 2002
21. Bramhall SR, Hallissey MT, Whiting J, et al: Marimastat as maintenance therapy for patients with advanced gastric cancer: A randomised trial. Br J Cancer 86:1864-1870, 2002
22. Miller KD, Gradishar W, Schuchter L, et al: A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer. Ann Oncol 13:1220-1224, 2002
23. Levitt NC, Eskens FA, O’Byrne KJ, et al: Phase I and pharmacological study of the oral matrix metalloproteinase inhibitor, MMI270 (CGS27023A), in patients with advanced solid cancer. Clin Cancer Res 7:1912-1922, 2001(Donald Bissett, Ken J. O’)
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
Princess Margaret Hospital, Toronto, Ontario, Canada
ABSTRACT
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.
INTRODUCTION
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.
PATIENTS AND METHODS
Treatment and Treatment Modifications
Eligible patients were randomly assigned to receive either prinomastat 15 mg bid or placebo orally, which was started on day 1 of chemotherapy and continued until termination of treatment was judged by the investigator to be in the patient’s best interest. During chemotherapy, the study medication was continued regardless of chemotherapy toxicity, delays in chemotherapy, and response to chemotherapy. The study medication was discontinued for 3 to 4 weeks if patients experienced grade 2 musculoskeletal toxicity (moderate pain interfering with function but not activities of daily living) of at least 3 weeks in duration or grade 3 symptoms (severe pain interfering with activities of daily living) of at least 7 days in duration. After the treatment break, the study medication could be restarted if musculoskeletal toxicity resolved to grade 0 or 1 (none, or mild pain not interfering with function), with treatment allocation remaining blinded but reduction in the prinomastat dose to 5 mg bid. If further musculoskeletal toxicity occurred, a second treatment rest was given, and a second dose reduction to prinomastat 2.5 mg bid was allowed. These dose adjustments were supported by early clinical experience with prinomastat, including pharmacokinetic data with doses of 1 to 2 mg bid showing trough plasma levels predicted to inhibit MMP-2 and MMP-9.12 The study medication was continued after chemotherapy, with the option to take the drug after disease progression and in combination with subsequent therapy.
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 ≥ 1,500/μL, platelets were ≥ 100,000/μL, creatinine was ≤ 2.0 mg/dL, and neurotoxicity was grade 2 or less. The doses of chemotherapy were modified based on the maximum grade of toxicity experienced in the previous course. The doses of both gemcitabine and cisplatin were reduced by 25% if febrile neutropenia, grade 4 thrombocytopenia, or grade 3 nonhematologic toxicity occurred. The dose of day 8 gemcitabine was reduced by 25% if neutrophils were 500 to 999/μL or platelets were 50,000 to 99,000/μL, and day 8 gemcitabine was withheld if neutrophils were less than 500/μL or platelets were less than 50,000/μL. Chemotherapy was discontinued in patients who experienced progressive disease or unacceptable toxicity.
Baseline and Treatment Evaluations
Before entering the study, patients underwent a medical history and physical examination, tumor measurement of palpable lesions, chest radiograph, full blood count, serum chemistry, ECG, vital signs, and calculated creatinine clearance. Additional prestudy assessments included tumor measurement by computed tomography scan or magnetic resonance imaging. The same assessment methods used to determine disease status at baseline were used consistently for efficacy evaluations throughout the study.
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
The study was powered to detect a 40% improvement in survival (two-sided test, {alpha} = .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).
Statistical Analysis
Intent-to-treat analyses were performed on data from all patients who were randomized to the study and received treatment. Estimates of time-to-event end points were calculated using the Kaplan-Meier method and compared using the log-rank test, stratified by region. Disease response rates for the populations having measurable disease in the two treatment arms were compared using a Cochrane-Mantel-Haenszel test, stratified by region.
RESULTS
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.
DISCUSSION
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.
Appendix
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
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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