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Clinical Cancer Research Vol. 11, 3417-3424, May 1, 2005
© 2005 American Association for Cancer Research

Cancer Therapy: Clinical

Phase I Trial of the Matrix Metalloproteinase Inhibitor Marimastat Combined with Carboplatin and Paclitaxel in Patients with Advanced Non–Small Cell Lung Cancer

John R. Goffin1,2, Ian C. Anderson1,4, Jeffrey G. Supko3, Joseph Paul Eder, Jr.1, Geoffrey I. Shapiro1, Thomas J. Lynch3, Margaret Shipp1, Bruce E. Johnson1 and Arthur T. Skarin1

Authors' Affiliations: 1 Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; 2 Tufts-New England Medical Center; and 3 Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts and 4 Redwood Regional Medical Group, Santa Rosa, California

Requests for reprints: Arthur T. Skarin, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Dana 1234, Boston, MA 02115. Phone: 617-632-3468; Fax: 617-632-4379; E-mail: Arthur_Skarin{at}dfci.harvard.edu.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: Marimastat is an orally bioavailable inhibitor of matrix metalloproteinases. A phase I study was initiated to determine whether conventional doses of carboplatin and paclitaxel are tolerated when combined with marimastat and to assess the influence of marimastat on paclitaxel pharmacokinetics.

Experimental Design: Three dose levels were evaluated. Marimastat (10 or 20 mg oral administration b.i.d.) was administered continuously with paclitaxel (175 or 200 mg/m2 as a 3-hour i.v. infusion) and carboplatin (at a dose providing an area under the free drug plasma concentration-time curve of 7 mg min/mL) administered each 3 weeks. Toxicity and response were evaluated throughout the intended four cycles of combined therapy. The plasma pharmacokinetics of paclitaxel was determined in each patient both without concurrent marimastat and after receiving marimastat for 1 week.

Results: Twenty-two chemotherapy-naive patients with stage IIIb (27%) or stage IV (73%) non–small cell lung cancer were enrolled. Their median age was 56 years (range, 39-73 years), 50% were female, and their performance status (Eastern Cooperative Oncology Group) ranged from 0 to 2. Treatment was well tolerated, as 18 (82%) of the patients completed all four cycles of chemotherapy without dose-limiting toxicity. Grade 2 musculoskeletal toxicities were reported in 3 of 12 patients receiving marimastat (20 mg b.i.d.). Nine patients required dose reductions, predominantly related to low-grade myelosuppression. Partial responses occurred in 12 of 21 (57%) evaluable patients with disease stabilization in another 5 (19%). Marimastat had no effect on paclitaxel pharmacokinetics.

Conclusions: The administration of marimastat (10 mg b.i.d.) with paclitaxel (200 mg/m2) and carboplatin at an area under the free drug plasma concentration-time curve of 7 mg min/mL was well tolerated with no apparent pharmacokinetic interaction. Study of this drug combination in the adjuvant setting should be considered if tissue inhibition of matrix metalloproteinase activity can first be shown.

Key Words: Chemotherapy • Clinical Trials • Human • Pharmacokinetics

Non–small cell lung cancer (NSCLC) comprises 86% of lung cancers (1) and 65% of newly diagnosed patients present with advanced disease (2). Metastatic disease is incurable with currently available therapy and the median survival ranges from only 8 to 10 months with the use of conventional chemotherapy. In the United States, first-line treatment typically includes combination chemotherapy with carboplatin and paclitaxel, for which response rates ranging from 20% to 30% have been reported in phase III trials (3–5). Clearly, improvements in therapy are greatly needed.

Tumor growth and metastasis is a multistep process involving the breakdown of tissue stroma, the migration of cells through the extracellular matrix into the systemic or lymphatic circulation, the extravasation of these cells with the establishment of new sites of disease, and the development of new vasculature (6). Interrupting any step in this process could, in theory, arrest or delay disease progression. Matrix metalloproteinases (MMP) are a family of nearly 30 zinc-dependent proteinases that predominantly serve to degrade the extracellular matrix, including the basement membrane, thereby facilitating the migration and metastasis of malignant cells and vascular genesis (7–9). They have been considered as attractive targets for therapeutic interventions (6). Although normally present at low levels, MMP expression is notably elevated in malignancy and in tissues undergoing remodeling (10). MMP expression is induced by growth factors, including endothelial growth factor (11), and cytokines, such as transforming growth factor ß-1 (12). In addition, malignant cells may release an extracellular MMP inducer or other factors that stimulate neighboring stromal cells to secrete MMPs (13, 14). Increased expression of MMPs has been observed in NSCLC (15) and has been shown to negatively influence prognosis (16–18).

Marimastat is a broad-spectrum MMP inhibitor with good oral bioavailability (8). Based on the results of an initial study in healthy volunteers (19), a phase I clinical trial of marimastat was undertaken to evaluate a continuous twice-daily administration schedule in patients with NSCLC or small cell lung carcinoma (20). The toxicity profile was dominated by a progressive inflammatory polyarthritis that typically began around 3 weeks from the initiation of treatment and no objective response to the treatment was observed. A dose of 50 mg b.i.d. was recommended for subsequent single-agent clinical trials, although it seemed that lower doses maintained sufficiently high plasma concentrations of the drug for adequate enzyme inhibition with less toxicity. A phase III trial involving 505 patients with stage III NSCLC randomized to receive either marimastat (10 mg oral administration b.i.d.) or placebo failed to show a significant difference in progression-free survival (median, 198 versus 210 days) or overall survival (median, 527 versus 528 days; hazard ratio for survival, 1.04; 95% confidence interval, 0.83-1.28) between the two groups (21). Another MMP inhibitor, BAY12-9566, also failed to improve survival when used as a single agent in the maintenance setting in patients with advanced NSCLC (22).

The present study was motivated by the apparent failure of single-agent marimastat therapy. This report describes the results of a phase I clinical trial that was undertaken to assess its administration together with carboplatin and paclitaxel, administered according to a conventional dosing regimen, in patients with advanced NSCLC. Although treatment with paclitaxel at doses as high as 225 mg/m2 may be beneficial (23), a starting dose of 175 mg/m2 administered as a 3-hour i.v. infusion was chosen for this study based on known tolerability when combined with carboplatin. The dose of carboplatin was individualized to achieve a target area under the free drug plasma concentration-time curve (AUCfc) of 7 mg min/mL (24). Delivering higher doses of carboplatin would have required a significant reduction in the paclitaxel dose, which was considered to be undesirable (25, 26). Carboplatin and paclitaxel were administered together every 3 weeks for up to four cycles, as there is evidence to suggest that more prolonged therapy is not advantageous (27, 28). A combined analysis of six clinical trials determined that twice-daily dosing of oral marimastat led to better control of tumor blood antigens than did once-daily dosing (29). Although the antigen effect did not differ significantly between the higher doses of 25 or 50 mg and the lower dose of 10 mg, musculoskeletal toxicity was greater at the higher doses. Another study in patients with pancreatic cancer determined that doses of up to 25 mg b.i.d. were tolerable over prolonged periods (30). To balance efficacy and toxicity, 10 mg oral administration b.i.d. of marimastat was used as the starting dose in the present trial. The study was designed to determine whether the pharmacokinetic behavior of paclitaxel is affected by the concurrent continuous administration of marimastat.


   Patients and Methods
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 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patient selection. Adults ages ≥18 and <75 years with histologically proven NSCLC were eligible if they had incurable stage IIIb or IV disease and had not previously received any approved or investigational anticancer drugs. Minimum eligibility requirements included the following: Eastern Cooperative Oncology Group performance status, ≤2; life expectancy, ≥3 months; absolute neutrophil count, ≥1,500/µL; platelet count, ≥100,000/µL; hemoglobin, ≥100 mg/mL; serum creatinine, ≤1.5 mg/dL; total bilirubin, ≤1.5 mg/dL; and serum transaminases, ≤2 times the upper limit of normal. The time from prior radiotherapy and entry into the study had to be at least 4 weeks. Patients were excluded for the following reasons: pregnant or lactating; central nervous system metastases; history of a total gastrectomy or ileocolectomy; active inflammatory bowel disease, ileus, or other malabsorption syndromes; significant pulmonary, cardiac, hepatic, or bone marrow disease requiring medical treatment; and a history of another malignancy within 5 years, with the exception of curatively treated nonmelanoma skin cancer or carcinoma in situ of the uterine cervix.

Treatment plan and evaluations. The study protocol was approved by the Institutional Scientific Review Committee and Human Protection Committee of Dana-Farber/Partners Cancer Care (Boston, MA). A signed written informed consent document satisfying all federal and institutional requirements was obtained as a condition of patient registration. Patients underwent a history, physical examination, an electrocardiogram, a complete blood count with differential counts, coagulation tests (prothrombin time and partial thromboplastin time), a serum chemistry profile, and urinalysis within 14 days and a chest X-ray within 28 days of initiating therapy.

Paclitaxel and carboplatin were acquired from commercial sources as the standard i.v. formulations. Marimastat was provided by British Biotech Pharmaceuticals Ltd. (Oxford, United Kingdom) as soft gelatin capsules containing 10 mg marimastat in medium-chain triglyceride oil packaged in light-proof containers. As summarized in Table 1, marimastat was administered orally b.i.d., approximately every 12 hours, with food starting at a dose of 10 mg for dose levels 1 and 2 and 20 mg for dose level 3. It was administered continuously over a period of 12 weeks, with the exception of a 2- or 5-week interval without dosing to permit characterization of paclitaxel pharmacokinetics in its absence. Paclitaxel was administered as a 3-hour i.v. infusion at an initial dose of 175 mg/m2, which was increased to 200 mg/m2 in the two successive dose levels. On completing the paclitaxel infusion, carboplatin was infused over 1 to 2 hours at a dose providing a target AUCfc of 7 mg min/mL (24). Treatment with paclitaxel and carboplatin was repeated every 3 weeks for a maximum of four cycles. Patients were allowed to continue receiving marimastat beyond the planned four cycles of combined therapy in the absence of disease progression; similarly, two additional cycles of carboplatin and paclitaxel chemotherapy were permitted.


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  		Table 1. Doses, administration schedules, and pharmacokinetic sampling

 
Three patients were to be enrolled into the first dose level. Escalation of the paclitaxel dose to 200 mg/m2 proceeded if the first three patients completed all four cycles of therapy without any evidence of dose-limiting toxicity (DLT) within 21 days after the last patient was recruited. Two additional patients were enrolled for treatment if a single patient experienced a DLT. Dose escalation proceeded in the absence of a DLT in these additional patients. A total of five subjects were then entered into dose level 2, which had two pharmacokinetic subgroups, as defined in Table 1. Finally, if a DLT occurred in not more than one of these patients, the marimastat dose was increased to 20 mg b.i.d. (dose level 3) and six patients were enrolled for treatment in each pharmacokinetic subgroup.

Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria version 1.0 (31). Musculoskeletal toxicity was not categorized in the Common Toxicity Criteria and it was defined as follows: grade 0, none; grade 1, aches and pains with no restriction of activity; grade 2, pain causing restriction of activity; grade 3, pain and presence of nodules or clinically inflamed joints or tendons; and grade 4, pain and presence of contracture. DLT was considered to be an absolute neutrophil count <2.0/µL for >7 days despite growth factor support or any grade 3 or 4 nonhematologic toxicity considered life threatening.

Marimastat was held and the dose was reduced for any musculoskeletal symptoms grade 2 or higher or any other toxicity grade 3 or higher attributed to marimastat. Dose reductions for marimastat were by 10 mg per overall daily dose (or 20 mg for grade 4 toxicity), down to a minimum dose of 10 mg every other day. Therapy was delayed and administration of granulocyte colony-stimulating factor was initiated from the following cycle if the absolute neutrophil count decreased below 2.0/µL. The dose of paclitaxel was reduced to 135 mg/m2 if the absolute neutrophil count again decreased to <2.0/µL before the next cycle. Treatment was also delayed for thrombocytopenia (platelet count, <100/µL). After a second or third cycle was delayed for thrombocytopenia, the carboplatin dose was reduced to provide an AUCfc of 6 mg min/mL. A further dose reduction to an AUCfc of 5 mg min/mL was permitted if delays still occurred due to thrombocytopenia <100/µL. Patients having grade 3 or 4 nonhematologic toxicity related to paclitaxel or carboplatin were to be removed from the study.

Chest radiograph, computed tomography scan, and other relevant imaging studies were repeated every 2 months, and tumor measurements and responses were assessed according to WHO guidelines (32). Patients were removed from the study if they had unacceptable toxicity or disease progression.

Pharmacokinetic studies. Sampling to characterize the plasma pharmacokinetics of paclitaxel was done during the first and second cycles of therapy in all patients. Blood specimens (7 mL) were drawn from a vein in the arm opposite to that used for dosing and collected in tubes containing freeze-dried sodium heparin before treatment, at 10, 90, 175, and 195 minutes, and at 4, 6, 9, 24, and 48 hours after starting the infusion. Actual drug infusion and sample collection times were monitored with a digital timer. Blood samples were promptly centrifuged for 10 minutes at ~2,500 x g and 4°C. Plasma was harvested and maintained frozen at –70°C until assayed using methods that have been reported previously. A validated analytic method based on isocratic reverse-phase high-performance liquid chromatography with automated column switching and UV detection was used to determine the concentration of paclitaxel in plasma (33).

Paclitaxel plasma concentration-time curves were analyzed by noncompartmental methods using routines supplied in the WinNonlin version 1.1 software package (Scientific Consulting, Apex, NC; ref. 34). Area under the plasma concentration-time curve from time 0 to infinity was estimated by the logarithmic-linear trapezoidal algorithm to the last data point, with extrapolation to time infinity using the estimated value of the slope of the terminal logarithmic-linear disposition phase. Pharmacokinetic variables are reported as the mean ± SD of the individual patient values for each dose level, group, or subgroup. The paired two-tailed t test was used to compare mean pharmacokinetic variables for paclitaxel administered alone or together with marimastat during two successive cycles of therapy within the same group of patients. The standard Student's t test was used for comparisons between different groups of patients. P < 0.05 (two-tailed) was considered to be significantly different.


   Results
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 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patient characteristics. Twenty-two patients were entered into the study and received treatment (Table 2). The median age of the patients was 56 years and both genders were equally represented. Only three patients had an Eastern Cooperative Oncology Group performance status of 2 and most (73%) had stage IV disease. Eleven patients had undergone some prior surgical procedure, of which 5 were resections of the primary disease. One patient was treated with radiation, 40 Gy to the T9-L1 vertebrae and 30 Gy to the left humerus.


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  		Table 2. Patient characteristics

 
Drug administration. The overall experience in delivering the combination regimen at each dose level evaluated in the study is summarized in Table 3. Five patients were treated at the first dose level: marimastat 10 mg b.i.d., carboplatin AUCfc 7 mg min/mL, and paclitaxel 175 mg/m2. Four of the patients completed the four scheduled cycles of therapy without a reduction in the marimastat dose. The third patient who was enrolled developed deep vein thrombosis after the first cycle and died of progressive disease following the second cycle of therapy. Two additional patients were enrolled for treatment at this dose level, although neither of these events were considered as being treatment related. The fourth subject also developed a deep vein thrombosis after the third cycle that was unrelated to treatment. Although there were no DLTs, treatment with seven cycles of carboplatin/paclitaxel was delayed in five patients (Table 3). Three of the delays were prompted by grade 1 to 2 thrombocytopenia, which also resulted in a chemotherapy dose reduction. Treatment was also delayed in the two patients with deep vein thromboses together with a dose reduction in one of these patients, whereas the other two treatment delays resulted from logistic reasons.


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  		Table 3. Administration of paclitaxel and carboplatin in combination with marimastat

 
Five patients were treated at the second dose level where the paclitaxel dose was increased to 200 mg/m2, whereas the doses of marimastat and carboplatin remained the same. One patient was removed from the study due to disease progression after completing three cycles of treatment. The other four patients completed all four cycles of chemotherapy with the full dose of marimastat. Delays in carboplatin/paclitaxel administration occurred in three instances in two patients, with two delays for grade 1 and 2 thrombocytopenia and one for logistical reasons. The chemotherapy dose was reduced in three patients due to thrombocytopenia, including a single grade 3 event and a single episode of grade 2 fatigue.

Twelve patients were treated at dose level 3, where the marimastat dose was increased to 20 mg b.i.d., whereas the carboplatin and paclitaxel doses were the same as dose level 2. The administration of marimastat was discontinued during the fourth cycle in two patients because of musculoskeletal toxicity. Two patients were removed from the study after receiving two cycles and another patient during the last cycle because of disease progression. The remaining seven patients received the full dose of marimastat throughout all four scheduled cycles of therapy. Delays in the administration of carboplatin/paclitaxel occurred on two occasions in one patient for low-grade thrombocytopenia and neutropenia, twice in another patient for resection of a melanoma, and once for logistic reasons. The patient with thrombocytopenia had a carboplatin dose reduction in the third cycle that was continued into the fourth cycle. The paclitaxel dose reduced in one patient in the last cycle for reason of a left arm cellulitis.

Eighteen of the 22 patients enrolled into the study received all four planned cycles of chemotherapy. The remaining four patients were removed from the study before completing treatment because of disease progression, including one patient who died due to disease-related causes. Fourteen patients continued to receive marimastat beyond the four planned cycles of therapy for a median of 108 days (range, 33-538 days). Six of these patients also received two additional cycles of paclitaxel and carboplatin. During the continuation period, the dose of marimastat was reduced in a total of eight patients because of musculoskeletal toxicity in addition to the development of skin nodules in two patients. Twelve patients stopped treatment due to disease progression, 1 patient died due to causes unrelated to treatment, and 1 patient withdrew because of spinal stenosis that was possibly attributable to the drug.

Toxicity. All patients were assessed for toxicity regardless of whether they completed four cycles of therapy. There was no occurrence of life-threatening grade 3 or 4 nonhematologic toxicity (Table 4). Musculoskeletal toxicity was the most common nonhematologic toxicity. It was most frequently grade 1, with the only three grade 2 cases occurring at the third dose level. In four patients, musculoskeletal toxicity consisted of arthralgia, in three it manifested as myalgia, and 11 patients had both arthralgia and myalgia. In five patients, joint or limb edema occurred without evidence of inflammation. Nausea, fatigue (neurocortical), and distal neuropathic (neurosensory) toxicity were also relatively common, with each occurring in nine patients and without apparent predilection for dose level. Grade 3 or 4 granulocytopenia occurred in 11 of the 22 patients, but no infection was related to the cytopenia (Table 5). Thrombocytopenia was less than grade 3, except in two cases. Hematologic toxicity was not evidently greater at the 20 mg b.i.d. dose than at the 10 mg b.i.d. dose of marimastat.


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  		Table 4. Nonhematologic toxicities

 

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  		Table 5. Hematologic toxicities and serum chemistry abnormalities

 
Response. One patient at the first dose level died before response assessment. After the first three cycles of treatment, partial responses were seen in 12 of 21 (57%) assessable patients: 3 at dose level 1, 3 at dose level 2, and 6 at dose level 3. Stable disease was seen in 4 (19%), and progressive disease was seen in 5 (24%) patients, including one subject at the second dose level who went on to a fourth cycle of treatment.

Paclitaxel pharmacokinetics. Mean paclitaxel pharmacokinetic variables determined at each dose level are summarized in Table 6. The mean ± SD total body clearance of paclitaxel in marimastat-naive patients measured during the first cycle of therapy was 11.2 ± 4.5 L/h/m2 (n = 5) and 12.4 ± 2.4 L/h/m2 (n = 9) for the cohorts treated with doses of 175 and 200 mg/m2, respectively. These values are in excellent agreement with previously reported values for comparable doses of single-agent paclitaxel administered as a 3-hour i.v. infusion to adult cancer patients (35, 36). There was no significant difference between any paclitaxel pharmacokinetic variable when determined without concurrent marimastat therapy and after 7 days of twice-daily treatment with 10 or 20 mg oral administration marimastat in the same groups of patients.


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  		Table 6. Pharmacokinetic variables of paclitaxel

 

   Discussion
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 Abstract
 Patients and Methods
 Results
 Discussion
References
 
The presence or absence of MMPs in tumor tissue seems to influence disease progression. Supporting the role of MMPs in the development of cancer are several studies involving knockout mice that lack specific metalloproteinases and show decreased tumorigenesis (37–39).

In NSCLC, tumors variously overexpress several MMPs (15, 40), and greater expression has been associated with more advanced disease and poorer prognosis (16–18). Although these observations support therapeutic efforts directed against MMPs, the various studies assessed different MMPs and varying degrees of expression were noted, making it difficult to recommend the targeting of specific MMPs.

Marimastat, a synthetic small molecule with good oral bioavailability, is a broad-spectrum MMP inhibitor (8). It is a peptidomimetic compound with a collagen-like backbone that facilitates binding to MMPs and a hydroxamic acid functional group that chelates a zinc ion present in the active site of the enzyme. It binds reversibly to MMPs 1, 2, 7 to 9, 12, and 13, with IC50s in the 2 to 16 nmol/L range, and 230 nmol/L for MMP-3. Treatment with oral marimastat decreased the extent of lung colonization by as much as 77% against the HOSP.1 mammary carcinoma model in rats and by 37% in the B16-BL6 mouse melanoma model in mice. In the former model, tumor weight was also reduced by 67% relative to controls. In nude mice inoculated with human small cell lung carcinoma line 841, the tumor size reductions were 62% for single-agent cisplatin, 28% for marimastat alone, and 78% for the combination (P < 0.05 for comparison of combination versus marimastat). Survival was superior when cisplatin and marimastat were administered in combination compared with the activity resulting from treatment with either agent alone (P < 0.01 for both comparisons; ref. 41).

In consideration of these findings, together with the poor outcome achieved with conventional chemotherapy when used alone in patients with advanced NSCLC, this phase I study was undertaken to evaluate the administration of marimastat in combination with carboplatin and paclitaxel. Based on an absence of grade 2 musculoskeletal toxicity at the lower dose of marimastat, the recommended dosing regimen for phase II studies was established as carboplatin at an AUCfc of 7 mg min/mL and paclitaxel 200 mg/m2, administered as sequential 1- to 2- and 3-hour i.v. infusions, respectively, together with marimastat 10 mg oral administration b.i.d. It is notable that the majority of patients were able to complete all four scheduled cycles of chemotherapy with only modest toxicity that did not require any reductions in the dose of marimastat; treatment was discontinued early in only four patients because of progressive disease or death. Treatment delays or reduction in the dose of the cytotoxic anticancer drugs in the remaining patients were related predominantly to hematologic toxicity induced by paclitaxel and carboplatin. During the four cycles of combined therapy, the dose of marimastat was reduced in only one patient and stopped in only two patients for reasons of musculoskeletal toxicity, and there was no treatment-related grade 3 or 4 nonhematologic toxicity. Only four patients were reported to have any degree of alopecia, but this is most likely a matter of underreporting. In addition, although it must be regarded as preliminary, the response rate observed in this study seemed to be at least as good as seen in other studies for metastatic NSCLC and did not seem to differ between the two doses of marimastat (4, 5, 42, 43).

The major routes by which marimastat is eliminated from the body have not been well defined. Oxidative hepatic metabolism represents a significant route of elimination for paclitaxel as well as some peptidomimetic drugs that have been recently introduced into the clinic (44–46). Consequently, determining whether prolonged administration of marimastat influences the plasma pharmacokinetics of paclitaxel was an important aspect of this clinical trial. In contrast, hepatic mechanisms of elimination are not significant for carboplatin; therefore, a pharmacokinetic interaction with marimastat was not anticipated (47). It was found that repeated daily treatment with marimastat at doses of 10 or 20 mg b.i.d. had no effect on the pharmacokinetic behavior of paclitaxel at doses of 175 or 200 mg/m2 administered as a 3-hour i.v. infusion.

To date, clinical trials with marimastat have been consistent in two regards. First, they almost always included patients with advanced or unresectable disease (20, 21, 48–55). Second, they more frequently employed marimastat as a single agent (20, 21, 48, 51–55) rather than combined with other therapies (49). Not surprisingly, with rare exception (50), these studies have produced negative results. A similar picture of negative trials in advanced disease has been seen with other MMP inhibitors (22, 56, 57).

It has been suggested that cytostatic agents, such as MMP inhibitors, may function optimally in early-stage disease, where tumor burden is minimal (58). Combining marimastat with cytotoxic agents in this setting could improve outcomes. Recent data in NSCLC suggest that paclitaxel and carboplatin improve survival after resection of stage Ib disease (59), and marimastat could be added to this combination in an adjuvant trial. Before embarking on a phase III study, however, it would be important to know that marimastat is affecting target MMPs in tumor tissue. Although an effect on tumors has been suggested by this and other studies (29, 50), the significant resources required for a large study in early-stage disease demand greater proof. Correlative studies with marimastat demonstrating post-treatment tumor MMP inhibition would be helpful in this regard. Ideally, accessible tumors at cutaneous sites might be biopsied before and after treatment with marimastat. Unfortunately, whereas such studies could feasibly be undertaken on MMP-expressing cancers, such as melanoma (60), NSCLC and other tumors infrequently cause cutaneous metastases. Plasma levels of MMPs may not be representative of MMP activity at the tumor site (8, 61) and do not necessarily correlate with drug administration (20). Cutaneous biopsies of normal skin might be a reasonable basis for proceeding to larger studies, although a reliable assay of in vivo MMP activity is needed (10). Finally, tumor marker responses to marimastat have not turned out to be indicative of clinical benefit in subsequent studies (29), warning against the use of this surrogate measure.


   Footnotes
 
Grant support: This study was funded by research support from British Biotech, Inc., Annapolis, Maryland. J.R.G. was supported by the Canadian Institutes of Health Research/Canadian Association of Medical Oncologists Research Award.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/20/04; revised 1/10/05; accepted 1/21/05.


   References
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 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

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