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Phase II Trial of Temozolomide Plus the Matrix Metalloproteinase Inhibitor, Marimastat, in Recurrent and Progressive Glioblastoma Multiforme

From the Departments of Neuro-Oncology and Biomathematics, University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Morris D. Groves, MD, M.D. Anderson Cancer Center, Department of Neuro-Oncology, 1515 Holcombe Blvd, No. 431, University of Texas, Houston, TX 77030.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Novel therapies are needed for patients with recurrent glioblastoma multiforme (GBM). Because there is evidence that temozolomide (TMZ) has some activity in GBM and is well tolerated, and because of laboratory evidence that metalloproteinases are important in glioma cell invasion, the combination of TMZ and the matrix metalloproteinase inhibitor marimastat (MRM) in patients with recurrent GBM was studied.

PATIENTS AND METHODS: Forty-four patients with recurrent GBM after standard radiotherapy were enrolled. For 19 patients, this therapy was their first chemotherapy after tumor progression after irradiation; 25 others had received chemotherapy previously. TMZ 150 to 200 mg/m² days 1 to 5 and MRM 50 mg days 8 to 28 was administered at 28-day intervals for two cycles; then patients were reevaluated. Treatment continued until progression of tumor or toxicity developed.

RESULTS: Joint and tendon pain was the major therapy-related toxicity and was reported in 47% of patients. Five patients (11%) were removed from the study because of intolerable joint pain. For all patients, the progression-free survival (PFS) at 6 months was 39%. Median PFS was 17 weeks, median overall survival was 45 weeks, and 12-month PFS was 16%.

CONCLUSION: The combination of TMZ and MRM resulted in a PFS at 6 months that exceeded the literature target by 29%. This drug combination met phase II study criteria; further study in recurrent patients with GBM might be warranted. Further study of therapy-induced joint pain is necessary.

	INTRODUCTION

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GLIOBLASTOMA multiforme (GBM) is the most commonly diagnosed malignant primary brain tumor in adults. Despite aggressive multidisciplinary treatment, outcomes for patients with GBM remain poor, with an overall median survival for patients with newly diagnosed GBM of only 42 to 50 weeks.¹ Current chemotherapies for recurrent GBM achieve unsatisfactory results, as evidenced by a recent report analyzing eight consecutive phase II trials of 225 recurrent patients with GBM treated with a variety of chemotherapeutic regimens. The 6-month progression-free survival (PFS) and median PFS for patients with GBM in that analysis were 15% and 9 weeks, respectively.² In a recent review of a large number of studies reporting the results of chemotherapy for patients with recurrent GBM, median survival ranged from 19 to 28 weeks.³

Temozolomide (TMZ; Temodar; Schering-Plough, Kenilworth, NJ) is a well tolerated, orally bioavailable alkylator with activity in glioma patients. It was recently approved for use in patients with recurrent anaplastic astrocytoma. TMZ undergoes chemical degradation to its active metabolite, monomethyl triazenoimidazole carboxamide,^4,5 at physiologic pH.^4,6 The cytotoxicity of monomethyl triazenoimidazole carboxamide is primarily due to alkylation at the O⁶ position of guanine.⁵ TMZ has activity in patients with recurrent GBM, as demonstrated in a recently published phase II study that compared single-agent TMZ to procarbazine in patients with recurrent GBM.⁷ In that study, patients treated with TMZ achieved a 6-month PFS of 21% v 8% in those patients treated with procarbazine (P = .008),⁷ suggesting that TMZ is a superior orally administered alkylating agent for patients with recurrent GBM.

Marimastat (MRM) is a low-molecular-weight peptide mimetic inhibitor of the family of enzymes known as matrix metalloproteinases (MMPs). MMPs are believed to be responsible for the breakdown of components of the extracellular matrix and to contribute to the tissue destruction required for cellular invasion, intravasation, extravasation, and migration; they may play a role in angiogenesis and sustained growth of metastatic lesions as well.^8,9 Preclinical studies have demonstrated that in animal models of malignancy, MMP inhibitors (MMPIs) can restrict the growth and regional spread of solid tumors, inhibit metastatic spread, and block the process of tumor neovascularization.^9,10 MMPs (especially MMP-2 and MMP-9) are upregulated in malignant gliomas and correlate with their malignant progression.^11-13 In vitro studies of MRM demonstrated significant inhibition of invasion of glioma cell lines.¹⁴ These results suggest that MMPIs may have a role in the treatment of GBM. Results from a recently completed study of MRM administered adjuvantly to patients with GBM after radiotherapy are not available yet.

Phase I and II trials of MRM in patients with non-CNS solid tumors demonstrated indirect evidence of efficacy with reductions in rates of increase of certain biomarkers. Five phase III studies of MRM in non-CNS solid tumor patients have been conducted. Three studies (lung cancer) demonstrated no survival benefit of MRM, one study in patients with gastric cancer demonstrated a survival benefit of MRM, and one trial in patients with pancreatic cancer continues.¹⁵ Dose-limiting toxicities of MRM were pain and tenderness in the tendons and joints of the shoulders and hands.¹⁶

MMPIs have been combined with cytotoxic agents with evidence of activity in animal models of lung carcinoma.^17,18 MRM has been safely combined with several cytotoxic agents (gemcitabine, carboplatin, 5-fluorouracil, doxorubicin, and cyclophosphamide) in patients with pancreatic, ovarian, colorectal, breast, and prostate cancer,^19-22 although recent results demonstrated MRM plus gemcitabine offered no survival advantage over gemcitabine alone in patients with pancreatic cancer.⁸ On the bases of the modest but well-defined efficacy of TMZ in recurrent patients with GBM and the importance of MMPs to glioma cell invasion, we chose to study TMZ plus MRM in patients with recurrent GBM, looking for improvement in 6-month PFS. The TMZ schedule was based on previous studies. The MRM schedule was chosen to allow patients a short time off the drug. Additionally, we felt this schedule might allow for some degree of synchronization of tumor cell cycling and migration, which might increase the antitumor effect of the combination.

	PATIENTS AND METHODS

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Eligibility
Patients 16 years of age with histologically proven supratentorial GBM and unequivocal evidence for tumor progression by magnetic resonance imaging (MRI) scan after radiation therapy were eligible. Patients may have had up to two previous chemotherapy regimens, but they must have recovered from the toxic effects of prior therapy with evidence of adequate bone marrow, liver, and renal functions. Patients were excluded if they had a Karnofsky performance status of less than 60%, any other active malignancy (except nonmelanoma skin cancer or carcinoma in situ of the cervix), an active infection, any serious disease that would obscure toxicity or dangerously alter drug metabolism, or were pregnant. All patients were required to sign an institutional review board–approved informed consent and were instructed to practice adequate contraception.

Treatment Regimen
TMZ was administered at 200 mg/m² once daily for 5 days every 28 days (patients were begun on treatment with 150 mg/m² if they had received prior myelosuppressive chemotherapy). Premedication with standard antiemetics was provided before TMZ treatment. MRM was administered orally in the morning (20 mg) and in the evening (30 mg) for 3 weeks (days 8 to 28) every 28 days. Treatment courses were repeated every 28 days after the first daily dose of TMZ from the previous course if all hematologic toxicities from the previous course had resolved to grade 2 or less and all drug-associated nonhematologic toxicities had recovered to either grade 0 or 1. If recovery had not occurred by day 28, the subsequent course of TMZ and MRM was delayed until these criteria were met.

Dose Modification
If patients developed musculoskeletal toxicities, they were allowed 1 or 2 weeks off the drug, as well as decreases in total MRM dose from 50 mg to as little as 30 mg per day. The dose of TMZ in subsequent courses was individually titrated according to the manufacturer’s guidelines; doses were based on each patient’s degree of myelosuppression. Treatment was continued without interruption as long as there was no tumor progression and as long as toxicity was acceptable.

Efficacy Measures
The primary end point of this study was PFS at 6 months, but patients were also observed for response to treatment. The combination of the neurologic examination and MRI brain scans performed before courses 3, 5, 7, and so on were used to define overall response or progression. Neurologic performance was monitored by grading both symptoms and signs. Evaluation was based on any changes in the neurologic examination (not related to a postictal state or other nontumor-related process) in the interval since the last examination. Patients were graded clinically as either definitely better (+2), possibly better (+1), unchanged (0), possibly worse (-1), or definitely worse (-2).

Brain MRI scans were graded as complete response (disappearance of contrast-enhancing tumor); partial response (decrease of 50% in the product of the two largest perpendicular diameters of the enhancing lesion); minor response (decrease in the product of the two perpendicular diameters of less than 50%); stable disease (no significant change in the product of the perpendicular diameters of the enhancing lesion); or progressive disease ( 25% increase in the product of the two largest perpendicular diameters of the enhancing lesion or development of a new lesion). All response determinations required that patients have a stable or improved clinical examination and be on stable or decreased doses of corticosteroids since the previous evaluation. Responses (complete, partial, or minor) were required to be sustained on two successive scans taken 8 weeks apart to be valid. PFS and overall survival (OS) were measured from the first day of treatment until progression or death. A minimum of 4 weeks of treatment (one 4-week course) was considered necessary for a patient to be considered to have received an adequate trial to evaluate efficacy.

Statistical Analysis
The primary objective of this study was to determine whether TMZ and MRM could significantly delay progression in patients with recurrent GBM; the primary end point was progression within 6 months (26 weeks). The historical values for comparison are from a database of 225 recurrent patients with GBM enrolled onto eight previous phase II studies in which the proportion of patients remaining alive and free from progression at 6 months was 15%.² The hypotheses to be tested were H0: p < p0 versus H1: p > p1, where p was the probability of remaining alive and free from progression at 6 months. We took alpha (false-positive rate) to be 10% and beta (false-negative rate) to be 5%. We set p0 to 10% because we would not want to use a drug that was significantly worse than the aggregate value from eight negative trials. We set p1 to 30% (looking for an improvement of 0.2).

On the basis of these figures, we proposed a single-stage study combining TMZ and MRM. We concluded that a study with 40 patients would give us acceptable error rates for our hypothesis testing and precision for estimation. To declare success, 12 responses (patients alive and progression free at 6 months) out of 40 patients (our target of 30%) were needed (the 95% confidence interval on the true response proportion is from 17% to 47%). Kaplan-Meier estimates for PFS were derived using StatXact; this SAS (Cary, NC) software package was used to analyze prognostic variables at study entry and 6-month PFS, and exact binomial methods were used for confidence intervals.

	RESULTS

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Patient Characteristics
Between March 24, 1999, and October 7, 1999, 44 patients were enrolled onto this study. Four patients were enrolled who did not receive an adequate trial of the study drugs. Two of these patients deteriorated within 3 weeks after beginning treatment, and analysis of brain MRI demonstrated progression after less than 1 month of treatment; one patient stopped treatment after only 2 weeks, and one patient died before his first 2-month follow-up appointment. Five patients (11%) discontinued the study because of joint-related MRM toxicity rather than progressive disease. The disease of all patients had not responded to previous radiotherapy. Patient characteristics are listed in Table 1.

View larger version (15K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curve of progression-free and overall survival for temozolomide + marimastat (n = 44).

Objective Responses
Partial responses with tumor shrinkage were documented in six (13.6%) of 44 patients. Median duration of response was 51 weeks (range, 26 to 69 weeks; three patients who had not progressed were censored at 69, 75, and 87 weeks). Stable disease occurred in 26 (59%) of 44 patients. Median duration of stable disease was 20 weeks (range, 10 to 57 weeks; two patients who had not progressed were censored at 57 and 70 weeks). Overall response rate (partial response + stable disease) was 32 (72.7%) of 44 patients. Median duration of responses plus stable disease was 23 weeks (range, 10 to 69 weeks).

Toxicity
All patients were assessable for toxicity. All adverse events are listed in Table 3. The most notable adverse event was arthropathy, which was particularly severe in the small joints of the hands (often manifesting first in the dominant hand) and shoulders. Joint complaints were reported in 21 patients (47%) and were grade 3 or 4 in 17 patients (38%). The MRM dose was decreased in 14 patients (32%), and five patients (11%) were removed from the study because of complaints of intolerable joint pain. Whether patients developed arthropathy was not related to corticosteroid use or dose. Class II narcotic pain medication was not adequate to control pain in several patients. Limitation of range of motion of the interphalangeal joints of the hands and shoulder joints was noted in the most severely affected patients. In a few patients, swan neck contractures developed in the small joints of the hands. The joint pain eventually resolved in all patients, but a few had contractures that persisted for up to 14 months after being removed from the study drugs. Only one patient required dose reduction of TMZ because of myelosuppression.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

There are a number of ways MRM and TMZ might impact tumor cells and therefore affect outcomes in patients with recurrent GBM. Combining drugs with these mechanisms of action may cause extreme cellular stress because two major pathways of cellular behavior are interrupted. There is evidence that astrocytoma cells either migrate or divide and that these activities are mutually exclusive.^24,25 For TMZ to be cytocidal, at least two cell-cycle divisions must occur after the drug enters the tumor cell. It follows that cells that are quiescent or arrested in any phase of the cell cycle may be resistant to alkylating agents such as TMZ.^26-28 Our own work suggests that exposure to TMZ can result in accumulation of glioma cells in S and G₂ phase.²⁹ This cell cycle block may interfere with TMZ’s cytotoxic effect. In vivo, the stress of TMZ exposure may cause tumor cell synchronization and cell cycle block with resultant inducement of MMPs in preparation for cellular migration.³⁰ If this migration is inhibited by MRM and cells are then forced toward mitosis, then MRM may, in a sense, act as a chemosensitizer of glioma cells to TMZ. MRM, through its interference with cell migration, may cause cells (especially those that are stressed and seeking nutrition, higher oxygen tension, or other safe harbors) to become more susceptible to TMZ. By inhibiting MMPs, MRM may also play a role in inhibition of new blood vessel growth and result in inadequate tumor blood supply.³¹

We believe these results provide evidence of the importance of MMPs to GBM progression and invasion. It is possible that these drugs may be more effective in the setting of minimal tumor volume, such as in adjuvant treatment or maintenance therapy after response to standard cytotoxics. Clearly, this combination is not a cure for this disease, but these results seem promising, and it may be possible to build on these data to further improve outcomes for patients. Whether the addition of other anti-invasion or antiangiogenic agents might improve the results we report here is an interesting question that deserves investigation. Understanding the best way to administer MMPIs in order to maximize their antitumor effect while minimizing musculoskeletal toxicity will be an important step in the further development of these compounds.

	ACKNOWLEDGMENTS

 
Supported in part by grant no. CA 55261 from the National Cancer Institute, Bethesda, MD.

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Submitted May 29, 2001; accepted November 7, 2001.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Groves, M. D. Articles by Levin, V. A. Search for Related Content PubMed PubMed Citation Articles by Groves, M. D. Articles by Levin, V. A.