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Randomized Phase III Trial of Marimastat Versus Placebo in Patients With Metastatic Breast Cancer Who Have Responding or Stable Disease After First-Line Chemotherapy: Eastern Cooperative Oncology Group Trial E2196

From the Albert Einstein Cancer Center, Montefiore Medical Center, Bronx; State University Hospital of New York, Stony Brook, NY; Dana-Farber Cancer Institute, Boston, MA; Northwestern University, Chicago, IL; Mayo Clinic, Rochester, MN; and the Johns Hopkins University, Baltimore, MD

Address reprint requests to Joseph A. Sparano, MD, Albert Einstein Cancer Center, Montefiore Medical Center, Weiler Division, 1825 Eastchester Rd, 2 South, Rm 47-48, Bronx, NY 10461; e-mail: Sparano{at}jimmy.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To determine whether a matrix metalloproteinase inhibitor improves progression-free survival (PFS) in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy.

PATIENTS AND METHODS: One hundred seventy-nine eligible patients were randomly assigned to receive oral marimastat (10 mg bid; n = 114) or a placebo (n = 65) within 3 to 6 weeks of completing six to eight cycles of first-line doxorubicin- and/or taxane-containing chemotherapy for metastatic disease. Patients were evaluated every 3 months until disease progression.

RESULTS: When comparing placebo with marimastat, there was no significant difference in PFS (median, 3.1 months v 4.7 months, respectively; hazard ratio, 1.26; 95% CI, 0.91 to 1.74; P = .16) or overall survival (median, 26.6 months v 24.7 months, respectively; hazard ratio, 1.03; 95% CI, 0.73 to 1.46; P = .86). Patients treated with marimastat were more likely to develop grade 2 or 3 musculoskeletal toxicity (MST), a known complication of the drug indicative of achieving a biologic effect, compared with patients administered placebo (63% v 22%, respectively; P < .0001). Patients with grade 2 or 3 MST had significantly inferior survival compared with patients who had grade 0 or 1 MST (median, 22.5 months v 28.2 months; P = .04). In addition, patients who had a marimastat plasma concentration of at least 10 ng/mL at month 1 and/or 3 were significantly more likely to have grade 2 to 3 MST (P < .0001).

CONCLUSION: Marimastat does not prolong PFS when used after first-line chemotherapy for metastatic breast cancer. Patients with higher marimastat levels exhibited MST, and MST was associated with inferior survival.

	INTRODUCTION

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The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that are involved in the degradation of the extracellular matrix. The MMPs play an important role in normal physiologic processes such as wound healing, but they also play a role in malignant disease by facilitating tumor growth, invasion, angiogenesis, and metastases.^1,2 Overexpression of MMPs by tumor or tumor-associated stroma has been associated with a worse prognosis in a variety of cancer types, including esophageal,³ colon,⁴ and pancreas.⁵ Preclinical data has demonstrated that interfering with MMP function or expression inhibits the metastatic cascade and tumor growth, including breast cancer models, making it a logical target for anticancer therapy.^6,7 This has led to the development of a number of MMP inhibitors (MMPIs), including peptidomimetic (batimastat and marimastat) and nonpeptidomimetic derivatives (BAY 12-9566, AG3340, and BMS-275291).⁸ Other drugs known to have MMPI activity are useful in treating human disease, including tetracycline derivatives for periodontal disease and corneal erosions^9-12 and bisphosphonates for osteolytic breast cancer bone metastases.^13-15

Marimastat (BB-2516) is a low molecular weight (331.4 da) peptidomimetic MMPI that, at nanomolar concentrations, produces 50% enzyme inhibition for collagenase (also known as MMP-1; 5 nmol/L), 72-kd gelatinase (also known as MMP-2; 6 nmol/L), 92-kd gelatinase (also known as MMP-9; 3 nmol/L), stromelysin-1 (also known as MMP-3; 200 nmol/L), and a variety of other MMPs. Preclinical studies have indicated that the concentration at which there is 90% enzyme inhibition of collagenase can be achieved at plasma concentrations of 40 ng/nL. An orally administered dose of 10 mg bid has resulted in mean plasma trough levels of between 50 and 110 ng/mL in patients with advanced cancer, indicating that one can expect almost total enzyme inhibition in most patients treated at this dose.¹⁶ Musculoskeletal symptoms consisting of pain and tenderness in muscles and joints is the most common toxicity, develops in approximately 30% of patients treated at this dose after a median of 3 to 6 months, and occurs with other MMPIs.¹⁷ It may be mediated by inhibition of the tumor necrosis factor alpha converting enzyme.^18,19

On the basis of these considerations, the Eastern Cooperative Oncology Group (ECOG) breast cancer committee initiated a randomized, double-blind trial comparing oral marimastat (10 mg bid) with an oral placebo in patients with metastatic breast cancer who had responding or stable disease after first-line chemotherapy. The primary objective of the study was to determine whether marimastat prolonged progression-free survival (PFS). Secondary objectives included determining the effect of marimastat on overall survival (OS) and determining whether there was any relationship between trough plasma marimastat level and either PFS or OS.

	PATIENTS AND METHODS

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Eligibility Criteria
Patients were required to have histologically confirmed adenocarcinoma of the breast that was responding or stable after treatment with first-line chemotherapy for metastatic disease. The prior chemotherapy for metastases must have included either doxorubicin, a taxane (ie, paclitaxel or docetaxel), or both. A minimum of six and a maximum of eight cycles of chemotherapy were required (except for patients who received weekly taxane therapy, who were required to have received at least 12 doses of taxane therapy to be eligible). Patients were also required to have recovered from all toxicity related to prior chemotherapy (except alopecia and/or neuropathy), to be registered no less than 3 and no more than 6 weeks since the last cycle of chemotherapy, and to be no more than 40 weeks beyond the first dose of chemotherapy for metastases. Other eligibility criteria included female sex, age 18 years or older, ECOG performance status of 0 or 1, adequate organ function (required laboratory values within 2 weeks before registration included granulocytes 1,500/µL, platelets 100,000/µL, serum creatinine 1.5 mg/dL, total bilirubin < 1.5 mg/dL, and AST two-fold above the institutional upper limit of normal), and a negative pregnancy test within 14 days before randomization if the patient was premenopausal or perimenopausal. All patients provided written informed consent that was approved by the local institutional review boards.

Study Drug Administration
This was a randomized, double-blind, placebo-controlled study. Patients received either 10 mg of marimastat or a matching placebo twice daily with water, approximately every 12 hours, either during or after meals. Marimastat and placebo were produced by British Biotech (Oxford, United Kingdom). Treatment continued until the development of progressive disease or prohibitive toxicity. Concurrent bisphosphonate therapy was permitted, and concomitant hormonal therapy was also permitted after a protocol amendment (see Protocol Amendments).

Response Assessment
Patients were required to undergo tumor measurement within 4 weeks before registration after completion of first-line chemotherapy. All sites of measurable and assessable disease were evaluated every 3 months after registration. Computed tomography of the chest, abdomen, and pelvis was used to assess all known sites of measurable disease that were not measurable on physical examination, and bone scan (and x-ray of corresponding abnormal areas on bone scan) was required for patients with known or suspected bone metastases. Standard ECOG criteria were used to define response and progression.²⁰ For the primary end point analysis, progression was defined as evidence of progressive disease by the standard ECOG response criteria or death from any cause if it occurred before documented disease progression.

Toxicity and Dose Modification
The National Cancer Institute Common Toxicity Criteria (version 2.0) was used to grade all toxicity, with the exception of musculoskeletal toxicity (MST), which was graded using a scale previously used in other marimastat trials as follows: grade 1, aches and pains, no restriction of activity; grade 2, pain causing restriction of activity; grade 3, pain and presence of nodules or clinically inflamed joints and tendons; and grade 4, pain and presence of contractures. Any patient who experience grade 2 or greater musculoskeletal pain (or other toxicity attributed to the study drug) had the drug discontinued until the symptoms resolved; then the drug was resumed once daily for the first dose reduction and then once every other day for the second dose reduction.

Protocol Amendments
The study was activated in September 1997. There were two protocol amendments after activation that were aimed at enhancing accrual. In August 1998, the protocol was modified to change the 1:1 randomization to a 2:1 randomization (marimastat v placebo). There were 34 patients enrolled before the change in the randomization schema; stratified log-rank analysis revealed no difference in PFS before or after the change in the randomization schema. In August 1999, a second amendment was made to permit concurrent hormonal therapy for physicians who chose to continue or initiate hormonal therapy after the completion of chemotherapy in patients who had hormone-sensitive disease. Patients could either continue the hormonal therapy that they had been taking before registration or initiate hormonal therapy concurrent with the initiation of the study drug after registration.

Correlative Studies
A plasma specimen was collected at baseline, and trough plasma levels (drawn approximately 12 hours after the last study drug dose) were drawn at 1, 3, 6, and 12 months. At each time point, approximately 20 mL of venous blood was collected into lithium heparin tubes, centrifuged at 4°C and 3,000 RPM within 15 to 30 minutes of collection, evenly aliquoted in two separate polypropylene tubes, and frozen immediately at –20°C. Samples were subsequently analyzed by British Biotech Pharmaceuticals GLP Laboratory. Marimastat plasma concentration was determined by high-pressure liquid chromatography with mass spectrometric detection, which measures total marimastat concentration (bound and free).

Statistical Methods
Randomization was performed using a stratified permuted block randomization algorithm that was balanced within main institutions. Stratification factors, as outlined in Table 1, included type of first-line chemotherapy for metastases (doxorubicin and no taxane v taxane and no doxorubicin v doxorubicin and taxane), number of disease sites at registration (none v one to two v three or more), osseous metastases only (yes v no), concurrent bisphosphonate therapy (yes v no), and concurrent hormonal therapy (yes v no). The study was designed to have 83% power to detect a 50% improvement in median PFS (5.0 to 7.5 months) using a one-sided stratified log-rank test with a type I error of 2.5%. The statistical design called for an accrual goal of 324 eligible patients over 24 months of accrual and a maximum of 7 months of additional follow-up. Two interim analyses, using O'Brien-Fleming group sequential methods, were planned. Termination of accrual was recommended by the ECOG Data Monitoring Committee in June 2001, nearly 4 years after initiation of the trial and after accrual of 189 patients. The median PFS in the placebo group was lower than anticipated (3.1 months); therefore, despite failing to meet the initial accrual goal, the study had 85% power to detect a 2.5-month improvement in median PFS, which is identical to the absolute increase in PFS that the study sought to determine. This analysis was based on data received by November 4, 2002.

The distributions of PFS and OS in the marimastat and placebo arms were estimated with the Kaplan-Meier method and compared using log-rank tests.^23,24 For the log-rank tests, statistical significance was set at a level of 0.025, and the P values reported were one-tailed values. Stratified log-rank tests with concurrent hormonal therapy as the stratification factor were also performed. In addition, stratified Cox proportional hazards models were used to examine the relationship between PFS and treatment, examining various prognostic factors including visceral metastases, response to first-line therapy, number of metastatic sites (three or more sites v < three sites), ECOG performance status (0 v 1), bisphosphonate therapy (yes v no), and estrogen and/or progesterone receptor expression (yes v no). To analyze the relationship between trough marimastat concentration and PFS, landmark analyses were conducted separately for data on marimastat levels available at months 1 and 3 and the maximum value at months 1 and 3. This was performed to control potential biases associated with using marimastat levels at the various time points to predict outcomes occurring before those time points. For analyses using month 1 levels, a landmark time of 1 month was used such that patients who progressed or died without documented disease of progression within the first month were excluded from the analysis. A landmark time of 3 months was similarly used for the analyses involving month 3 levels and the maximum level at months 1 and 3. Two-sided, 0.05-level, stratified log-rank tests with concurrent hormonal therapy as the stratification factor were conducted for data available at the aforementioned time points to detect whether a difference in PFS existed between patients who had trough marimastat levels below and above the following cut points: 10 ng/mL versus less than 10 ng/mL, 20 ng/mL versus less than 20 ng/mL, 30 ng/mL versus less than 30 ng/mL, and 40 ng/mL versus less than 40 ng/mL. Furthermore, stratified Cox proportional hazards models²⁵ were examined with respect to PFS using trough marimastat concentration data and known prognostic factors. Similar landmark analyses analyzing the relationship between trough marimastat and OS were conducted. For these analyses, patients who died before the various landmark times were excluded.

	RESULTS

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Patient Characteristics
One hundred eighty-nine patients were enrolled onto this study between September 1997 and June 2001. Ten patients were ineligible, including six patients in the marimastat group and four in the placebo group. Reasons for ineligibility in the marimastat and placebo groups included more than one or an unknown prior systemic chemotherapy regimen for treatment of metastases (n = 3 and n = 3, respectively), progressive disease before registration (n = 1 and n = 0, respectively), and granulocytes less than 1,500/µL (n = 2 and n = 1, respectively). Therefore, 179 eligible patients were included in all the analyses, including four patients who never took the study drug. Reasons for not beginning assigned therapy in the marimastat and placebo arms included patient refusal (n = 2 and n = 0, respectively), the development of brain metastasis (n = 0 and n = 1, respectively), or progressive systemic disease discovered before treatment started (n = 0 and n = 1, respectively). The characteristics of the 179 eligible and assessable patients are listed in Table 1. The groups were well balanced, with the exception of performance status, which was not a stratification factor.

PFS
At the time of this analysis, in the marimastat arm, 96 patients (84%) had disease progression, and six patients (5%) died without documented progression. In the placebo arm, 57 patients (88%) experienced disease progression, and two patients (3%) died without documented progression. The Kaplan-Meier estimate of the distribution of PFS for the two arms is shown in Figure 1. Median PFS was 3.1 months in the placebo arm and 4.7 months in the marimastat arm (hazard ratio, 1.26; 95% CI, 0.91 to 1.74; P = .16). There was no significant difference in the risk of disease progression in the Cox proportional hazards model that adjusted for a variety of prognostic factors or in the reduced model that included only treatment arm, performance status, and visceral metastases.

View larger version (15K): [in this window] [in a new window]   Fig 1. Progression-free survival.

View larger version (15K): [in this window] [in a new window]   Fig 2. Overall survival.

MST
Data regarding MST in 175 patients with toxicity information are listed in Table 2. The distribution of worst-degree MST was found to be significantly different between the two treatment arms (P < .0001). Patients in the marimastat arm versus the placebo arm were more likely to have grade 2 (47% v 22%, respectively) and grade 3 (16% v 0%, respectively) MST and were more likely to interrupt therapy (50% v 15%, respectively) or permanently discontinue therapy (8% v 0%, respectively) because of MST. Patients with grade 2 or 3 MST had a significantly inferior survival compared with those who had grade 0 or 1 MST (median, 22.5 v 28.2 months; P = .04).

	DISCUSSION

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We performed a randomized, double-blind, placebo-controlled trial evaluating the MMPI marimastat in patients with metastatic breast cancer who had responding or stable disease after first-line chemotherapy. Previous studies in this patient population have indicated that patients experience disease progression after a median of about 3 to 6 months after discontinuing chemotherapy.^26-31 We chose a dose and schedule of marimastat that was known to achieve plasma concentrations capable of inhibiting most of the major MMPs in vitro. In addition, this dose had been shown to result in stabilization of plasma cancer-associated tumor markers in a variety of other cancer types, an effect that was associated with improved survival compared with patients who did not exhibit marker stabilization.¹⁷ Although we did not achieve the initial accrual goal, our trial had sufficient power to detect an increase in PFS from 3.0 to 5.5 months, an effect that is comparable to that expected for continuing chemotherapy. We found that marimastat had no significant effect on the primary end point of PFS or on OS. As expected, significantly more patients treated with marimastat demonstrated MST, indicating that the majority of patients were taking doses sufficient to induce a biologic effect. Reassuringly, the median PFS observed in the placebo arm of this trial was identical to the median PFS noted in a recently reported phase III trial that compared a tumor vaccine (consisting of a synthetic form of the tumor-associated antigen sialyl-Tn conjugated to the carrier protein keyhole limpet hemocyanin) with a placebo in over 1,000 patients with metastatic breast cancer who likewise had responding or stable disease after first-line chemotherapy (median PFS, 3.4 months in vaccination group v 3.0 months in control group; P = .35).³²

There was no information regarding phase III trials evaluating MMPIs when our trial was initiated in 1997. Since that time, a number of reports have indicated no benefit for both peptidomimetic and nonpeptidomimetic MMPIs when used either in combination with chemotherapy or sequentially after first-line chemotherapy in a variety of disease types, including small-cell lung cancer,³³ non-small-cell lung cancer,^34,35 pancreatic cancer,^36-38 and glioblastoma multiforme.³⁹ In fact, two studies have demonstrated diminished survival with one MMPI (BAY 12-9566) evaluated in pancreatic cancer (when compared with gemcitabine) and small-cell lung cancer (when compared with placebo after induction chemotherapy), prompting the pharmaceutical company to discontinue the development program for this agent. Only one study has demonstrated a possible benefit for MMPI therapy. Although marimastat significantly improved PFS and OS in a subgroup of 132 patients with unresectable or metastatic gastric or gastroesophageal adenocarcinoma who either had not received prior chemotherapy or were stable after initial chemotherapy, the study failed to meet the primary end point of improving PFS in the entire group of 369 patients.⁴⁰ Therefore, our findings are consistent with the disappointing findings for this class of drugs in patients with advanced cancer.

Secondary objectives of our trial were to correlate PFS and OS with plasma marimastat level and MST, an analysis that has not been reported in previous studies in patients with advanced disease. We anticipated that, if marimastat was found to be beneficial, that the benefit might be restricted to patients who had therapeutic plasma marimastat levels and/or patients who had MST. This analysis yielded several important observations. First, only 22% of assessable patients had a therapeutic trough plasma marimastat level (40 ng/mL) at 1 or 3 months, and only approximately 50% achieved half of the target level (20 ng/mL). Second, there was no correlation between a detectable or therapeutic plasma marimastat level and PFS, indicating no clinical benefit even in patients who achieved target blood levels. Third, there was a positive correlation between detectable trough marimastat levels and MST, demonstrating that the biologic effects of the drug were associated with achieving a detectable drug level. Fourth, patients who developed MST had an inferior survival (median, 22.5 months v 28.2 months for patients who did not develop MST; P = .04). Finally, an unplanned subset analysis demonstrated an inferior survival for patients who had higher marimastat levels. These findings demonstrate no benefit even in the subset of individuals taking adequate doses of the drug and even suggest of a worse outcome for patients who took doses of the drug that were sufficient to induce clinically quantifiable biologic effects (ie, MST).

One could argue that MMPIs would not be expected to have a beneficial effect in patients with metastatic disease but could have a potential role as a component of adjuvant therapy in patients with carcinoma that has been completely resected but who are at high risk for relapse. Miller et al⁴¹ reported a randomized phase II trial of marimastat at two different dose levels (5 or 10 mg bid) for 1 year after completion of adjuvant chemotherapy in 63 patients with operable breast cancer, either alone or in combination with tamoxifen. Six patients (19%) receiving the 5-mg dose and 11 patients (35%) receiving the 10-mg dose discontinued marimastat therapy before the completion of 1 year of therapy because of toxicity. Trough plasma levels in the 5-mg group (7.5 ng/mL) and the 10-mg group (11.9 ng/mL) were well below the target range of 40 ng/mL and were not influenced by concurrent tamoxifen. A second trial performed by the same group evaluated another orally administered MMPI (BMS-275291), an agent specifically designed to spare inhibition of the tumor necrosis factor alpha converting enzyme. Patients with operable breast cancer who had completed adjuvant chemotherapy were randomly assigned to receive BMS-275291 (1,200 mg/d; n = 38) or a placebo (n = 19) for up to 1 year.⁴² Adverse events consisting of arthralgias or skin rash led to discontinuation of therapy in 21% of patients receiving BMS-275291 compared with 11% of patients receiving placebo. In both cases, the investigators concluded that administration of these MMPIs as adjuvant therapy in patients with operable breast cancer was not feasible.

The reasons for the uniformly disappointing results observed for MMPIs as cancer therapy are not clear. Notwithstanding the compelling preclinical data supporting this approach, it is likely that the complexity of a metastatic process requires targeting multiple steps and biologic process rather than only MMPs. In addition, MMP inhibition may have paradoxical effects that promote rather than inhibit tumor growth and angiogenesis.^43,44 For example, endogenous production of angiostatin and endostatin, both known to be potent endogenous inhibitors of angiogenesis, are mediated by certain MMPs^45,46; reduction of MMP activity may, therefore, enhance rather than inhibit angiogenesis. Other potential deleterious effects may include inhibition of other endogenous angiosuppressive pathways,⁴⁷ or an MMPI-induced enhancement of MMP production or activity.⁴⁸ Another concern is that we may have failed to achieve therapeutic MMPI drug levels in humans, defined as a plasma concentration known to inhibit most MMPs in vitro. We believe that an important contribution of our study is the demonstration that PFS was not improved in patients who had either a therapeutic or detectable trough level, making it unlikely that insufficient blood levels accounted for the negative result. In fact, patients who had higher marimastat levels had an inferior OS. Taken together with the uniformly disappointing results of MMPIs noted in other studies, the results of our trial raise additional concern about continued evaluation of MMPIs in the clinic until their biologic effects are better understood. To better understand these biologic effects, we are planning additional studies on banked plasma specimens from our trial to evaluate the effect of marimastat on plasma metalloproteinase concentrations and other plasma proteins using proteomic technology⁴⁹ and to determine their relationship with toxicity, disease progression, and survival.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service grant Nos. CA23318, CA66636, CA21115, CA14958, CA17145, CA13650, and CA16116, and the National Cancer Institute, National Institutes of Health; and Department of Health and Human Services, Bethesda, MD.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002, and at the American Society of Clinical Oncology Molecular Therapeutics Symposium, San Diego, CA, November 8-10, 2002.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted August 7, 2003; accepted September 23, 2004.

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