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© 2000 American Society for Clinical Oncology Phase I and Pharmacologic Study of the Specific Matrix Metalloproteinase Inhibitor BAY 12-9566 on a Protracted Oral Daily Dosing Schedule in Patients With Solid MalignanciesFrom the Institute for Drug Development, Cancer Therapy and Research Center; University of Texas Health Science Center; and Brooke Army Medical Center, San Antonio, TX; and Pharmaceuticals Division, Bayer Corporation, West Haven, CT. Address reprint requests to Eric Rowinsky, MD, Institute for Drug Development, Cancer Therapy and Research Center, 8122 Datapoint Dr, Ste 700, San Antonio, TX 78229; email erowinsk{at}saci.org
PURPOSE: To evaluate the feasibility of administering BAY 12-9566, a matrix metalloproteinase (MMP) inhibitor with relative specificity against MMP-2, MMP-3, and MMP-9, on a protracted oral daily dosing schedule in patients with advanced solid malignancies. The study also sought to determine the principal toxicities of BAY 12-9566, whether plasma BAY 12-9566 steady state concentrations (Css) of biologic relevance could be sustained for prolonged periods, and whether BAY 12-9566 affected plasma concentrations of MMP-2, MMP-9, and tissue inhibitor of MMP-2 (TIMP-2). PATIENTS AND METHODS: Patients with solid malignancies were treated with BAY 12-9566 at daily oral doses ranging from 100 to 1,600 mg. BAY 12-9566 dose schedules included 100 mg once daily, 400 mg once daily, 400 mg twice daily, 400 mg three times daily, 400 mg four times daily, and 800 mg twice daily. Plasma was collected to study the range of BAY 12-9566 Css values achieved, and exploratory studies were performed to assess the effects of BAY 12-9566 on plasma concentrations of MMP-2, MMP-9, and TIMP-2. RESULTS: Twenty-one patients were treated with 47 28-day courses of BAY 12-9566. The most common side effects were headache, nausea, vomiting, abnormalities in hepatic functions, and thrombocytopenia, which were rarely clinically significant. BAY 12-9566 was well tolerated on all dose schedules, and there was no consistent dose-limiting toxicity that precluded treatment in the range of dose schedules evaluated. Instead, dose escalation was terminated because BAY 12-9566 plasma Css values increased less than proportionately and plateaued as the daily dose was increased within the dose range of 100 to 1,600 mg/d, suggesting saturable drug absorption. Mean plasma Css values achieved with all dose schedules exceeded BAY 12-9566 concentrations required to inhibit MMPs in vitro and in vascular invasion and tumor proliferation in vivo models. There were no consistent effects of BAY 12-9566 on the plasma concentrations of MMP-2 and MMP-9 over the continuous dosing period at any dose schedule level. However, plasma levels of TIMP-2 seemed to increase in a dose-dependent manner (r2 = .50, P = .046). CONCLUSIONS: The recommended dose of BAY 12-9566 for subsequent disease directed studies is 800 mg twice daily, which resulted in biologically relevant plasma Css values and an acceptable toxicity profile. Although exploratory studies of MMPs in plasma were not revealing, it is conceivable that some tumor types and disease settings are more likely to produce more readily quantifiable levels of activated MMPs than others. Therefore, attempts to identify and quantify surrogate markers of MMP inhibitory effects should continue to be performed in disease-directed studies in more homogenous patient populations.
MATRIX Metalloproteinases (MMPs) are a family of secreted or transmembrane proteins that are capable of digesting the extracellular matrix and basement membrane components under physiologic conditions.1,2 The three major subgroups of MMPs, classified by their substrate preferences, include collagenases, which degrade collagen; stromelysis, which prefer proteoglycans and glycoproteins; and gelatinases, which are especially potent at digesting nonfibrillar and denatured collagen (gelatin).2-5 The MMPs are secreted as latent proenzymes and require activation by a series of proteolytic enzymes. Once activated, they may be inhibited by the general serum proteinase inhibitor  2-macroglobulin and a family of specific tissue inhibitors called tissue inhibitors of MMPs (TIMPs).2-7 MMPs and TIMPs are usually secreted by stromal cells and macrophages of normal tissues, as well as by vascular endothelial cells. Malignant neoplasms are capable of synthesizing and activating MMPs, particularly MMP-2 and MMP-9, and studies in which MMPs or TIMPs have been manipulated genetically or pharmacologically suggest that both factors are key regulators of tumor growth at both primary and metastatic sites.1-13 The net degradative effects of the MMPs on the extracellular matrix reflect a dynamic equilibrium between the secretion and activation of MMPs and TIMPs.1-13 The impact of this dynamic equilibrium and the various effects of specific MMPs and TIMPs on the invasiveness and metastatic potential of malignant neoplasms are complex and not fully understood.14-16 However, the overall actions of the MMPs in degrading the extracellular matrix and the contribution of these effects on the aggressiveness of malignant tumors seem to be more closely related to the net expression of activated MMPs and TIMPs than the absolute levels of any specific MMP or TIMP.1-3,5,17-19 The complexity of the interactions between MMPs and TIMPs on the various intracellular and extracellular compartments of both tumors and stromal tissues also confounds efforts directed at identifying components of these processes that accurately reflect the net effects of MMPs and TIMPs in malignant tumors and that can be measured reliably in the clinic.20,21 Based on the results of preclinical studies delineating the critical roles of MMPs in tumor invasion, malignant angiogenesis, and metastases, therapeutic strategies targeting MMPs and subcellular constituents involved in the degradation of the basement membrane and extracellular matrix are being evaluated in patients with malignant diseases.3,4,22,23 BAY 12-9566 (Fig 1) is an orally bioavailable biphenyl compound that was originally synthesized and screened for inhibitory activity against MMP-3 (stromelysis). In addition to inhibiting MMP-3, BAY 12-9566 is a potent inhibitor of the critical enzymes MMP-2 and MMP-9, but it is much less effective at inhibiting MMP-1, which seems to be associated with the development of polyarthritis and tendonitis.20,22-24 In preclinical studies, the inhibitory activities of BAY 12-9566 in both in vitro and in vivo models of matrix invasion, malignant angiogenesis, and tumor growth were notable.24-31
BAY 12-9566 was active in various models of tumor metastases.25,26 In a subcutaneously implanted Lewis lung carcinoma that spontaneously metastasized to the lungs, daily oral treatment of mice with BAY 12-9566 beginning 3 days after implantation delayed the growth of primary tumors by 50% and reduced the total number of lung metastases and lung lesions greater than 3 mm3 by 86% and 90%, respectively.25,26 In an experimental metastasis model in which B16.F10 murine melanoma cells were injected into the tail vein of mice, treatment with BAY 12-9566 from 24 hours before implantation to 48 hours after implantation reduced the total number of lung metastases and lesions greater than 2 mm3 by 58% and 80%, respectively.25,26 BAY 12-9566 also inhibited the growth of well-established subcutaneous xenografts of human colon carcinomas.28,29 Furthermore, the agent inhibited growth and metastases of orthotopically-implanted human HCT 16 colon cancer, which more closely resembles the clinical situation with regard to tumor-stromal interactions than tumor xenografts. Therefore, BAY 12-9566 may be superior to traditional xenografts to screen for compounds that inhibit matrix invasion, malignant angiogenesis, and metastasis.28,29 Preclinical pharmacologic studies in mice, rats, guinea pigs, and dogs indicated that BAY 12-9566 is highly bioavailable (70% to 98%) after oral administration, with peak plasma concentrations attained by 0.5 to 2 hours.32 In rats and dogs, drug disposition was almost exclusively through hepatic metabolism and biliary excretion of both parent compound and metabolites.32 Hepatotoxicity, characterized by reversible elevations in serum transaminases, was the principal toxic effect of BAY 12-9566 in both rodents and dogs.30 BAY 12-9566 also modestly depressed erythropoiesis and produced a reversible tubular nephropathy in female rats.30 In vitro studies of the effects of BAY 12-9566 on P450 subfamilies have also indicated that the agent would only be a weak inducer of human P450 isoenzymes.30 In healthy human volunteers treated with BAY 12-9566 at doses up to 100 mg/d, the pharmacokinetics were linear; however, higher doses resulted in less than proportionate increases in plasma drug concentrations.31 The principal objectives of this study were to: (1) characterize and quantify the toxicities of BAY 12-9566 administered on a protracted daily oral dosing schedule in patients with advanced solid malignancies; (2) determine the maximum-tolerated dose of BAY 12-9566 on a oral protracted daily dosing schedule; (3) evaluate the range of steady state BAY 12-9566 plasma concentrations (Css) that can be sustained for protracted durations; (4) seek preliminary information about the effects of BAY 12-9566 on plasma concentrations of specific MMPs and TIMPs that are of potential clinical relevance; and (5) seek preliminary evidence of antitumor activity and clinical benefit.
Eligibility Patients with histologically or cytologically documented assessable or measurable solid malignancies refractory to conventional chemotherapy or for whom no effective therapy existed were candidates for this study. Eligibility criteria also included: (a) age  18 years; (b) an Eastern Cooperative Oncology Group performance status  2 (capable of self-care); (c) a life-expectancy of at least 12 weeks; (d) no treatment with investigational or cytotoxic agents within 28 days, mitomycin C and nitrosoureas within 42 days, or wide-field radiation within 14 days of entering onto study; (e) adequate hematopoietic function (absolute neutrophil count 1,500/µL and platelet count 100,000/µL), hepatic function (serum bilirubin < 1.5 mg/dL; AST and ALT two times the upper limit of institutional normal values; and alkaline phosphatase four times the upper limit of the institutional normal value), and renal function (serum creatinine < 2.0 mg/dL); (f) no history of a major cardiovascular event within 3 months of entering onto study; (g) no known history of hepatitis or human immunodeficiency viral infection; (h) no history of hypersensitivity to any of the components of the study medications, significant drug allergies, or any clinically significant hypersensitivity disorder; (i) no history of primary or metastatic malignant involvement of the CNS; (j) no history or evidence of gastrointestinal disease that could potentially interfere with the absorption of the study medication; and (k) no coexisting medical or psychiatric problems of sufficient severity to limit full compliance with the study. All patients gave written informed consent before treatment according to federal and institutional guidelines.
Study Design, Dosage, and Drug Administration At least three new patients were to be treated at each dose level. Dose escalation in new patients was permitted if no dose-limiting toxicity (DLT) was experienced by a minimum of three patients treated for at least 28 days. If one of three patients experienced DLT during the first 28-day period, at least three additional patients were treated. Intrapatient dose escalation was not permitted. Dose reduction by one dose level was permitted for patients who experienced DLT, which was defined as (1) any grade 3 or 4 toxicity; (2) symptomatic grade 2 toxicity on optimal pharmacologic management; and (3) any grade 2 biochemical toxicity that persisted longer than 7 days. The dose of BAY 12-9566 was held for patients who developed more than or equal to grade 3 toxicity or grade 2 toxicity associated with symptoms or biochemical abnormalities lasting longer than 7 days. After resolution of the toxicity to less than or equal to grade 1, treatment with BAY 12-9566 was resumed at either the same or a reduced dose. If recovery to grade 1 toxicity did not occur within 3 weeks, the patient was withdrawn from the study. Toxicities were evaluated according to the National Cancer Institute Common Toxicity Criteria. The recommended dose for subsequent phase II studies was defined as the highest dose level in which less than two of six new patients experienced DLT. BAY 12-9566 was supplied by Bayer Corporation, Pharmaceutical Division (West Haven, CT) as 12.5-mg, 50-mg, or 200-mg tablets containing micronized BAY 12-9566, anhydrous lactose, microcrystalline cellulose, sodium lauryl sulfate, croscarmelloe sodium, magnesium stearate, and purified water, which was removed during the granulation drying procedure.
Pretreatment and Follow-Up Studies
Pharmacologic Studies of BAY 12-9566 The procedures used for sample extraction and high-performance liquid chromatography (HPLC) were previously reported.33 Briefly, 0.5 mL of plasma was added to 1 mL of a 0.5% phosphoric acid in acetonitrile solution containing BAY 13-8825 internal standard (4-[4-{chlorophenyl}phenyl]-4-oxo-2S-[4-ethylphenylthiomethyl]) butanoic acid. After centrifugation, a 50- to 75-µL sample was injected onto the HPLC system. An Ultrasphere C8 5 mm, 250 x 4.6–mm column (Beckman, Palo Alto, CA) was used for a gradient elution followed by reverse-phase HPLC separation using ultraviolet detection at 280 nanometers (nm). The mobile phase consisted of varying proportions of solution A (100 mmol/L acetate buffer, pH 3.5) with solution B (100 mmol/L acetate buffer, pH 3.5 solution/acetonitrile [10/90 volume per volume ]) at a flow rate ranging from 0.8 to 1.8 mL/min. Retention times were 16.2 to 16.7 minutes and 19.8 to 20.6 minutes for BAY 12-9566 and BAY 13-8825, respectively. Standard curves were formulated using known BAY 12-9566 concentrations (0.05 to 50 µg/mL). BAY 12-9566 plasma concentrations were derived by linear correlation based on known concentrations of BAY 13-8825 and the relative peak height response ratio of BAY 12-9566 to the internal standard. The standard linear regression curves of concentration versus peak height response ratios were first order with a 1/yr weighting factor. The assay had a lower limit of detection of 0.02 µg/mL, a lower limit of quantification of 0.05 µg/mL, a precision ranging from 0% to 6.23% relative standard deviation, and an accuracy exceeding 91.3%.
MMP and TIMP-2 Studies Active MMP-9 was measured using a similar Biotrak "sandwich" ELISA kit. Ninety-six well plates were precoated with polyclonal antibodies to MMP-9 to bind both free active and pro-MMP-9. To measure the bound active MMP-9 fraction after incubation with the primary antibody, the sample was incubated with a pro-form of a detection enzyme (S-2444) that is cleaved in the presence of active MMP-9 to yield a chromogenic peptide product. Plasma was diluted 1/32 with a buffer solution. Standards and samples were initially incubated in microtiter wells precoated with antiMMP-9 antibody. After an overnight incubation at 4°C followed by washing, 50 µL of detection solution, which consisted of the S-2444 peptide substrate and a detection enzyme solution composed of modified urokinase in 50 mmol/L Tris HCl buffer pH 7.6, 150 mmol/L sodium chloride, 5 mmol/L calcium chloride, 1 µmol/L zinc chloride, and 0.01% BRIJ 35 (Biotrak), was added to each well. The resultant color was measured at 405 nm using a microtiter plate spectrophotometer. The lower limit of assay sensitivity was 500 pg/mL.
General Twenty-one patients, whose characteristics are listed in Table 1, were treated with 47 28-day courses of BAY 12-9566 through six discrete dose schedule levels, as listed in Table 2. Prior treatment consisted of at least chemotherapy in 20 subjects and immunotherapy only in one subject. The median number of therapy courses administered was two (range, one to six courses). Two individuals required dose schedule modifications for toxicity. In one of these subjects, the BAY 12-9566 dose schedule was modified from 400 mg three times daily to 400 mg twice daily because of an isolated grade 3 elevation in serum bilirubin. The other individual experienced protracted grade 2 nausea, vomiting, and malaise, resulting in a BAY 12-9566 dose schedule modification from 400 mg four times daily to 400 mg three times daily.
A maximum-tolerated BAY 12-9566 dose was not determined in the range of total daily doses evaluated, and the feasibility of administering higher total daily doses was not assessed because plasma BAY 12-9566 Css values exceeded biologically relevant concentrations, increased proportionately less than increasing BAY 12-9566 doses, and seemed to plateau as total daily BAY 12-9566 doses were increased.
Toxicity The most common biochemical abnormalities noted during the study were elevations in serum concentrations of hepatic transaminases and/or bilirubin and hypophosphatemia. A heavily pretreated 33-year-old man with an osteosarcoma and liver metastases experienced an isolated elevation in total serum bilirubin. The patient’s total serum bilirubin increased from a pretreatment value of 0.8 mg/dL to a peak value of 1.5 mg/dL on day 18 of his first course of treatment with BAY 12-9566 at the 400-mg three times daily dose level. Concomitant elevations in hepatic transaminases and/or alkaline phosphatase were not noted. This modest, albeit grade 3, toxicity resolved completely within 5 days after treatment was discontinued and did not recur after resumption of BAY 12-9566 at a reduced dose of 400 mg twice daily. Five other subjects experienced isolated, grade 1 and 2 elevations in AST and ALT at most dose schedule levels, which may have been related to the study drug. Hypophosphatemia, which was noted in 12 patients at some time during treatment, was not associated with any other specific symptom, physical manifestation, or biochemical abnormality and was readily corrected after oral treatment with inorganic phosphorous. Hematologic effects of potential clinical significance were uncommon. Albeit uncommon, thrombocytopenia was the principal hematologic effect of BAY 12-9566. Although absolute decrements in platelet counts were common, clinically significant reductions in platelets to less than 100,000/µL were noted in only four subjects. The most profound event was experienced by a 73-year-old heavily pretreated woman with metastatic breast cancer whose platelet count decreased from a pretreatment level of 242,000/µL to 39,000/µL on day 15 of her second course of BAY 12-9566 at the 400-mg three times daily dose level. Moderate anemia was also evident. The study drug was discontinued, and treatment was never restarted because of tumor progression. Additionally, a 54-year-old heavily pretreated woman with a widely metastatic malignant carcinoid neoplasm developed grade 2 thrombocytopenia (nadir platelet count, 69,000/µL) during her first course of BAY 12-9566 at the 400-mg four times daily dose level. She also experienced intermittent, albeit persistent, nausea and vomiting, which led to a BAY 12-9566 dose level reduction to 400 mg three times daily. During three subsequent courses of BAY 12-9566 at this dose level, her platelet counts ranged from 61,000/µL to 100,000/µL, and nausea and vomiting were seldom experienced. Two other heavily pretreated patients developed grade 1 thrombocytopenia (nadir platelet counts, 83,000/µL and 88,000/µL) at some time during their treatment with BAY 12-9566 at the 400-mg three times daily and 400-mg four times daily dose levels. Anemia, mild to moderate in severity, occurred occasionally and required an RBC transfusion in only one individual. WBC depressions were not noted.
Studies of MMPs in Plasma
Pharmacologic Studies BAY 12-9566 plasma concentrations peaked 4 to 8 hours after treatment. Css values from plasma sampled before treatment on days 15, 29, and 57 were similar. A scatterplot of individual, as well as mean (± SD), plasma Css values from samples obtained before dosing on day 15 of the first course as a function of the dose schedule of BAY 12-9566 is shown in Fig 3. Css values increased less than proportionately as the daily BAY 12-9566 dose was increased within the dose range of 100 to 1,600 mg/d. Plasma Css averaged 35.77 ± 4.16 µg/mL (100 mg once daily), 86.80 ± 8.99 µg/mL (400 mg once daily), 113.25 ± 21.55 µg/mL (400 mg twice daily), 115.39 ± 39.19 µg/mL (400 mg three times daily), 105 ± 43.08 µg/mL (400 mg four times daily), and 141.86 ± 53.57 µg/mL (800 mg twice daily). BAY 12-9566 plasma Css values averaged 121.99 ± 48.23 µg/mL in patients treated with a total daily BAY 12-9566 dose of 1,600 mg/d. Except for Css values at the 100 mg/d dose level that were significantly less than those at all other dose levels (Student’s t test; P < .05), there were no significant differences in plasma Css values resulting from treatment with BAY 12-9655 at daily doses of 400, 800, 1,200, and 1,600 mg. However, the numbers of patients at each dose schedule level were small. No relationships between BAY 12-9566 plasma Css and changes in plasma concentrations of total MMP-2 and MMP-9 levels were evident.
MMPs play important roles in tumor growth, invasion, and metastasis, and represent logical strategic targets for anticancer therapeutic development.1-4,23 BAY 12-9566 is a potent and selective inhibitor of MMP-2, MMP-3, and MMP-9, which are associated with tumor invasiveness and metastasis.1-11 The rationale for developing selective inhibitors of MMPs is that these agents may exhibit higher therapeutic indices than the first generation of nonspecific MMP inhibitors. This reasoning is based on the hypothesis that musculoskeletal toxicity is related to the nonspecific inhibition of the collagenases MMP-1 and MMP-13, which may not be as important targets as MMP-2, MMP-3, and MMP-9 in treating malignant diseases.1-11,20,23,33,34 Inflammation of the tendons and ligaments, which is the principal toxicity of the first generation nonspecific oral MMP inhibitor marimastat (British Biotech, Inc, Oxford, United Kingdom), was not observed in animal toxicology studies of BAY 12-9566.4,20,23,34,35 Similarly, musculoskeletal effects were not noted in patients with advanced solid malignancies who were treated with BAY 12-9566 in the present study or in other early clinical investigations with BAY 12-9566.36-38 In fact, there were no consistent adverse effects or an unacceptably high incidence of DLTs to preclude dose escalation of BAY 12-9566 on the daily treatment schedules evaluated in the present study. The most common adverse effects were headache, nausea, vomiting, thrombocytopenia, elevations of hepatic transaminases, and hypophosphatemia. These toxicities were neither dose- nor concentration-dependent, were generally mild to moderate in severity, were and self-limiting and/or responsive to conservative measures of treatment. Unfortunately, the refractory nature of the malignant neoplasms of the patients in phase I studies, in general, preclude ascertaining much relevant information about the long-term effects of BAY 12-9566 and other cytostatic agents that have required protracted administration for optimal efficacy in preclinical studies. However, the limited experience with the four individuals who were treated for at least 4 months in the present study suggests good long-term tolerance of BAY 12-9566 on a protracted divided daily dosing schedule. Because BAY 12-9566 and other MMP inhibitors may be combined with cytotoxic agents in many disease settings,4,30 both acute and chronic overlapping toxicities may occur, particularly if BAY 12-9566 is administered in combination with agents that commonly induce thrombocytopenia and/or hepatotoxicity. This concern is only speculative at this juncture, and, in fact, the preliminary clinical results with BAY 12-9566 suggest a low likelihood for clinically relevant toxicologic interactions with several commonly used cytotoxic anticancer agents.4,30 It may be prudent, however, to evaluate the potential for both toxicologic and pharmacokinetic drug interactions in the phase I setting before disease-directed evaluations of BAY 12-9566–based combination chemotherapy are performed. The decision to terminate further dose escalation in the present study was based on progressively smaller increases in plasma Css values as the daily dose of BAY 12-9566 was increased from 100 to 1,600 mg and the plateau effect of plasma Css values at the higher doses. Mean plasma Css values increased from 35.77 ± 4.16 µg/mL to 86.80 ± 8.99 µg/mL as the total daily dose of BAY 12-9566 was increased from 100 to 400 mg. This situation of diminishing pharmacologic returns was much more pronounced at the higher dose levels; plasma BAY 12-9566 Css values averaged 113.25 ± 21.55 µg/mL, 115.39 ± 39.19 µg/mL, and 121.99 ± 48.23 µg/mL after treatment with total daily doses of 800, 1,200, and 1,600 mg, respectively. Although the lack of individual plasma concentration time plots at all dose levels precludes drawing definite conclusions regarding the etiology of this behavior, these results suggest that the absorption of BAY 12-9566 is a saturable process. Based on the pharmacologic profile, the acceptable toxicologic profile associated with protracted dosing at the 1,600-mg/d dose level and the nearly identical toxicologic and pharmacologic profiles associated with four times daily and twice daily dosing schedules, an 800-mg twice daily dosing schedule is recommended for further disease-directed evaluations. However, it must be acknowledged that all BAY 12-9566 dose schedules with total daily doses of 800, 1,200, and 1,600 mg/d in this study resulted in similar Css values, although the statistical power of such comparisons is low because of the small numbers of patients treated at each dose level. Therefore, it is possible that all of these dose schedules may result in similar functional and therapeutic effects. It is encouraging that plasma Css values were at least two to three orders of magnitude higher than the Ki values reported for MMP-2, MMP-3, and MMP-9.24 Although projections about the use of deriving optimal therapeutic doses of compounds by comparing pharmacologic parameters achieved in plasma with in vitro data may be misleading, the sheer magnitude of the plasma Css values achieved in the present study negates, at least in part, concerns that the pharmacologic behavior of BAY 12-9566 in the plasma compartment may not accurately reflect drug behavior in peripheral tissues and tumors. For example, differences between protein concentrations in preclinical studies and human plasma and interspecies differences in the magnitude and avidity of protein binding may result in difficulties gauging the relevance of any particular plasma Css value, as well as using plasma Css to guide dosing recommendations. For BAY 12-9566, the absolute magnitude of plasma Css values achieved in patients relative to MMP Ki values determined in vitro is much less impressive, even after the potential influence of high protein binding (99.9%) is taken into account.31 However, the relationships between free drug concentrations and drug effect is not known. The exploratory studies of MMP-2, MMP-9, and TIMP-2 in the present trial were undertaken to identify readily assessable and quantifiable parameters that reflect MMP inhibition. Hypothetically, such markers may be used to monitor MMP activity, determine the optimal dose schedule of MMP inhibitors, detect disease progression, and quantify responsiveness to therapy.2,4,13-16,20-23,39-48 However, despite achieving biologically relevant plasma concentrations of BAY 12-9566, there were no consistent effects of BAY 12-9566 on plasma concentrations of MMP-2, and MMP-9. On the other hand, the percent decrement in TIMP-2 was moderately related to the total daily dose of BAY 12-9566. The mechanism accounting for this possible relationship is not known, but the overall direction of the relationship is somewhat paradoxical because a compensatory decrease in TIMP-2 might have been expected after inhibition of MMP-2. Nearly identical results have been reported using enzyme zymography to measure plasma concentrations of MMP-2 and MMP-9 in phase I trials of the MMP inhibitors marimastat and batimastat (BB-94; British Biotech, Inc, Oxford, United Kingdom).4,20,23,46 The preliminary results of exploratory studies measuring plasma concentrations of vascular endothelial growth factor and basic fibroblast growth factor and urinary levels of pyridinoline and deoxypyridinoline in other phase I studies of BAY 12-9566 also revealed no consistent patterns.36 However, these negative results do not absolutely indicate that MMP inhibitors are incapable of affecting relevant subcellular targets in humans. There may be substantial differences in the activities of MMP-2, MMP-9, and TIMP-2 between peripheral tissues and plasma, and, therefore, inferences regarding these proteins in tumors based on measurements in plasma may be inaccurate. In addition, little is known about the relationships between the total and activated forms of MMPs and TIMPs in both the plasma and tissue compartments.1-4,40,47 Still, it is conceivable that some tumor types are more likely to produce readily quantifiable levels of activated MMPs than others, and attempts to identify reliable surrogates of effect should continue in disease-directed studies and more homogenous patient populations. Although the recommended dose of BAY 12-9566 for subsequent disease-directed studies, 800 mg twice daily, is based, in part, on the achievement of biologically relevant pharmacologic end points and the leveling off of Css values in the higher range of BAY 12-9566 doses evaluated in this study, optimal dose selection in phase I studies may not be as clear for other MMP inhibitors and other classes of cytostatic agents. In addition to guiding optimal dose schedule selection, the identification of readily assessable surrogate markers of biologic activity will likely facilitate the screening of novel MMP inhibitors and cytostatic agents for clinically relevant activity in the phase II setting before initiating resource-intensive phase III evaluations. Although a somewhat loose notion regarding the potential usefulness of such agents may be obtained by comparing end points such as progression-free and overall survival in phase II studies with historical data, there are many potential flaws inherent in such nonrandomized approaches. The availability of validated and readily quantifiable surrogates of target effect is likely to facilitate clinical screening and enhance decision making about the potential use of novel therapeutics in early developmental phases. However, because reliable surrogates of MMP inhibition are not yet available, and, given the many potential flaws of nonrandomized phase II screening studies to assess the antiproliferative effects of such cytostatic agents, randomized phase III evaluations in relevant clinical settings may be the next most logical developmental step for BAY 12-9566, and such studies are currently in progress.
Supported by a research grant from Bayer Corporation, Pharmaceuticals Division, West Haven, CT.
Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
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INTRODUCTION
