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© 2002 American Society for Clinical Oncology Matrix Metalloproteinase Inhibitor COL-3 in the Treatment of AIDS-Related Kaposi’s Sarcoma: A Phase I AIDS Malignancy Consortium StudyByFrom the Beth Israel Deaconess Medical Center; Boston Medical Center; and Massachusetts General Hospital, Boston, MA; Northwestern University, Chicago, IL; Washington University, St Louis, MO; Memorial Sloan-Kettering Cancer Center, New York, NY; Clinical Pharmacokinetics Section and Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and AIDS Malignancy Consortium Operations Center, University of Alabama at Birmingham, Birmingham, AL. Address reprint requests to Bruce Dezube, MD, Beth Israel Deaconess Medical Center, 330 Brookline Ave, CC-913, Boston, MA 02215; email: bdezube{at}caregroup.harvard.edu
PURPOSE: Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and are overexpressed in Kaposi’s sarcoma (KS) cells. The primary aim was to define the safety and toxicity of the MMP inhibitor COL-3 in patients with AIDS-related KS. Secondary aims were to evaluate tumor response, pharmacokinetics, and changes in blood levels of MMP-2, MMP-9, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF). PATIENTS AND METHODS: COL-3 was administered orally once daily, and doses were escalated in cohorts of three to six subjects. Patients with symptomatic visceral KS or severe tumor-associated edema were excluded. Antiretroviral therapy was permitted but not required. Study end points were grade 3 or 4 toxicity or progressive KS. Serial blood specimens were obtained for pharmacokinetics and levels of MMP-2, MMP-9, VEGF, and bFGF. RESULTS: Eighteen patients received COL-3 in dosing cohorts of 25, 50, and 70 mg/m2/d. Prior KS therapy was reported by 17 patients (94%). COL-3–related grade 3 or 4 adverse events were reported by six patients and included photosensitivity, rash, and headache. There was one complete response and seven partial responses, for an overall response rate of 44%, with a median response duration of 25+ weeks. The median COL-3 half-life was 39.3 hours (range, 4.1 to 251.1 hours). There was a significant difference between responders and nonresponders with respect to the change in MMP-2 serum levels from baseline to minimum value on treatment (P = .037). CONCLUSION: COL-3 administered orally once daily to patients with AIDS-related KS is reasonably well tolerated. The most common adverse event was dose-related photosensitivity. Antitumor activity was noted. Further evaluation of COL-3 for the treatment of KS is warranted.
ANGIOGENESIS PLAYS a key role in the pathogenesis of Kaposi’s sarcoma (KS), the most common malignancy among patients infected with the human immunodeficiency virus (HIV).1 In vitro KS cells secrete cytokines, such as vascular endothelial growth factor (VEGF)2 and basic fibroblast growth factor (bFGF),3 which stimulate angiogenesis through autocrine and paracrine mechanisms. The process of angiogenesis involves many critical steps, one of which is the breakdown of the extracellular matrix. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are involved in the destruction of extracellular matrix proteins.4 MMPs may be divided into three classes based on their substrate specificity: collagenases, gelatinases, and stromelysins. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) degrade collagen IV, the major component of basement membranes, are involved in tumor invasion and metastasis,5-7 and are constitutively overexpressed in KS cells.8 Naturally occurring tissue inhibitors of matrix metalloproteinases (TIMPs) have been identified and shown to inhibit tumor-cell invasion and angiogenesis.9-11 In murine models, increasing levels of skin and liver TIMP expression lead to inhibition of the growth and metastasis of T-cell lymphomas, whereas decreasing the TIMP levels leads to more rapid tumor growth, metastases, and death.12 Similarly, synthetic matrix metalloproteinases inhibitors (MMPIs) have been shown to inhibit angiogenesis and tumor-cell growth in murine models.13-16 COL-3, 6-demethyl-6-deoxy-4-dedimethylaminotetracycline (Metastat; Collagenex Pharmaceuticals, Newtown, PA) is a chemically modified tetracycline.17 COL-3 inhibits the in vitro activity of activated neutrophil gelatinase and the expression of MMPs in human colon and breast carcinoma cell lines in a dose-dependent manner. Furthermore, COL-3 inhibited the invasion of multiple carcinoma cell lines into matrigel and the invasiveness of a human melanoma cell line through basement membrane matrix. The ability of COL-3 to inhibit the activity, activation, and production of MMPs distinguishes it from other MMPIs, which target only the active enzyme.18 Administration of COL-3 via oral lavage to rats at the time of subcutaneous implantation of tumor cells resulted in marked diminution of both palpable and pulmonary metastases. Preclinical studies in rats and monkeys revealed gastrointestinal toxicity to be dose-limiting. On the basis of preclinical pharmacology-toxicology studies, a daily oral schedule of COL-3 was chosen to determine its safety and toxicity and, secondarily, to evaluate its antitumor activity, pharmacokinetics, and effects on levels of MMP-2, MMP-9, VEGF, and bFGF in patients with AIDS-related KS.
Patients Eighteen patients with biopsy-proven AIDS-related KS were accrued at sites participating in the AIDS Malignancy Consortium (AMC) of the National Cancer Institute (NCI). All patients gave written informed consent in accordance with human experimentation guidelines of the United States Department of Health and Human Services and the Human Investigations Committees at each of the participating sites. Patients were required to have KS that involved the skin, with a minimum of five measurable lesions and no pulmonary involvement, symptomatic gastrointestinal involvement, or severe tumor-associated edema. Additional eligibility criteria included documentation of HIV infection, a Karnofsky performance status  60%, and the following laboratory parameters: hemoglobin 9.0 gm/dL, absolute neutrophil count 1,000 cells/mm3, platelet count 75,000/mm3, serum creatinine  1.5 mg/dL (or measured creatinine clearance of > 60 mL/min), AST and ALT 2.5 times the upper limit of normal, and a normal total bilirubin. HIV infection was documented by a positive enzyme-linked immunosorbent assay (ELISA; R&D Systems, Minneapolis, MN), Western Blot, or other federally approved, licensed HIV test. Exclusion criteria included pregnancy, concurrent active opportunistic infection, symptomatic visceral KS that required cytotoxic therapy, and a history of noniatrogenic bleeding disorders. Patients could not have received treatment for KS within 3 weeks of study entry. Antiretroviral therapy was permitted but not required. Patients taking antiretroviral therapy could not have had a medication change within 4 weeks of study entry. No blood products were permitted within 4 weeks of study entry, and granulocyte colony-stimulating factor and erythropoietin were not permitted within 2 weeks of study entry.
Phototoxicity had been observed in ongoing trials of COL-3, and, therefore, all patients on this trial were instructed to wear sunscreen of SPF
Study Design Dose-limiting toxicity (DLT) was defined as any toxicity attributable to the study drug that was grade 3 or greater (NCI common toxicity criteria) except for grade 3 phototoxicity or lymphopenia of any grade. Dose escalations occurred after a minimum of three patients had completed 28 days of therapy without a DLT. If one subject out of the initial three patients on a dose level exhibited a DLT during this 28-day period, up to three additional patients were to be added to that level. If a second subject exhibited a treatment-related DLT, then the next lowest dose level was considered to be the maximum-tolerated dose, and a total of six patients were then treated on that level. No intrapatient dose escalations were allowed. The study end points were grade 3 or 4 toxicity or disease progression. With the first occurrence of a DLT, COL-3 was not administered until the DLT resolved. If the DLT resolved within 2 weeks, then COL-3 was restarted at the next lowest dose level.
Schedule of Events
Pharmacokinetics
Assays for MMP-2, MMP-9, VEGF, and bFGF
Statistics and Response Criteria Summary statistics were used to describe the study population and pharmacokinetic results by dose level. The results of the safety and tumor evaluations were tabulated by dose levels. The tumor response rate was estimated for each dose group and for all dose groups combined. Descriptive statistics were used to evaluate the incidence of adverse events. The binomial proportion and its 95% confidence interval were used to estimate the objective response rate. The Wilcoxon signed rank test was used to evaluate changes in MMP-2, MMP-9, VEGF, and bFGF levels from baseline to minimum value on treatment. The Wilcoxon rank sum test was used to compare responders and nonresponders with respect to change from baseline to minimum value on treatment in MMP-2, MMP-9, VEGF, and bFGF levels. The Spearman Rank Correlation Coefficient was used to test correlations between pharmacokinetic parameters (AUC0-t) with clinical toxicity, as well as with changes in MMP-2, MMP-9, VEGF, and bFGF levels. Criteria for statistical significance was at the .05 level.
Baseline Characteristics Three patients were enrolled onto and treated at level A. Because none of these patients developed a dose-limiting toxicity during the first 28 days of treatment, three patients were enrolled onto level B. When the first level B patient developed dose-limiting photosensitivity, the level B cohort was expanded. After the fourth patient was enrolled onto level B, however, a second patient on this level developed severe photosensitivity. At that point, two additional patients were enrolled onto level A. Shortly after their entry onto the study, one developed a severe rash that required discontinuation of COL-3, and one of the initial level A patients developed severe photosensitivity. Subsequently, nine patients were enrolled onto level A0. Thus, a total of 18 patients were enrolled: five onto level A, four onto level B, and nine onto level A0. Baseline patient characteristics are listed in Table 1. Prior therapy for KS was reported by 17 patients (94%). The most frequently reported prior therapies were single-agent chemotherapy with liposomal daunorubicin (61%), paclitaxel (50%), and liposomal doxorubicin (44%). At the time of study entry, 14 patients (78%) were receiving highly active antiretroviral therapy that consisted of nucleoside reverse transcriptase inhibitors in combination with a protease inhibitor and/or non–nucleoside reverse transcriptase inhibitors. Although the protocol required that patients be on a stable antiretroviral regimen for only 28 days before study entry, 12 of these 14 patients had been on the same regimen for more than 90 days before study entry. The median time between initiation of the stable highly active antiretroviral therapy regimen and study entry was 12 months (range, 28 days to 16 months).
Clinical Events The median duration of therapy was 9.5 weeks. Six patients (33%) remained on study for more than 6 months. Seventeen patients have terminated study drug therapy. Nine patients (50%) terminated because of adverse events: five patients in arm A0 (two of whom experienced grade 3 events), two in arm A, and two in arm B. The reasons for termination included rash, pruritus, fever, nausea, arthralgia, myalgia, and fatigue in arm A0; rash and photosensitivity in arm A; and photosensitivity in both arm-B patients. The protocol excluded grade 3 phototoxicity as a dose-limiting toxicity. However, we found that grade 2 (painful erythema or eruption/erythema/desquamation that covers < 50% of body surface) and grade 3 (eruption/erythema/desquamation that covers 50% of body surface) phototoxicity were not tolerated by patients and led to treatment discontinuations or dose reductions. Level A0 was, therefore, defined as the MTD according to protocol-defined criteria based on the occurrence of only one nonphototoxic grade 3 adverse event in the nine patients treated at this level. All patients reported adverse events. The most common were photosensitivity and rash. Two (22%) of the patients on arm A0 developed photosensitivity of any grade, as did three (60%) on arm A and three (75%) on arm B. No significant difference was detected between patients with photosensitivity and those without photosensitivity with respect to AUC0-t. Of the eight patients who reported rashes, five were on arm A0, one was on arm A, and two were on arm B. Five patients (28%) reported adverse events of grade 3 or higher that were possibly, probably, or definitely related to the study drug (Table 2). In one arm-A patient, the rash was generalized and urticarial and required systemic corticosteroids for treatment. Biopsy samples from this patient showed interface and perivascular dermatitis typical of a drug reaction. No grade 3 or higher hematologic toxicities have been reported. One patient on arm A had elevated alkaline phosphatase and transaminases (grade 3), and one patient on arm B had elevated bilirubin levels (grade 3).
Pharmacokinetics The median peak plasma concentration (Cmax) increased with dose but varied between patients within each dose level (Table 3). Median Cmax was 1,285, 1,532, and 2,174 ng/mL for the 25-, 50-, and 70-mg/m2 dose levels, respectively. The median single-dose t1/2 was 39.3 hours (range, 4.1 to 251.1 hours). The median ClT/F of COL-3 and median Vdpss/F were 0.849 L/h and 49.9 L, respectively. Because the sampling schedule was limited to 24 hours in this trial and because COL-3 had been noted to have a median t1/2 of 56 hours in patients with refractory metastatic cancer in a another trial conducted at the NCI, the t1/2, ClT/F, and Vdpss/F are estimates.21 In the NCI trial, pharmacokinetic sampling had been obtained during a period of 130 hours. Although the time of maximal concentration (tmax) ranged from 2.0 to 48.1 hours in that trial, the tmax and Cmax were less susceptible to limited sampling.
To explore the relationship between COL-3 pharmacokinetics and body-surface area (BSA), the correlation between clearance and BSA was analyzed. Clearance was chosen because it is a dose-independent pharmacokinetic parameter. Although apparent clearance increased when BSA increased (r = .728, P = .002), the clinical relevance of this finding is uncertain on the basis of our limited phase I study.22
Plasma MMP, VEGF, and bFGF Levels
Antitumor Effects We observed one complete response and seven partial responses, for an overall response rate of 44% (95% confidence interval, 21% to 67%) (Table 5). Three arm-A0 patients whose response could not be evaluated ceased therapy after less than 2 weeks because of adverse events. Two of these patients had grade 2 phototoxicity, which although not prospectively defined by the protocol as a DLT, proved intolerable. The baseline viral load of the responders (median, 297 copies/mL; range, 178 to 74,687 copies/mL) was not statistically significant from that of the nonresponders (median 4,703 copies/mL; range, 271 to 750,000 copies/mL). Median time to response was 4 weeks (range, 2 to 34 weeks), and median response duration was 25+ weeks.
KS, which can be characterized as an angiogenic inflammatory neoplasm, serves as an excellent model to study angiogenesis and angiogenesis inhibitors. This angiogenic-inflammatory milieu is created by the MMPs, VEGF, bFGF, and many other cytokines, which are expressed by KS cells.23-24 The rationale for studying COL-3 in KS patients was based on its ability to inhibit this angiogenic-inflammatory neoplasm in preclinical model systems. COL-3 administered orally once daily to patients with AIDS-related KS was reasonably well tolerated. The most commonly reported severe adverse event was photosensitivity. The frequency of any grade of photosensitivity seemed to increase with dose; however, the small sample size does not permit a firm association to be made. One complete response and seven partial responses were seen on this trial, for an overall response rate of 44%. The median time to response was 4 weeks, and median response duration was 25+ weeks. Four responses lasted longer than 6 months. Other tetracycline analogs (ie, doxycycline, demeclocycline, lymecycline, methacycline, minocycline, oxytetracycline, and tetracycline) have t1/2s that range from 5.1 to 26.1 hours.25-32 In the NCI trial, the median t1/2 of COL-3 was 56.7 hours,21 whereas in this trial, the median t1/2 was 39.3 hours. This may have been underestimated, however, because the pharmacokinetic sampling lasted only 24 hours. Cmax and tmax in our trial were consistent with those of the NCI trial. Although not corrected for plasma protein, the Cmax in our trial after a single dose was within the range noted to have antitumor activity in preclinical models. COL-3 has a longer t1/2 and larger apparent volume of distribution than other tetracycline analogs, which may reflect this compound’s lipophilic nature. We measured blood levels of MMP-2, MMP-9, VEGF, and bFGF levels in this trial as potential indicators of the biologic activity of COL-3. Although we did not observe significant decreases in the levels of any of these with treatment, responding and nonresponding patients showed a significant difference when changes in MMP-2 levels were compared. There was also a marked differential change between responders and nonresponders in VEGF levels, but this did not reach statistical significance, perhaps because of the small sample size. The biologic significance of these differences is not clear, however, and may bear no relationship to the mechanism of action of COL-3. Measurement of changes induced in the tumors may be of greater sensitivity and biologic relevance than changes in the blood; such evaluations were, however, not performed in this study. Furthermore, it is possible that the observed therapeutic responses were mediated by the modulation of other cytokines that were not measured. For example, tetracycline derivatives have been demonstrated to downregulate the expression of proinflammatory and autoimmune mediators, such as tumor necrosis factor-alpha, interleukin-1 beta, nitric oxide synthase, and prostaglandin E2.33 In conclusion, COL-3 administered orally once daily is reasonably well tolerated and has moderate antitumor activity in patients with AIDS-related KS. To our knowledge, this is the first study in patients with AIDS-related KS of a drug developed specifically as an MMPI, and the first in which MMP levels were measured. Our findings support further evaluation of COL-3 as a single agent in patients with early KS and in combination with other agents in patients with more advanced disease, along with additional studies to investigate the mechanism of COL-3–induced tumor regression. A phase II AMC trial of COL-3 at fixed doses in AIDS-related KS is currently in progress.
APPENDIX
Supported by grant nos. U01 CA70047, U01 CA70054, U01 CA70072, U01 CA70080, U01 CA71375, U01 CA70062, U01 CA70019, and U01 CA83035 from the National Cancer Institute, Bethesda, MD, and grant nos. RR 01032, RR 00036, and RR 00533 from the General Clinical Research Center Program, National Center for Research Resources, Bethesda, MD. We thank Jamie Von Roenn, MD, and Ellen Feigal, MD, for their support and input into the design of this study, Brad Zerler, PhD, of Collagenex Pharmaceuticals for helpful suggestions, and the many study coordinators and research nurses. The AMC thanks all the participating patients and all their referring physicians.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
