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Randomized Phase II Trial of Matrix Metalloproteinase Inhibitor COL-3 in AIDS-Related Kaposi's Sarcoma: An AIDS Malignancy Consortium Study

Bruce J. Dezube, Susan E. Krown, Jeannette Y. Lee, Kenneth S. Bauer, David M. Aboulafia

From the Beth Israel Deaconess Medical Center, Boston, MA; Memorial Sloan-Kettering Cancer Center, New York, NY; Virginia Mason Cancer Center, Seattle, WA; School of Pharmacy, University of Maryland, Baltimore, 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; e-mail: bdezube{at}bidmc.harvard.edu

	ABSTRACT

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PURPOSE: Matrix metalloproteinases (MMPs) are involved in tumor metastasis and are overexpressed in Kaposi's sarcoma (KS) cells. In a phase I trial of the MMP inhibitor COL-3 in patients with AIDS-related KS, the drug was well tolerated, KS regression was observed, and MMP-2 levels decreased significantly in responders compared with nonresponders. The aim of this trial was to extend these initial observations.

PATIENTS AND METHODS: This was a randomized, parallel-group, phase II study. COL-3 was administered orally once daily at one of two doses (group A received 50 mg and group B received 100 mg) to patients with AIDS-related KS. Antiretroviral therapy was permitted but not required. Serial tumor assessments and plasma levels of MMPs were obtained. Study end points were progressive KS and recurrent dose-limiting toxicity.

RESULTS: Seventy-five patients received COL-3: 37 in group A and 38 in group B. Fifty-seven patients (76%) had received prior KS therapy. Thirty-three patients (44%) had more than 50 KS lesions. The response rate in group A was 41%, which was significantly greater than the prespecified target rate of 20% (95% CI, 25% to 58%; P = .003); the response rate of group B was 29% (P = not significant). There were significant declines in MMP-2 and MMP-9 plasma levels from baseline to minimum value with treatment (MMP-2, P < .001; MMP-9, P = .001). The most common adverse events were photosensitivity and rash.

CONCLUSION: COL-3, when administered as 50 mg/d, is both active and well tolerated in the treatment of AIDS-related KS. COL-3 is a promising agent for the treatment of this opportunistic neoplasm of AIDS.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Acknowledgment and Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Kaposi's sarcoma (KS) is the most common tumor arising in HIV-infected patients and is an AIDS-defining illness. The pathogenesis of AIDS-related KS is multifactorial and involves the KS-associated herpesvirus/human herpesvirus-8, which creates an inflammatory-angiogenic state.^1-3 The process of angiogenesis involves many critical steps, one of which is 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 MMP-2 (gelatinase A) and MMP-9 (gelatinase B) degrade collagen IV, the major component of basement membranes. MMPs facilitate tumor invasion and metastasis, and are constitutively overexpressed in KS cells.^5-8 Overexpression of endothelin-1 in KS lesions increases the secretion and activation of several MMPs.⁹ The HIV-1 transactivating protein, Tat, also upregulates the synthesis and release of MMPs from endothelial and inflammatory cells.¹⁰

COL-3, a chemically modified tetracycline (CollaGenex Pharmaceuticals, Newtown, PA), is a matrix metalloproteinase inhibitor that is distinct in its ability to inhibit the activity, activation, and production of MMPs, whereas other inhibitors of MMPs target only the active enzyme.^11-13 COL-3 inhibits activated neutrophil gelatinase in vitro and the expression of MMPs in human colon and breast carcinoma cells, inhibits invasion of various cancer cell lines in vitro, and inhibits tumor growth and metastasis in a rat model.^14,15

The AIDS Malignancy Consortium (AMC), a clinical trials group supported by the National Cancer Institute (NCI), conducted a phase I study of COL-3 administered once daily to 18 patients with AIDS-related KS.¹⁶ The overall response rate was 44%, and the median response duration was 25+ weeks. Responders and nonresponders differed significantly with respect to the change in MMP-2 plasma levels from baseline to minimum value on treatment. The most common adverse event was dose-related photosensitivity. These findings supported the initiation of a phase II trial of COL-3 in AIDS-related KS to confirm and extend these initial observations and to define more precisely the optimal drug dose. We randomly assigned patients to receive one of two doses of COL-3 in this phase II trial (50 or 100 mg/d), based on the observed tolerance and antitumor activity of similar doses (25 and 50 mg/m², respectively) tested in the phase I trial.

	PATIENTS AND METHODS

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Patient Eligibility
All patients gave written informed consent in accordance with human experimental guidelines of the Department of Health and Human Services and the human investigations committees at each of the participating sites. Patients were required to be 18 years or older, have AIDS-related KS with a minimum of five measurable, previously nonirradiated, cutaneous lesions with asymptomatic or minimally symptomatic GI tract or pulmonary involvement. Additional eligibility criteria included documentation of HIV infection, a Karnofsky performance status 60%, and the following laboratory parameters: hemoglobin 8.0 g/dL, absolute neutrophil count 750 cells/µL, platelet count 75,000/µL, serum creatinine 1.5 mg/dL, AST and ALT 2.5x the upper limit of normal, and a normal total bilirubin. Exclusion criteria included pregnancy, concurrent active opportunistic infection, concurrent neoplasia requiring cytotoxic chemotherapy, history of a bleeding disorder, evidence of a prior myocardial infarction or cardiac ischemia, or acute treatment for a serious medical illness within 14 days before study entry. Patients could not have received antineoplastic treatment within 3 weeks of study entry or local therapy of any KS indicator lesion within 60 days. Antiretroviral therapy was permitted but not required, but the therapy had to be stable for the 4 weeks before 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.

Study Design and Treatment
This was a prospective, randomized, parallel-group, phase II study to evaluate two doses of COL-3 (group A received 50 mg/d; group B received 100 mg/d). COL-3 was supplied by the Cancer Therapy Evaluation Program, NCI, through a collaborative agreement with CollaGenex Pharmaceuticals, and was formulated as 10- and 25-mg hard gelatin capsules. Because phototoxicity had been observed in the phase I trial of COL-3, all patients were instructed to wear sunscreen of skin protection factor 20 on all exposed skin, even during normal activities of daily living, and to cover their skin as much as possible when outdoors.

Patients continued on study as long as their KS was stable or responding and recurrent dose-limiting toxicity (DLT) had not occurred. Reasons for treatment discontinuation included disease progression, pregnancy or breastfeeding, noncompliance with study, or requirement for treatment with systemic chemotherapy or another investigational agent.

DLT was defined as any toxicity attributable to the study drug that was grade 3 or greater (NCI Common Toxicity Criteria, version 2.0) except that only grade 4 thrombocytopenia and grade 2 phototoxicity or rash were considered DLTs. Lymphopenia of any grade was not considered a DLT. With the first occurrence of a DLT, study medication was withheld until the DLT resolved to grade 1 or to baseline within 2 weeks of drug discontinuation. If the DLT resolved, study medication was then resumed at the next lower dose level. Patients with hemoglobin less than 8 g/dL were treated with packed RBC counts and/or erythropoietin, and those with an absolute neutrophil count less than 500 cells/µL were treated with granulocyte colony-stimulating factor. If anemia or neutropenia persisted despite these supportive measures, then the dose of COL-3 was reduced. Patients randomly assigned to group B could have their dose reduced two times: first to 50 mg/d and then to 30 mg/d. Patients randomly assigned to group A could have their dose reduced only once, to 30 mg/d, before being removed from the study. If the DLT did not resolve to grade 1 or to baseline within 2 weeks of drug discontinuation, the patient was removed from the study.

Schedule of Events
Clinical assessments, including history and physical examinations, tumor assessments, complete blood count, serum electrolytes, renal and liver function tests, and amylase and albumin tests were performed 7 to 30 days before study entry; then on days 1, 8, 15, 29; and then every 28 days. CD4⁺ T-lymphocyte counts and HIV-1 viral loads were obtained before study entry, then on day 29, and then every 3 months thereafter. Plasma for measurements of MMP levels were collected before COL-3 administration; on days 29, 57, and 113; and then every 2 months thereafter. Tumor assessments were performed at baseline, at days 29, 57, 113; and then every 2 months thereafter. These assessments were based on measurements of five cutaneous marker lesions and on the overall number and characteristics of cutaneous lesions.¹⁷ In patients with 50 total skin and oral lesions, all lesions were evaluated for change in number and characteristics. In patients with more than 50 lesions, up to three representative anatomic areas were chosen for ongoing evaluation of lesion number and characteristics.

Response Assessment
Responses were graded as complete response, partial response, stable disease, or progressive disease using previously described criteria.¹⁷ All responses were evaluated by three of the authors (B.J.D., D.M.A., and J.Y.L.) based on the data submitted from the study sites.

Assays for MMP-2 and MMP-9
Plasma levels of MMP-2 and MMP-9 were analyzed using Biotrak ELISA kits (RPN2617 for MMP-2; RNP2614 for MMP-9; Amersham Pharmacia Biotech, Piscataway, NJ). The assays used a two-site enzyme-linked immunoassay sandwich format using two antibodies directed against different epitopes of MMP-2 or MMP-9. The assays were performed according to protocol using 100 µL of plasma. The concentration of pro-MMPs in samples was determined by interpolation from a standard curve. MMP-2 was measured in the range of 1.5 to 24 ng/mL and MMP-9 was measured in the range of 4 to 128 ng/mL. The MMP-2 samples were diluted 200-fold with the assay buffer to bring the sample readings into the range of the standard curve.

Statistical Considerations
There was no intent to compare the two dose levels; rather each dose level was tested independently and powered to rule out a response rate of no more than 20%. To test the null hypothesis that the response rate was less than 20% against the alternative hypothesis that it was more than 40% at the one-sided 5% significance level with a power of 80% required 29 patients per group. The enrollment target was set at 75 patients based on anticipated dropouts. The 20% value was based on the response rate below which there would be no interest in pursuing COL-3 as a potential therapeutic target. The value of 40% was based on previous therapeutic KS trials conducted by the AMC in which activity was noted.^16,18 Descriptive statistics were used to evaluate demographic and baseline characteristics. The exact Clopper-Pearson binomial CIs were used to estimate the response rates. The Kaplan-Meier method was used to evaluate treatment duration, response duration, and time to progression. The Wilcoxon signed rank test was used to evaluate changes in the secondary end points MMP-2 and MMP-9 levels from baseline to minimum value on treatment for patients in each group.

	RESULTS

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Patient Characteristics
Seventy-five patients with biopsy-proven AIDS-related KS were accrued from July 2001 to March 2003 from 17 AMC sites. There were no differences between the groups with respect to any of the baseline characteristics (Table 1). The majority had been treated previously for KS, most commonly with liposomal anthracyclines (65%) or paclitaxel (20%). At study entry, most patients (80%) were receiving highly active antiretroviral therapy (HAART). The median time of HAART administration was 17 months (range, 4 weeks to 7 years). Only one patient in group A who was HAART-naïve started taking HAART during the study.

Tumor Response
An intent-to-treat analysis included all 37 and 38 patients in groups A and B, respectively. The response rate in group A was 41% (95% CI, 25% to 58%) and was significantly greater than 20% (P = .003; Table 2). The response rate in group B was 29% (95% CI, 15% to 46%) and was not significantly greater than 20% (P = .12). Three patients had a biopsy-confirmed complete response. The median time to first response was 10 weeks in group A and 19 weeks in group B. The median response duration was 52 weeks in group A and was not reached in group B; 62% of patients were still responding at the time of analysis. There was no difference in response rate at either dose level based on prior receipt of systemic therapy for KS (data not shown). Nonprogressive disease, defined as response plus stable disease, was achieved in 78% of group A patients and 63% of group B patients. When the patients inassessable for response are excluded, the response rates in group A and B are 47% and 35%, respectively.

CD4⁺ Cell Count, HIV-1 Viral Load, and Plasma MMP Levels
To evaluate the relationship between absolute CD4⁺ count at baseline and response (complete or partial), a cut point of 100 cells/µL was used. Responses were observed in three of 14 patients (21%) with CD4⁺ counts less than 100 and in 23 of 61 patients (38%) with CD4⁺ counts 100 (P = .36). The median baseline HIV-1 viral loads of groups A and B were 188 copies/mL (range, < 50 to 531,631 copies/mL) and 400 copies/mL (range, < 50 to 750,000 copies/mL), respectively. The median HIV-1 viral load did not change significantly while on study. To evaluate the relationship between viral load at baseline and response rate, a cut point of 500 copies/mL was used. Responses were observed in 13 of 42 patients (31%) with viral load less than 500 copies/mL, and 10 of 27 patients (37%) with viral load 500 copies/mL (P = .61).

To evaluate the MMP-2 and MMP-9 data, the median change from the baseline to minimum value on treatment was analyzed. Statistically significant decreases in MMP-2 and MMP-9 levels were observed when the two dose level groups were combined (Table 3). The changes in MMP levels from baseline to minimum level on treatment for both MMP-2 and MMP-9 did not differ between responders and nonresponders (P = .41 for MMP-2; P = .88 for MMP-9).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Acknowledgment and Appendix Authors' Disclosures of... Author Contributions REFERENCES

Seventy-five patients with biopsy-proven AIDS-related KS were randomly assigned to receive one of two doses of COL-3 administered orally once daily: group A received 50 mg and group B received 100 mg. The tumor response rates to COL-3 based on intention to treat in groups A and B were 41% and 29%, respectively. The median times to first response in groups A and B were 10 and 19 weeks, respectively.

This study was a randomized, phase II study and thus not powered to compare response rates across treatment arms. Nonetheless, the response rate of 41% in group A patients is similar to that reported in AIDS-associated KS for a number of investigational and approved agents,^16,18-20 and was associated with a favorable toxicity profile. In contrast, the response rate in group B was not significantly greater than 20%, and the higher COL-3 dose was less well tolerated. Our choice of 20% as the response rate below which we would have no interest in pursuing additional clinical investigation of COL-3 is supported by the findings of a phase III trial of IM862 in patients with AIDS-associated KS.²¹ In that trial, which was contemporaneous with this study, patients had similar baseline characteristics. Patients in the placebo arm showed a response rate of 21%, which may have reflected late responses to ongoing highly active antiretroviral therapy.

COL-3 was reasonably well tolerated, as it was in the prior phase I trial. The most commonly reported severe adverse events were photosensitivity and rash. These were also the most common causes for dose reductions and/or interruptions. Severe adverse events were more frequent at the higher dose (10 patients) than at the lower dose (two patients), and 16 (43%) of group A patients took COL-3 for more than 24 weeks.

Plasma levels of MMP-2 and MMP-9 were measured as potential indicators of the biologic activity of COL-3. There was a statistically significant decrease from baseline in both MMP-2 and MMP-9 levels in patients receiving COL-3. However, in contrast to the smaller phase I study, the changes in MMP-2 levels did not differ in responders and nonresponders. Measurement of changes induced in the tumors may be of even greater biologic relevance than changes in the plasma. Furthermore, it is possible that the observed tumor responses were mediated by the modulation of other cytokines that were not measured. Tetracycline derivatives have been demonstrated to downregulate the expression of multiple proinflammatory and autoimmune mediators.¹¹ Minocycline, another tetracycline derivative, decreases the expression of CNS inflammatory markers in a simian immunodeficiency virus-macaque model.²² Minocycline also inhibits both simian immunodeficiency virus and HIV replication.²² Although COL-3 in our trial was not associated with any change in HIV viral load, the study was not designed to assess such activity.

In conclusion, COL-3 administered orally once daily, is reasonably well tolerated and demonstrates antitumor activity in patients with AIDS-related KS. As discussed recently in an editorial by Wieand in this journal,²³ although formal comparison of response rates is not possible because of the limited nature of a randomized phase II trial, a winner may be chosen by integrating information such as response rate and toxicity. In the case of this randomized phase II study, the 50-mg dose appears to be the winner based on its superior tolerability and higher response rate. Furthermore, MMP-2 and MMP-9 levels declined significantly while patients were receiving the study drug. Our findings support additional evaluation of COL-3 at a dose of 50 mg either as a single agent or in combination with other agents in patients with AIDS-related KS.

	Acknowledgment and Appendix

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Appendix
The following investigators participated in the study: Beth Israel Deaconess Medical Center, Boston: B. Dezube; Boston Medical Center, Boston: T. Cooley; Columbia University, New York: Mary Keohan; Massachusetts General Hospital, Boston: D. Scadden; Memorial Sloan-Kettering Cancer Center, New York: S. Krown; Montefiore Medical Center, New York: J. Sparano; Ohio State University, Columbus: M. Shah; Pennsylvania Oncology Hematology Associates, Philadelphia: D. Henry; Roswell Park Cancer Institute, Buffalo: Z. Bernstein; San Francisco General Hospital, San Francisco: L. Kaplan; Tulane University, New Orleans: E. Zakris; University of California, Los Angeles, Los Angeles: S. Miles and R. Mitsuyasu; University of Hawaii, Honolulu: B. Shiramizu; University of Miami, Miami: W. Harrington Jr; University of Southern California, Norris Cancer Hospital, Los Angeles: A. Tulpule; University of Washington, Seattle: A. Rose; and Virginia Mason Medical Center, Seattle: D. Aboulafia.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Bruce J. Dezube CollaGenex(A) CollaGenex(A) Susan E. Krown CollaGenex (A) David M. Aboulafia CollaGenex (A)

Dollar Amonut Codes (A) < $10,000 (B) $10,000-$99,900 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Bruce J. Dezube, Susan E. Krown, Jeannette Y. Lee, Kenneth S. Bauer, David M. Aboulafia Administrative support: Jeannette Y. Lee Provision of study materials or patients: Bruce J. Dezube, Susan E. Krown, David M. Aboulafia Collection and assembly of data: Bruce J. Dezube, Susan E. Krown, Jeannette Y. Lee, Kenneth S. Bauer, David M. Aboulafia Data analysis and interpretation: Bruce J. Dezube, Susan E. Krown, Jeannette Y. Lee, Kenneth S. Bauer, David M. Aboulafia Manuscript writing: Bruce J. Dezube, Susan E. Krown, Jeannette Y. Lee, Kenneth S. Bauer, David M. Aboulafia Final approval of manuscript: Bruce J. Dezube, Susan E. Krown, Jeannette Y. Lee, Kenneth S. Bauer, David M. Aboulafia

 

	Acknowledgment

 
We thank Jodi Black, PhD, for her support and input into the design of this study; Brad Zerler, PhD, and Klaus Theobald, MD, of Collagenex Pharmaceuticals for helpful suggestions, and the many study coordinators and research nurses. The AMC thanks all of the participating patients.

	NOTES

 
Supported by the National Cancer Institute Grants No. U01CA070019, U01CA070047, U01CA070054, U01CA70058, U01CA070062, U01CA070079, U01CA070072, U01CA070080, U01CA70081, U01CA071375, U01CA083118, U01CA083216, and U01CA083038; Cancer Therapy Evaluation Program/NCI; and CollaGenex Pharmaceuticals.

Presented in part at the International Conference on Malignancies in AIDS and Other Immune Deficiencies, April 29-30, 2004, Bethesda, MD.

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

	REFERENCES

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Submitted October 14, 2005; accepted January 12, 2006.

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