Randomized phase II trial of matrix metalloproteinase inhibitor COL-3 in AIDS-related Kaposi's sarcoma: an AIDS Malignancy Consortium Study.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. bdezube@bidmc.harvard.edu
Bruce J
BJ
Dezube
Susan E
SE
Krown
Jeannette Y
JY
Lee
Kenneth S
KS
Bauer
David M
DM
Aboulafia
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged; D012514:Sarcoma, Kaposi / Q000188:drug therapy*; D013754:Tetracyclines / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D013754:Tetracyclines; C117155:tetracycline CMT-3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9