Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi's sarcoma: a phase I AIDS malignancy consortium study.
OBJECTIVE
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).


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/m(2)/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).


CONCLUSIONS
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.
Cianfrocca
Mary
M
Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
Cooley
Timothy P
TP
Lee
Jeannette Y
JY
Rudek
Michelle A
MA
Scadden
David T
DT
Ratner
Lee
L
Pluda
James M
JM
Figg
William D
WD
Krown
Susan E
SE
Dezube
Bruce J
BJ
D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016228:Endothelial Growth Factors / Q000097:blood; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood / Q000187:drug effects; D015658:HIV Infections / Q000150:complications; D006801:Humans; D008222:Lymphokines / Q000097:blood / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000187:drug effects; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000209:etiology; D018709:Statistics, Nonparametric; D013752:Tetracycline / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013754:Tetracyclines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D061965:Matrix Metalloproteinase Inhibitors; D013754:Tetracyclines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C117155:tetracycline CMT-3; D016222:Fibroblast Growth Factor 2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D013752:Tetracycline