A phase I and pharmacologic study of the combination of marimastat and paclitaxel in patients with advanced malignancy.
BACKGROUND
Marimastat is a potent inhibitor of matrix metalloproteinases and in preclinical studies enhances the anti-tumor activity of certain chemotherapeutics. We performed a phase I clinical evaluation of the combination of oral marimastat and intravenous paclitaxel, to determine if these drugs could be co-administered safely, and to determine whether marimastat alters paclitaxel pharmacokinetics.


METHODS
Marimastat was administered twice daily and paclitaxel as a three hour infusion every three weeks. Doses of both marimastat and paclitaxel were escalated in cohorts of patients up to maximal doses of 10 mg for marimastat and 175 mg/m2 for paclitaxel. Paclitaxel plasma pharmacokinetic parameters were assessed in the absence (cycle 1) and presence (cycle 2) of marimastat. Trough marimastat plasma levels were evaluated during cycle 2.


RESULTS
A total of 19 patients were treated at three different dose levels. There were no dose-limiting toxicities during the first cycle of therapy, resulting in dose escalation up to the planned maximal dose for each drug. Neutropenia was the most common significant toxicity at the highest dose level, with grade 3 or higher neutropenia occurring in 38% of patients. There were no complete or partial responses. Pharmacokinetic analyses indicate that marimastat does not alter paclitaxel clearance. At the 10 mg dose, the mean trough marimastat level was 14.8 Kg/L.


CONCLUSIONS
Marimastat and paclitaxel can be co-administered safely at doses equivalent to those recommended for single-agent administration. Additional studies are necessary to determine whether this combination is more effective in controlling tumor progression than paclitaxel alone.
Toppmeyer
Deborah L
DL
Departments of Medicine and Pharmacology, Robert-Wood Johnson Medical School and The Cancer Institute, University of Medicine and Dentistry, New Brunswick, New Jersey, USA.
Gounder
Murugesan
M
Much
Judie
J
Musanti
Rita
R
Vyas
Viral
V
Medina
Melissa
M
Orlando
Tammy
T
Pennick
Michael
M
Lin
Yong
Y
Shih
Weichung
W
Goodin
Susan
S
Rubin
Eric
E
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C100342:marimastat; D017239:Paclitaxel