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A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer.

Publication ,  Journal Article
Rizvi, NA; Humphrey, JS; Ness, EA; Johnson, MD; Gupta, E; Williams, K; Daly, DJ; Sonnichsen, D; Conway, D; Marshall, J; Hurwitz, H
Published in: Clin Cancer Res
March 15, 2004

PURPOSE: BMS-275291 is a novel broad-spectrum inhibitor of matrix metalloproteinase (MMPs) rationally designed to spare a class of closely related metalloproteinases known as sheddases. Inadvertent sheddase inhibition is hypothesized to play a role in the dose-limiting joint toxicities occurring with hydroxamate-based MMP inhibitors. This trial was conducted to establish the recommended phase II dose; determine safety, toxicity, and pharmacokinetics of BMS-275291; and to assess potential markers of sheddase activity [tumor necrosis factor-alpha (TNFalpha) release and TNFalpha-RII shedding]. EXPERIMENTAL DESIGN: This was an open label, single arm, phase I study conducted at two centers. Patients with advanced or metastatic cancer were treated with once-daily oral BMS-275291 at doses escalating from 600 to 2400 mg/day. Six to eight patients/dose level were to be studied with the recommended phase II dose level expanded to a total of 15 patients. Pharmacokinetic sampling was performed on days 1, 15, and 29 at 0, 0.5, 1, 2, 4, 6, 8, and 24 h after dosing. Radiological tumor assessment was performed every 8 weeks. RESULTS: Forty-four evaluable patients were enrolled in this study with the most frequent tumor types being colorectal cancer and non-small cell lung cancer. Dose limiting toxicities were observed at 600 mg/day (one of eight patients with grade 3 transaminitis) and at 1200 mg/day (1 of 15 patients with grade 3 rash and grade 4 shortness of breath), both in the context of predisposing conditions. No dose-limiting toxicities occurred at 900, 1800, or 2400 mg/day. The most frequent adverse events considered possibly, probably, or definitely drug-related were joint toxicity (myalgia/arthralgia), rash, fatigue, headache, nausea, and taste change, all of which were mild, grade 1, grade 2, and not dose-limiting. No objective tumor responses were observed. Twelve of forty-four patients received treatment for 4+ months, six for 8+ months, three for >1 year. Desired trough levels of parent BMS-275291 were maintained with once daily dosing. The mean plasma concentration of parent BMS-275291 at trough exceeded the calculated in vitro IC(80) value for MMP-2 and IC(90) value for MMP-9 at the recommended phase II dose of 1200 mg/day. No major changes in serum concentrations of sheddase enzymatic products, TNFalpha or TNFalpha-RII, were observed. CONCLUSIONS: BMS-275291 is a nonhydroxamate MMP inhibitor with a novel mercaptoacyl zinc-binding group. In this study, plasma concentrations of BMS-275291 continuously exceeded in vitro MMP IC(50) values without dose-limiting joint toxicity. In this refractory patient population, a suggestion of disease stabilization was observed in 12 patients. On the basis of preclinical, clinical, and pharmacokinetic data, the recommended phase II dose for future study is 1200 mg/day.

Duke Scholars

Published In

Clin Cancer Res

DOI

ISSN

1078-0432

Publication Date

March 15, 2004

Volume

10

Issue

6

Start / End Page

1963 / 1970

Location

United States

Related Subject Headings

  • Safety
  • Organic Chemicals
  • Oncology & Carcinogenesis
  • Neoplasms
  • Neoplasm Staging
  • Neoplasm Metastasis
  • Middle Aged
  • Matrix Metalloproteinase Inhibitors
  • Male
  • Imidazoles
 

Citation

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Rizvi, N. A., Humphrey, J. S., Ness, E. A., Johnson, M. D., Gupta, E., Williams, K., … Hurwitz, H. (2004). A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer. Clin Cancer Res, 10(6), 1963–1970. https://doi.org/10.1158/1078-0432.ccr-1183-02
Rizvi, Naiyer A., Jeffrey S. Humphrey, Elizabeth A. Ness, Michael D. Johnson, Elora Gupta, Kathleen Williams, Diana J. Daly, et al. “A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer.Clin Cancer Res 10, no. 6 (March 15, 2004): 1963–70. https://doi.org/10.1158/1078-0432.ccr-1183-02.
Rizvi NA, Humphrey JS, Ness EA, Johnson MD, Gupta E, Williams K, et al. A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer. Clin Cancer Res. 2004 Mar 15;10(6):1963–70.
Rizvi, Naiyer A., et al. “A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer.Clin Cancer Res, vol. 10, no. 6, Mar. 2004, pp. 1963–70. Pubmed, doi:10.1158/1078-0432.ccr-1183-02.
Rizvi NA, Humphrey JS, Ness EA, Johnson MD, Gupta E, Williams K, Daly DJ, Sonnichsen D, Conway D, Marshall J, Hurwitz H. A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer. Clin Cancer Res. 2004 Mar 15;10(6):1963–1970.

Published In

Clin Cancer Res

DOI

ISSN

1078-0432

Publication Date

March 15, 2004

Volume

10

Issue

6

Start / End Page

1963 / 1970

Location

United States

Related Subject Headings

  • Safety
  • Organic Chemicals
  • Oncology & Carcinogenesis
  • Neoplasms
  • Neoplasm Staging
  • Neoplasm Metastasis
  • Middle Aged
  • Matrix Metalloproteinase Inhibitors
  • Male
  • Imidazoles