A Randomized Phase II Feasibility Trial of BMS-275291 in Patients with Early Stage Breast Cancer

Kathy Miller, Thomas J. Saphner, David M. Waterhouse, T. T. Chen, Anita Rush-Taylor, Joseph A. Sparano, Antonio C. Wolff, Melody A. Cobleigh, Susan Galbraith, George W. Sledge

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Purpose: This pilot trial was performed to evaluate the safety, pharmacokinetics and feasibility of incorporating BMS-275291, a matrix metalloproteinase inhibitor (MMPI), into adjuvant breast cancer therapy. Experimental Design: Patients with stage I (T1c)-IIIA breast cancer were eligible if planned adjuvant therapy consisted of either tamoxifen alone, doxorubicin + cyclophosphamide every 21 days for four cycles (AC), or AC followed by paclitaxel every 21 days for 4 cycles (AC>T). Patients were stratified by planned adjuvant therapy and randomized (2:1 ratio) to BMS-275291 (1200 mg/day) or matched placebo for 1 year. Results: Seventy-two patients were recruited from March 2001 to July 2002. Grade ≥ 2 musculoskeletal toxicity, generally reversible arthralgia, was reported by 36.2% of patients receiving BMS-275291 compared with 16.7% of patients receiving placebo; difference = 19. 5% (95% confidence interval: -0.06, 0.44; P = NS). Two patients receiving BMS-275291 developed palpable nodules along tendons. Grade ≥ 3 rash was reported by 8.5% of patients receiving BMS-275291 compared with 4.2% of patients receiving placebo; difference = 4.3% (95% confidence interval: -0.18, 0.3; P = NS). Overall, 33% of BMS-275291 patients and 21% of placebo patients discontinued treatment due to adverse events. BMS-275291 trough levels tended to decrease over time; 9 of 47 (19%) had ≥50% of trough concentrations > 124 ng/ml (IC90 for matrix metalloproteinase-9). Conclusions: The pattern of arthralgia in BMS-275291-treated patients was consistent with matrix metalloproteinase inhibitor toxicity. Although the differential incidence of arthralgia did not reach statistical significance, the trial was terminated. An adjuvant trial in this patient population is not feasible.

Original languageEnglish
Pages (from-to)1971-1975
Number of pages5
JournalClinical Cancer Research
Volume10
Issue number6
DOIs
StatePublished - Mar 15 2004

Fingerprint

Breast Neoplasms
Arthralgia
Placebos
Matrix Metalloproteinase Inhibitors
N-((2S)-2-mercapto-1-oxo-4-(3,4,4- trimethyl-2,5-dioxo-1-imidazolidinyl)butyl)-L-leucyl-N,3- dimethyl-L-Valinamide
Confidence Intervals
Matrix Metalloproteinase 9
Tamoxifen
Therapeutics
Paclitaxel
Exanthema
Tendons
Doxorubicin
Cyclophosphamide
Research Design
Pharmacokinetics
Safety
Incidence
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Miller, K., Saphner, T. J., Waterhouse, D. M., Chen, T. T., Rush-Taylor, A., Sparano, J. A., ... Sledge, G. W. (2004). A Randomized Phase II Feasibility Trial of BMS-275291 in Patients with Early Stage Breast Cancer. Clinical Cancer Research, 10(6), 1971-1975. https://doi.org/10.1158/1078-0432.CCR-03-0968

A Randomized Phase II Feasibility Trial of BMS-275291 in Patients with Early Stage Breast Cancer. / Miller, Kathy; Saphner, Thomas J.; Waterhouse, David M.; Chen, T. T.; Rush-Taylor, Anita; Sparano, Joseph A.; Wolff, Antonio C.; Cobleigh, Melody A.; Galbraith, Susan; Sledge, George W.

In: Clinical Cancer Research, Vol. 10, No. 6, 15.03.2004, p. 1971-1975.

Research output: Contribution to journalArticle

Miller, K, Saphner, TJ, Waterhouse, DM, Chen, TT, Rush-Taylor, A, Sparano, JA, Wolff, AC, Cobleigh, MA, Galbraith, S & Sledge, GW 2004, 'A Randomized Phase II Feasibility Trial of BMS-275291 in Patients with Early Stage Breast Cancer', Clinical Cancer Research, vol. 10, no. 6, pp. 1971-1975. https://doi.org/10.1158/1078-0432.CCR-03-0968
Miller, Kathy ; Saphner, Thomas J. ; Waterhouse, David M. ; Chen, T. T. ; Rush-Taylor, Anita ; Sparano, Joseph A. ; Wolff, Antonio C. ; Cobleigh, Melody A. ; Galbraith, Susan ; Sledge, George W. / A Randomized Phase II Feasibility Trial of BMS-275291 in Patients with Early Stage Breast Cancer. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 6. pp. 1971-1975.
@article{01089059e532437cb85e0490220d9a89,
title = "A Randomized Phase II Feasibility Trial of BMS-275291 in Patients with Early Stage Breast Cancer",
abstract = "Purpose: This pilot trial was performed to evaluate the safety, pharmacokinetics and feasibility of incorporating BMS-275291, a matrix metalloproteinase inhibitor (MMPI), into adjuvant breast cancer therapy. Experimental Design: Patients with stage I (T1c)-IIIA breast cancer were eligible if planned adjuvant therapy consisted of either tamoxifen alone, doxorubicin + cyclophosphamide every 21 days for four cycles (AC), or AC followed by paclitaxel every 21 days for 4 cycles (AC>T). Patients were stratified by planned adjuvant therapy and randomized (2:1 ratio) to BMS-275291 (1200 mg/day) or matched placebo for 1 year. Results: Seventy-two patients were recruited from March 2001 to July 2002. Grade ≥ 2 musculoskeletal toxicity, generally reversible arthralgia, was reported by 36.2{\%} of patients receiving BMS-275291 compared with 16.7{\%} of patients receiving placebo; difference = 19. 5{\%} (95{\%} confidence interval: -0.06, 0.44; P = NS). Two patients receiving BMS-275291 developed palpable nodules along tendons. Grade ≥ 3 rash was reported by 8.5{\%} of patients receiving BMS-275291 compared with 4.2{\%} of patients receiving placebo; difference = 4.3{\%} (95{\%} confidence interval: -0.18, 0.3; P = NS). Overall, 33{\%} of BMS-275291 patients and 21{\%} of placebo patients discontinued treatment due to adverse events. BMS-275291 trough levels tended to decrease over time; 9 of 47 (19{\%}) had ≥50{\%} of trough concentrations > 124 ng/ml (IC90 for matrix metalloproteinase-9). Conclusions: The pattern of arthralgia in BMS-275291-treated patients was consistent with matrix metalloproteinase inhibitor toxicity. Although the differential incidence of arthralgia did not reach statistical significance, the trial was terminated. An adjuvant trial in this patient population is not feasible.",
author = "Kathy Miller and Saphner, {Thomas J.} and Waterhouse, {David M.} and Chen, {T. T.} and Anita Rush-Taylor and Sparano, {Joseph A.} and Wolff, {Antonio C.} and Cobleigh, {Melody A.} and Susan Galbraith and Sledge, {George W.}",
year = "2004",
month = "3",
day = "15",
doi = "10.1158/1078-0432.CCR-03-0968",
language = "English",
volume = "10",
pages = "1971--1975",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - A Randomized Phase II Feasibility Trial of BMS-275291 in Patients with Early Stage Breast Cancer

AU - Miller, Kathy

AU - Saphner, Thomas J.

AU - Waterhouse, David M.

AU - Chen, T. T.

AU - Rush-Taylor, Anita

AU - Sparano, Joseph A.

AU - Wolff, Antonio C.

AU - Cobleigh, Melody A.

AU - Galbraith, Susan

AU - Sledge, George W.

PY - 2004/3/15

Y1 - 2004/3/15

N2 - Purpose: This pilot trial was performed to evaluate the safety, pharmacokinetics and feasibility of incorporating BMS-275291, a matrix metalloproteinase inhibitor (MMPI), into adjuvant breast cancer therapy. Experimental Design: Patients with stage I (T1c)-IIIA breast cancer were eligible if planned adjuvant therapy consisted of either tamoxifen alone, doxorubicin + cyclophosphamide every 21 days for four cycles (AC), or AC followed by paclitaxel every 21 days for 4 cycles (AC>T). Patients were stratified by planned adjuvant therapy and randomized (2:1 ratio) to BMS-275291 (1200 mg/day) or matched placebo for 1 year. Results: Seventy-two patients were recruited from March 2001 to July 2002. Grade ≥ 2 musculoskeletal toxicity, generally reversible arthralgia, was reported by 36.2% of patients receiving BMS-275291 compared with 16.7% of patients receiving placebo; difference = 19. 5% (95% confidence interval: -0.06, 0.44; P = NS). Two patients receiving BMS-275291 developed palpable nodules along tendons. Grade ≥ 3 rash was reported by 8.5% of patients receiving BMS-275291 compared with 4.2% of patients receiving placebo; difference = 4.3% (95% confidence interval: -0.18, 0.3; P = NS). Overall, 33% of BMS-275291 patients and 21% of placebo patients discontinued treatment due to adverse events. BMS-275291 trough levels tended to decrease over time; 9 of 47 (19%) had ≥50% of trough concentrations > 124 ng/ml (IC90 for matrix metalloproteinase-9). Conclusions: The pattern of arthralgia in BMS-275291-treated patients was consistent with matrix metalloproteinase inhibitor toxicity. Although the differential incidence of arthralgia did not reach statistical significance, the trial was terminated. An adjuvant trial in this patient population is not feasible.

AB - Purpose: This pilot trial was performed to evaluate the safety, pharmacokinetics and feasibility of incorporating BMS-275291, a matrix metalloproteinase inhibitor (MMPI), into adjuvant breast cancer therapy. Experimental Design: Patients with stage I (T1c)-IIIA breast cancer were eligible if planned adjuvant therapy consisted of either tamoxifen alone, doxorubicin + cyclophosphamide every 21 days for four cycles (AC), or AC followed by paclitaxel every 21 days for 4 cycles (AC>T). Patients were stratified by planned adjuvant therapy and randomized (2:1 ratio) to BMS-275291 (1200 mg/day) or matched placebo for 1 year. Results: Seventy-two patients were recruited from March 2001 to July 2002. Grade ≥ 2 musculoskeletal toxicity, generally reversible arthralgia, was reported by 36.2% of patients receiving BMS-275291 compared with 16.7% of patients receiving placebo; difference = 19. 5% (95% confidence interval: -0.06, 0.44; P = NS). Two patients receiving BMS-275291 developed palpable nodules along tendons. Grade ≥ 3 rash was reported by 8.5% of patients receiving BMS-275291 compared with 4.2% of patients receiving placebo; difference = 4.3% (95% confidence interval: -0.18, 0.3; P = NS). Overall, 33% of BMS-275291 patients and 21% of placebo patients discontinued treatment due to adverse events. BMS-275291 trough levels tended to decrease over time; 9 of 47 (19%) had ≥50% of trough concentrations > 124 ng/ml (IC90 for matrix metalloproteinase-9). Conclusions: The pattern of arthralgia in BMS-275291-treated patients was consistent with matrix metalloproteinase inhibitor toxicity. Although the differential incidence of arthralgia did not reach statistical significance, the trial was terminated. An adjuvant trial in this patient population is not feasible.

UR - http://www.scopus.com/inward/record.url?scp=12144287866&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12144287866&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-03-0968

DO - 10.1158/1078-0432.CCR-03-0968

M3 - Article

VL - 10

SP - 1971

EP - 1975

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 6

ER -