Marimastat in the treatment of patients with biochemically relapsed prostate cancer: A prospective randomized, double-blind, phase I/II trial

Eli Rosenbaum, Marianna Zahurak, Victoria Sinibaldi, Michael A. Carducci, Roberto Pili, Menachem Laufer, Theodore L. DeWeese, Mario A. Eisenberger

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Purpose: To evaluate the safety and biological activity of three different doses of marimastat given for 6 months to patients with biochemically relapsed prostate cancer. Experimental Design: Patients with a biochemical relapse within 2 years of primary therapy, a prostate-specific antigen (PSA) increase of at least 50% within 6 months of study entry, and no prior systemic therapy were eligible. Patients were randomized to receive marimastat at total daily doses of 5, 20, or 40 mg for 6 months unless dose-limiting toxicity or new evidence of disease occurred. Results: Thirty-nine patients were treated. Grade 3-4 reversible musculoskeletal toxicity was the only dose-limiting toxicity. Increasing dose was associated with increased probability of experiencing dose-limiting toxicity (5.9%, 42.9%, and 88.9% for the 5, 20, and 40 mg groups, respectively; P = 0.03). Accrual was discontinued early on the two higher dose levels due to toxicity. A significant decrease in PSA slope was shown in the 20 mg group when compared with the 5 mg group (0.117 and -0.0046, respectively; P = 0.03) The 40 mg group (versus the 5 mg group) showed a similar change (0.109) with a trend towards significance (P = 0.07). An increased serum matrix metalloproteinase 2 level at month 3 compared with the baseline correlated with a decrease in PSA slopes (Slope, 0.001; 95% confidence interval, 0.0002-0.0018; P = 0.02). Conclusion: These data suggest that marimastat has a biological effect and may effectively delay progression in patients with biochemical relapsed prostate cancer, as shown by the change in PSA slope; however, dose-limiting toxicity at active doses is significant. Confirmatory studies with less toxic matrix metalloproteinase inhibitors employing more conventional end points are indicated. This design is feasible and potentially efficient for screening anti metastaticgents.

Original languageEnglish (US)
Pages (from-to)4437-4443
Number of pages7
JournalClinical Cancer Research
Volume11
Issue number12
DOIs
StatePublished - Jun 15 2005
Externally publishedYes

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Prostatic Neoplasms
Prostate-Specific Antigen
Therapeutics
Matrix Metalloproteinase Inhibitors
Poisons
Matrix Metalloproteinase 2
Research Design
marimastat
Confidence Intervals
Safety
Recurrence
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Marimastat in the treatment of patients with biochemically relapsed prostate cancer : A prospective randomized, double-blind, phase I/II trial. / Rosenbaum, Eli; Zahurak, Marianna; Sinibaldi, Victoria; Carducci, Michael A.; Pili, Roberto; Laufer, Menachem; DeWeese, Theodore L.; Eisenberger, Mario A.

In: Clinical Cancer Research, Vol. 11, No. 12, 15.06.2005, p. 4437-4443.

Research output: Contribution to journalArticle

Rosenbaum, Eli ; Zahurak, Marianna ; Sinibaldi, Victoria ; Carducci, Michael A. ; Pili, Roberto ; Laufer, Menachem ; DeWeese, Theodore L. ; Eisenberger, Mario A. / Marimastat in the treatment of patients with biochemically relapsed prostate cancer : A prospective randomized, double-blind, phase I/II trial. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 12. pp. 4437-4443.
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title = "Marimastat in the treatment of patients with biochemically relapsed prostate cancer: A prospective randomized, double-blind, phase I/II trial",
abstract = "Purpose: To evaluate the safety and biological activity of three different doses of marimastat given for 6 months to patients with biochemically relapsed prostate cancer. Experimental Design: Patients with a biochemical relapse within 2 years of primary therapy, a prostate-specific antigen (PSA) increase of at least 50{\%} within 6 months of study entry, and no prior systemic therapy were eligible. Patients were randomized to receive marimastat at total daily doses of 5, 20, or 40 mg for 6 months unless dose-limiting toxicity or new evidence of disease occurred. Results: Thirty-nine patients were treated. Grade 3-4 reversible musculoskeletal toxicity was the only dose-limiting toxicity. Increasing dose was associated with increased probability of experiencing dose-limiting toxicity (5.9{\%}, 42.9{\%}, and 88.9{\%} for the 5, 20, and 40 mg groups, respectively; P = 0.03). Accrual was discontinued early on the two higher dose levels due to toxicity. A significant decrease in PSA slope was shown in the 20 mg group when compared with the 5 mg group (0.117 and -0.0046, respectively; P = 0.03) The 40 mg group (versus the 5 mg group) showed a similar change (0.109) with a trend towards significance (P = 0.07). An increased serum matrix metalloproteinase 2 level at month 3 compared with the baseline correlated with a decrease in PSA slopes (Slope, 0.001; 95{\%} confidence interval, 0.0002-0.0018; P = 0.02). Conclusion: These data suggest that marimastat has a biological effect and may effectively delay progression in patients with biochemical relapsed prostate cancer, as shown by the change in PSA slope; however, dose-limiting toxicity at active doses is significant. Confirmatory studies with less toxic matrix metalloproteinase inhibitors employing more conventional end points are indicated. This design is feasible and potentially efficient for screening anti metastaticgents.",
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T2 - A prospective randomized, double-blind, phase I/II trial

AU - Rosenbaum, Eli

AU - Zahurak, Marianna

AU - Sinibaldi, Victoria

AU - Carducci, Michael A.

AU - Pili, Roberto

AU - Laufer, Menachem

AU - DeWeese, Theodore L.

AU - Eisenberger, Mario A.

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AB - Purpose: To evaluate the safety and biological activity of three different doses of marimastat given for 6 months to patients with biochemically relapsed prostate cancer. Experimental Design: Patients with a biochemical relapse within 2 years of primary therapy, a prostate-specific antigen (PSA) increase of at least 50% within 6 months of study entry, and no prior systemic therapy were eligible. Patients were randomized to receive marimastat at total daily doses of 5, 20, or 40 mg for 6 months unless dose-limiting toxicity or new evidence of disease occurred. Results: Thirty-nine patients were treated. Grade 3-4 reversible musculoskeletal toxicity was the only dose-limiting toxicity. Increasing dose was associated with increased probability of experiencing dose-limiting toxicity (5.9%, 42.9%, and 88.9% for the 5, 20, and 40 mg groups, respectively; P = 0.03). Accrual was discontinued early on the two higher dose levels due to toxicity. A significant decrease in PSA slope was shown in the 20 mg group when compared with the 5 mg group (0.117 and -0.0046, respectively; P = 0.03) The 40 mg group (versus the 5 mg group) showed a similar change (0.109) with a trend towards significance (P = 0.07). An increased serum matrix metalloproteinase 2 level at month 3 compared with the baseline correlated with a decrease in PSA slopes (Slope, 0.001; 95% confidence interval, 0.0002-0.0018; P = 0.02). Conclusion: These data suggest that marimastat has a biological effect and may effectively delay progression in patients with biochemical relapsed prostate cancer, as shown by the change in PSA slope; however, dose-limiting toxicity at active doses is significant. Confirmatory studies with less toxic matrix metalloproteinase inhibitors employing more conventional end points are indicated. This design is feasible and potentially efficient for screening anti metastaticgents.

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