A multicenter phase II study of bortezomib in ecurrent or metastatic sarcomas

Robert G. Maki, Andrew Kraft, Kelly Scheu, Jennifer Yamada, Scott Wadler, Cristina R. Antonescu, John J. Wright, Gary K. Schwartz

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

BACKGROUND. Based on evidence of activity in preclinical and Phase studies, the authors undertook a study of bortezomib, a reversible proteasome inhibitor, for patients with metastatic sarcomas. METHODS. Two arms were opened, each using a Simon two-stage design. Arm A included patients with osteogenic sarcoma, Ewing sarcoma, and rhabdomyosarcoma. Arm B accrued patients with other types of soft tissue sarcomas. Patients were not allowed to have received previous chemotherapy for metastatic disease. The initial dose of bortezomib was a 1.5 mg/m2 intravenous push twice weekly followed by a rest week. The dose was escalated to 1.7 mg/m2 if patients tolerated Cycle 1 well. The dose escalation was eliminated due to toxicity observed in the first six patients. RESULTS. Painful neuropathy, myalgias, and asthenia were the most significant observed toxicities. The most frequent toxicities included fatigue, diarrhea, con-stipation, and nausea. Pharmacodynamic data from 18 patients with complete data collection did not show consistent differences between patients with or without Grade 2 or Grade 3 neuropathy (toxicity graded according the National Cancer Institute Common Toxicity Criteria). Arm A had low accrual and was closed. One confirmed partial response among 21 evaluable patients was observed on Arm B in a patient with leiomyosarcoma. Due to the inactivity of this agent, the study was closed after the first stage of accrual. CONCLUSIONS. Bortezomib has minimal activity in soft tissue sarcoma as a single agent. If studied further in sarcomas, bortezomib should be investigated in combination with agents with demonstrated preclinical synergy.

Original languageEnglish (US)
Pages (from-to)1431-1438
Number of pages8
JournalCancer
Volume103
Issue number7
DOIs
StatePublished - Apr 1 2005
Externally publishedYes

Fingerprint

Sarcoma
Bortezomib
Asthenia
Proteasome Inhibitors
Ewing's Sarcoma
Leiomyosarcoma
Rhabdomyosarcoma
National Cancer Institute (U.S.)
Myalgia
Osteosarcoma
Nausea
Fatigue
Diarrhea
Drug Therapy

Keywords

  • Bortezomib
  • Pharmacokinetics
  • Phase II
  • Proteasome
  • Sarcoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Maki, R. G., Kraft, A., Scheu, K., Yamada, J., Wadler, S., Antonescu, C. R., ... Schwartz, G. K. (2005). A multicenter phase II study of bortezomib in ecurrent or metastatic sarcomas. Cancer, 103(7), 1431-1438. https://doi.org/10.1002/cncr.20968

A multicenter phase II study of bortezomib in ecurrent or metastatic sarcomas. / Maki, Robert G.; Kraft, Andrew; Scheu, Kelly; Yamada, Jennifer; Wadler, Scott; Antonescu, Cristina R.; Wright, John J.; Schwartz, Gary K.

In: Cancer, Vol. 103, No. 7, 01.04.2005, p. 1431-1438.

Research output: Contribution to journalArticle

Maki, RG, Kraft, A, Scheu, K, Yamada, J, Wadler, S, Antonescu, CR, Wright, JJ & Schwartz, GK 2005, 'A multicenter phase II study of bortezomib in ecurrent or metastatic sarcomas', Cancer, vol. 103, no. 7, pp. 1431-1438. https://doi.org/10.1002/cncr.20968
Maki RG, Kraft A, Scheu K, Yamada J, Wadler S, Antonescu CR et al. A multicenter phase II study of bortezomib in ecurrent or metastatic sarcomas. Cancer. 2005 Apr 1;103(7):1431-1438. https://doi.org/10.1002/cncr.20968
Maki, Robert G. ; Kraft, Andrew ; Scheu, Kelly ; Yamada, Jennifer ; Wadler, Scott ; Antonescu, Cristina R. ; Wright, John J. ; Schwartz, Gary K. / A multicenter phase II study of bortezomib in ecurrent or metastatic sarcomas. In: Cancer. 2005 ; Vol. 103, No. 7. pp. 1431-1438.
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abstract = "BACKGROUND. Based on evidence of activity in preclinical and Phase studies, the authors undertook a study of bortezomib, a reversible proteasome inhibitor, for patients with metastatic sarcomas. METHODS. Two arms were opened, each using a Simon two-stage design. Arm A included patients with osteogenic sarcoma, Ewing sarcoma, and rhabdomyosarcoma. Arm B accrued patients with other types of soft tissue sarcomas. Patients were not allowed to have received previous chemotherapy for metastatic disease. The initial dose of bortezomib was a 1.5 mg/m2 intravenous push twice weekly followed by a rest week. The dose was escalated to 1.7 mg/m2 if patients tolerated Cycle 1 well. The dose escalation was eliminated due to toxicity observed in the first six patients. RESULTS. Painful neuropathy, myalgias, and asthenia were the most significant observed toxicities. The most frequent toxicities included fatigue, diarrhea, con-stipation, and nausea. Pharmacodynamic data from 18 patients with complete data collection did not show consistent differences between patients with or without Grade 2 or Grade 3 neuropathy (toxicity graded according the National Cancer Institute Common Toxicity Criteria). Arm A had low accrual and was closed. One confirmed partial response among 21 evaluable patients was observed on Arm B in a patient with leiomyosarcoma. Due to the inactivity of this agent, the study was closed after the first stage of accrual. CONCLUSIONS. Bortezomib has minimal activity in soft tissue sarcoma as a single agent. If studied further in sarcomas, bortezomib should be investigated in combination with agents with demonstrated preclinical synergy.",
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AB - BACKGROUND. Based on evidence of activity in preclinical and Phase studies, the authors undertook a study of bortezomib, a reversible proteasome inhibitor, for patients with metastatic sarcomas. METHODS. Two arms were opened, each using a Simon two-stage design. Arm A included patients with osteogenic sarcoma, Ewing sarcoma, and rhabdomyosarcoma. Arm B accrued patients with other types of soft tissue sarcomas. Patients were not allowed to have received previous chemotherapy for metastatic disease. The initial dose of bortezomib was a 1.5 mg/m2 intravenous push twice weekly followed by a rest week. The dose was escalated to 1.7 mg/m2 if patients tolerated Cycle 1 well. The dose escalation was eliminated due to toxicity observed in the first six patients. RESULTS. Painful neuropathy, myalgias, and asthenia were the most significant observed toxicities. The most frequent toxicities included fatigue, diarrhea, con-stipation, and nausea. Pharmacodynamic data from 18 patients with complete data collection did not show consistent differences between patients with or without Grade 2 or Grade 3 neuropathy (toxicity graded according the National Cancer Institute Common Toxicity Criteria). Arm A had low accrual and was closed. One confirmed partial response among 21 evaluable patients was observed on Arm B in a patient with leiomyosarcoma. Due to the inactivity of this agent, the study was closed after the first stage of accrual. CONCLUSIONS. Bortezomib has minimal activity in soft tissue sarcoma as a single agent. If studied further in sarcomas, bortezomib should be investigated in combination with agents with demonstrated preclinical synergy.

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