Multicenter Phase II trial assessing effectiveness of imatinib mesylate on relapsed or refractory KIT-positive or PDGFR-positive sarcoma

Hideshi Sugiura, Yasuhiro Fujiwara, Masashi Ando, Akira Kawai, Akira Ogose, Toshifumi Ozaki, Ryohei Yokoyama, Toru Hiruma, Takeshi Ishii, Hideo Morioka, Hideo Mugishima

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Abstract

Background: Imatinib myselate is a molecularly targeted drug that inhibits Abl tyrosine kinase, as well as type III tyrosine kinase receptors such as platelet-derived growth factor receptor (PDGFR), KIT, colony-stimulating factor 1 receptor (CSF-1R), and discoidin domain receptor (DDR). Ph1 chromosome-positive chronic myeloid leukemias (CMLs), KIT-positive gastrointestinal stromal tumors (GISTs), and PDGFR-positive dermatofibrosarcoma protuberans (DFSP) have been reported to be responsive to imatinib treatment. We conducted a multicenter Phase II trial of imatinib in patients with relapsed or refractory KIT-positive (excluding GISTs) or PDGFR-positive sarcomas. Methods: Patient ages ranged from 12 and 75 years. Eligibility criteria included (1) metastatic sarcomas with a definitive diagnosis based on histopathology or that were completely unresectable and locally advanced; (2) relapsed or refractory cases that had completed standard treatment; and (3) a tumor confirmed by immunohistochemical staining to be KIT- or PDGFR-positive. A 600-mg dose of imatinib was administered to patients once a day, with each patient receiving six courses of the drug and each course lasting 4 weeks. In cases categorized as stable or progressive, the imatinib dose was increased to 800 mg/day administered twice daily. Results: A total of 25 patients who met the eligibility criteria were enrolled in the trial; 22 were evaluated for response. The response rate with a 600 mg/day dose of imatinib was 4.5% (0 complete response, 1 partial response). There were no other objective responses after increasing imatinib to 800 mg/day (0/10). We estimated 50% progression-free survival to be 61.0 days for an imatinib dose of 600 mg/day based on the Kaplan-Meier method. Side effects of imatinib were generally similar to those observed in previous clinical trials. Conclusions: Our results did not indicate effectiveness of imatinib monotherapy at a dose of 600 or 800 mg/day in patients with relapsed or refractory KIT-positive (excluding GISTs) or PDGFR-positive sarcomas. Our findings suggest the need to evaluate the synergistic effect of combination therapy with other anticancer drugs.

Original languageEnglish
Pages (from-to)654-660
Number of pages7
JournalJournal of Orthopaedic Science
Volume15
Issue number5
DOIs
Publication statusPublished - 2010 Sep

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Platelet-Derived Growth Factor Receptors
Sarcoma
Gastrointestinal Stromal Tumors
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Colony-Stimulating Factor Receptors
Imatinib Mesylate
Pharmaceutical Preparations
Dermatofibrosarcoma
Philadelphia Chromosome
Macrophage Colony-Stimulating Factor
Receptor Protein-Tyrosine Kinases
Protein-Tyrosine Kinases
Disease-Free Survival
Therapeutics
Clinical Trials
Staining and Labeling

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine

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Multicenter Phase II trial assessing effectiveness of imatinib mesylate on relapsed or refractory KIT-positive or PDGFR-positive sarcoma. / Sugiura, Hideshi; Fujiwara, Yasuhiro; Ando, Masashi; Kawai, Akira; Ogose, Akira; Ozaki, Toshifumi; Yokoyama, Ryohei; Hiruma, Toru; Ishii, Takeshi; Morioka, Hideo; Mugishima, Hideo.

In: Journal of Orthopaedic Science, Vol. 15, No. 5, 09.2010, p. 654-660.

Research output: Contribution to journalArticle

Sugiura, H, Fujiwara, Y, Ando, M, Kawai, A, Ogose, A, Ozaki, T, Yokoyama, R, Hiruma, T, Ishii, T, Morioka, H & Mugishima, H 2010, 'Multicenter Phase II trial assessing effectiveness of imatinib mesylate on relapsed or refractory KIT-positive or PDGFR-positive sarcoma', Journal of Orthopaedic Science, vol. 15, no. 5, pp. 654-660. https://doi.org/10.1007/s00776-010-1506-9
Sugiura, Hideshi ; Fujiwara, Yasuhiro ; Ando, Masashi ; Kawai, Akira ; Ogose, Akira ; Ozaki, Toshifumi ; Yokoyama, Ryohei ; Hiruma, Toru ; Ishii, Takeshi ; Morioka, Hideo ; Mugishima, Hideo. / Multicenter Phase II trial assessing effectiveness of imatinib mesylate on relapsed or refractory KIT-positive or PDGFR-positive sarcoma. In: Journal of Orthopaedic Science. 2010 ; Vol. 15, No. 5. pp. 654-660.
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abstract = "Background: Imatinib myselate is a molecularly targeted drug that inhibits Abl tyrosine kinase, as well as type III tyrosine kinase receptors such as platelet-derived growth factor receptor (PDGFR), KIT, colony-stimulating factor 1 receptor (CSF-1R), and discoidin domain receptor (DDR). Ph1 chromosome-positive chronic myeloid leukemias (CMLs), KIT-positive gastrointestinal stromal tumors (GISTs), and PDGFR-positive dermatofibrosarcoma protuberans (DFSP) have been reported to be responsive to imatinib treatment. We conducted a multicenter Phase II trial of imatinib in patients with relapsed or refractory KIT-positive (excluding GISTs) or PDGFR-positive sarcomas. Methods: Patient ages ranged from 12 and 75 years. Eligibility criteria included (1) metastatic sarcomas with a definitive diagnosis based on histopathology or that were completely unresectable and locally advanced; (2) relapsed or refractory cases that had completed standard treatment; and (3) a tumor confirmed by immunohistochemical staining to be KIT- or PDGFR-positive. A 600-mg dose of imatinib was administered to patients once a day, with each patient receiving six courses of the drug and each course lasting 4 weeks. In cases categorized as stable or progressive, the imatinib dose was increased to 800 mg/day administered twice daily. Results: A total of 25 patients who met the eligibility criteria were enrolled in the trial; 22 were evaluated for response. The response rate with a 600 mg/day dose of imatinib was 4.5{\%} (0 complete response, 1 partial response). There were no other objective responses after increasing imatinib to 800 mg/day (0/10). We estimated 50{\%} progression-free survival to be 61.0 days for an imatinib dose of 600 mg/day based on the Kaplan-Meier method. Side effects of imatinib were generally similar to those observed in previous clinical trials. Conclusions: Our results did not indicate effectiveness of imatinib monotherapy at a dose of 600 or 800 mg/day in patients with relapsed or refractory KIT-positive (excluding GISTs) or PDGFR-positive sarcomas. Our findings suggest the need to evaluate the synergistic effect of combination therapy with other anticancer drugs.",
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AU - Sugiura, Hideshi

AU - Fujiwara, Yasuhiro

AU - Ando, Masashi

AU - Kawai, Akira

AU - Ogose, Akira

AU - Ozaki, Toshifumi

AU - Yokoyama, Ryohei

AU - Hiruma, Toru

AU - Ishii, Takeshi

AU - Morioka, Hideo

AU - Mugishima, Hideo

PY - 2010/9

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N2 - Background: Imatinib myselate is a molecularly targeted drug that inhibits Abl tyrosine kinase, as well as type III tyrosine kinase receptors such as platelet-derived growth factor receptor (PDGFR), KIT, colony-stimulating factor 1 receptor (CSF-1R), and discoidin domain receptor (DDR). Ph1 chromosome-positive chronic myeloid leukemias (CMLs), KIT-positive gastrointestinal stromal tumors (GISTs), and PDGFR-positive dermatofibrosarcoma protuberans (DFSP) have been reported to be responsive to imatinib treatment. We conducted a multicenter Phase II trial of imatinib in patients with relapsed or refractory KIT-positive (excluding GISTs) or PDGFR-positive sarcomas. Methods: Patient ages ranged from 12 and 75 years. Eligibility criteria included (1) metastatic sarcomas with a definitive diagnosis based on histopathology or that were completely unresectable and locally advanced; (2) relapsed or refractory cases that had completed standard treatment; and (3) a tumor confirmed by immunohistochemical staining to be KIT- or PDGFR-positive. A 600-mg dose of imatinib was administered to patients once a day, with each patient receiving six courses of the drug and each course lasting 4 weeks. In cases categorized as stable or progressive, the imatinib dose was increased to 800 mg/day administered twice daily. Results: A total of 25 patients who met the eligibility criteria were enrolled in the trial; 22 were evaluated for response. The response rate with a 600 mg/day dose of imatinib was 4.5% (0 complete response, 1 partial response). There were no other objective responses after increasing imatinib to 800 mg/day (0/10). We estimated 50% progression-free survival to be 61.0 days for an imatinib dose of 600 mg/day based on the Kaplan-Meier method. Side effects of imatinib were generally similar to those observed in previous clinical trials. Conclusions: Our results did not indicate effectiveness of imatinib monotherapy at a dose of 600 or 800 mg/day in patients with relapsed or refractory KIT-positive (excluding GISTs) or PDGFR-positive sarcomas. Our findings suggest the need to evaluate the synergistic effect of combination therapy with other anticancer drugs.

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