A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas

Z. Eroglu, H. A. Tawbi, J. Hu, M. Guan, P. H. Frankel, N. H. Ruel, S. Wilczynski, Scott D Christensen, David R Gandara, W. A. Chow

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Abstract

Background:The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.Methods:Seventy-one adults with advanced STS who received ≤2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).Results:There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N=11) over single agent (N=10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P=0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each).Conclusions:While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.

Original languageEnglish (US)
Pages (from-to)1644-1651
Number of pages8
JournalBritish Journal of Cancer
Volume112
Issue number10
DOIs
StatePublished - May 12 2015

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Sarcoma
Disease-Free Survival
Leiomyosarcoma
Mucositis
Lymphopenia
AZD 6244
temsirolimus
Mitogen-Activated Protein Kinase Kinases
Sirolimus
Neutropenia
Anemia
Cell Proliferation
Confidence Intervals
Cell Line
Growth

Keywords

  • leiomyosarcoma
  • selumetinib
  • soft-tissue sarcomas
  • temsirolimus

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Eroglu, Z., Tawbi, H. A., Hu, J., Guan, M., Frankel, P. H., Ruel, N. H., ... Chow, W. A. (2015). A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas. British Journal of Cancer, 112(10), 1644-1651. https://doi.org/10.1038/bjc.2015.126

A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas. / Eroglu, Z.; Tawbi, H. A.; Hu, J.; Guan, M.; Frankel, P. H.; Ruel, N. H.; Wilczynski, S.; Christensen, Scott D; Gandara, David R; Chow, W. A.

In: British Journal of Cancer, Vol. 112, No. 10, 12.05.2015, p. 1644-1651.

Research output: Contribution to journalArticle

Eroglu, Z, Tawbi, HA, Hu, J, Guan, M, Frankel, PH, Ruel, NH, Wilczynski, S, Christensen, SD, Gandara, DR & Chow, WA 2015, 'A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas', British Journal of Cancer, vol. 112, no. 10, pp. 1644-1651. https://doi.org/10.1038/bjc.2015.126
Eroglu, Z. ; Tawbi, H. A. ; Hu, J. ; Guan, M. ; Frankel, P. H. ; Ruel, N. H. ; Wilczynski, S. ; Christensen, Scott D ; Gandara, David R ; Chow, W. A. / A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas. In: British Journal of Cancer. 2015 ; Vol. 112, No. 10. pp. 1644-1651.
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abstract = "Background:The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.Methods:Seventy-one adults with advanced STS who received ≤2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).Results:There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N=11) over single agent (N=10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P=0.01). Four-month PFS rate was 50{\%} (95{\%} confidence interval 0.19-0.81) with the combination vs 0{\%} with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29{\%}), lymphopenia (26{\%}), neutropenia and anaemia (20{\%} each).Conclusions:While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.",
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T1 - A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas

AU - Eroglu, Z.

AU - Tawbi, H. A.

AU - Hu, J.

AU - Guan, M.

AU - Frankel, P. H.

AU - Ruel, N. H.

AU - Wilczynski, S.

AU - Christensen, Scott D

AU - Gandara, David R

AU - Chow, W. A.

PY - 2015/5/12

Y1 - 2015/5/12

N2 - Background:The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.Methods:Seventy-one adults with advanced STS who received ≤2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).Results:There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N=11) over single agent (N=10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P=0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each).Conclusions:While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.

AB - Background:The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.Methods:Seventy-one adults with advanced STS who received ≤2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).Results:There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N=11) over single agent (N=10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P=0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each).Conclusions:While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.

KW - leiomyosarcoma

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KW - soft-tissue sarcomas

KW - temsirolimus

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