Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2015 May 12;112(10):1644-51.
doi: 10.1038/bjc.2015.126. Epub 2015 Apr 21.

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

Z Eroglu  1 , H A Tawbi  2 , J Hu  3 , M Guan  1 , P H Frankel  1 , N H Ruel  1 , S Wilczynski  1 , S Christensen  4 , D R Gandara  4 , W A Chow  1
Affiliations
Clinical Trial

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

Z Eroglu et al. Br J Cancer. .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Inhibition of proliferation by temsirolimus, selumetinib (AZD), and the combination (T&A) in logarithmic concentrations in STS cell lines (SK-UT-1: leiomyosarcoma, HT1080: fibrosarcoma, SW872: liposarcoma) compared with control (dimethyl sulfoxide, DMSO).
Figure 2
Figure 2
(A) Ras-PI3K-mTORC1 pathway; (B) CONSORT diagram.
Figure 3
Figure 3
Progression-free survival (A) All patients (B) leiomyosarcoma cohort waterfall plots of response (by RECIST) (C) All patients (D) Leiomyosarcoma cohort.
Figure 4
Figure 4
Change in ERK phosphorylation in PBMCs pre to posttreatment.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Investig. 2008;118 (9:3065–3074. - PMC - PubMed
    1. Chawla SP, Staddon AP, Baker LH, Schuetze SM, Tolcher AW, D'Amato GZ, Blay JY, Mita MM, Sankhala KK, Berk L, Rivera VM, Clackson T, Loewy JW, Haluska FG, Demetri GD. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J clin oncol. 2012;30 (1:78–84. - PubMed
    1. Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, Benjamin RS. Correlation of CT and PET in patients with metastatic GIST treated at a single institution with imatinib mesylate: proposal of new CT response criteria. J Clin Oncol. 2007;25:1753–1759. - PubMed
    1. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55. - PubMed
    1. Hernando E, Charytonowicz E, Dudas ME, Menendez S, Matushansky I, Mills J, Socci ND, Behrendt N, Ma L, Maki RG, Pandolfi PP, Cordon-Cardo C. The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med. 2007;13 (6:748–753. - PubMed

Publication types

MeSH terms