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Clinical Studies

Randomised, Phase II study of selumetinib, an oral inhibitor of MEK, in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer



Cisplatin and gemcitabine (CisGem) are standard chemotherapy for advanced biliary tract cancer (BTC). The MEK inhibitor selumetinib showed synergy with gemcitabine when administered sequentially in BTC. This randomised Phase 2 trial aimed to assess the efficacy of sequential or continuous selumetinib with CisGem.


Patients with advanced BTC received CisGem; arm A included selumetinib every day, arm B: selumetinib, days 1–5, 8–19 each cycle. Arm C received CisGem alone. Selumetinib was dosed at 75 mg BID but amended to 50 mg BID due to toxicity.


In all, 51 participants were evaluable for response. No significant difference was seen in mean change in tumour size at 10 weeks between arms A and C (−7.8% vs −12.8%, P = 0.54) or arms B and C (−15% vs −12.8%, P = 0.78). There was no difference in median progression-free survival (6.0, 7.0, 6.3 months, P > 0.95) or overall survival (11.7, 11.7, 12.8 months, P = 0.70) for arms A, B and C, respectively. More participants experienced grade 3–4 toxicities in selumetinib-containing arms. More participants in arm A required chemotherapy dose reductions (P = 0.01) with lower chemotherapy dose intensity during the first 10 weeks.


Adding sequential or continuous selumetinib to CisGem failed to improve efficacy and increased toxicity in patients with advanced BTC.

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Fig. 1: Trial profile.
Fig. 2
Fig. 3: Survival outcomes by study arm.

Data availability

Supporting data for this study are held by the Drug Development Programme, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.


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This study was funded as externally sponsored research by AstraZeneca, who provided investigational selumetinib. Additional funding was provided by the Princess Margaret Cancer Foundation.

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Authors and Affiliations



MD—conceptualisation, methodology, investigation and manuscript preparation; VT—investigation, manuscript review; MM—conceptualisation, methodology and manuscript review; RJ—investigation and manuscript review; DH—conceptualisation, investigation and manuscript review; EC—investigation and manuscript review; ND—investigation and manuscript review; PT—investigation and manuscript review; HWS—investigation and manuscript review; GO’K—investigation and manuscript review; SD—resources and investigation; LW—formal analysis; TP—data curation and project administration; JK—conceptualisation, methodology, investigation and manuscript review.

Corresponding author

Correspondence to Jennifer J. Knox.

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Competing interests

MD received research funding from AstraZeneca and Merck, and speaking honoraria from AstraZeneca, Roche, Merck, Boehringer Ingelheim, Eisai and Takeda. VT received research funding from AstraZeneca, Eisai, Exelixis, Ipsen, Merck, Roche, travel support from Amgen, and speaking honoraria from AstraZeneca, Eisai, Ipsen and Roche. MM received research support from Servier, Ipsen, and NuCana, travel/accommodation support from Bayer and Ipsen, speaker honoraria from Pfizer, Ipsen, NuCana, and Mylan, and consulted for Celgene, Ipsen, Sirtex, Baxalta and Incyte. RJ received research funding from AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Lilly, Merck and Novartis, and consulted for Ipsen and Novartis. EC received research funding from AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Merck and Novartis, and speaking honoraria from Bayer, Eisai and Taiho. ND received speaker honoraria from Celgene and Sanofi, and consulted for Celgene and Incyte. PT received travel support from Amgen and consulted for Amgen, AstraZeneca, Celgene, Eisai, Genomic Health International, Merck, Pfizer, Taiho and Teva. HWS received research funding from Abbvie and Bristol-Meiers Squibb. GO’K received speaking honoraria from Eisai and Roche, travel support from AstraZeneca, and consulted for Eisai and Roche. JK received research funding from and consulted for AstraZeneca, Ipsen and Merck, and speaking honoraria from Novartis and Roche. The remaining authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Research Ethics Boards of the Princess Margaret Cancer Centre and Tom Baker Cancer Centre. All patients provided informed consent and the study was carried out in accordance with the Declaration of Helsinki. The trial was registered with, ID NCT02151084.

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Doherty, M.K., Tam, V.C., McNamara, M.G. et al. Randomised, Phase II study of selumetinib, an oral inhibitor of MEK, in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer. Br J Cancer (2022).

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