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dc.contributor.authorHaslett, Kate
dc.contributor.authorKoh, Pek K
dc.contributor.authorHudson, Andrew M
dc.contributor.authorRyder, W David J
dc.contributor.authorFalk, Sally
dc.contributor.authorMullan, Damian
dc.contributor.authorTaylor, Ben
dc.contributor.authorCalifano, Raffaele
dc.contributor.authorBlackhall, Fiona H
dc.contributor.authorFaivre-Finn, Corinne
dc.date.accessioned2021-04-20T08:08:19Z
dc.date.available2021-04-20T08:08:19Z
dc.date.issued2021en
dc.identifier.citationHaslett K, Koh P, Hudson A, Ryder WD, Falk S, Mullan D, et al. Phase I trial of the MEK inhibitor selumetinib in combination with thoracic radiotherapy in non-small cell lung cancer. Clin Transl Radiat Oncol. 2021;28:24-31.en
dc.identifier.pmid33748440en
dc.identifier.doi10.1016/j.ctro.2021.02.008en
dc.identifier.urihttp://hdl.handle.net/10541/623926
dc.description.abstractBackground: The RAS/RAF/MEK/ERK signalling pathway has a pivotal role in cancer proliferation and modulating treatment response. Selumetinib inhibits MEK and enhances effects of radiotherapy in preclinical studies. Patients and methods: Single-arm, single-centre, open-label phase I trial. Patients with stage III NSCLC unsuitable for concurrent chemo-radiotherapy, or stage IV with dominant thoracic symptoms, were recruited to a dose-finding stage (Fibonacci 3 + 3 design; maximum number = 18) then an expanded cohort (n = 15). Oral selumetinib was administered twice daily (starting dose 50 mg) commencing 7 days prior to thoracic radiotherapy, then with radiotherapy (6-6.5 weeks; 60-66 Gy/30-33 fractions). The primary objective was to determine the recommended phase II dose (RP2D) of selumetinib in combination with thoracic radiotherapy. Results: 21 patients were enrolled (06/2010-02/2015). Median age: 62y (range 50-73). M:F ratio 12(57%):9(43%). ECOG PS 0:1, 7(33%):14(67%). Stage III 16(76%); IV 5(24%). Median GTV 64 cm3 (range 1-224 cm3). 15 patients comprised the expanded cohort at starting dose. All 21 patients completed thoracic radiotherapy as planned and received induction chemotherapy. 13 (62%) patients received the full dose of selumetinib.In the starting cohort no enhanced radiotherapy-related toxicity was seen. Two patients had dose-limiting toxicity (1x grade 3 diarrhoea/fatigue and 1x pulmonary embolism). Commonest grade 3-4 adverse events: lymphopaenia (19/21 patients) and hypertension (7/21 patients). One patient developed grade 3 oesophagitis. No patients developed grade ≥3 radiation pneumonitis. Two patients were alive at the time of analysis (24 and 26 months follow-up, respectively). Main cause of first disease progression: distant metastases ± locoregional progression (12/21 [57.1%] patients). Six patients had confirmed/suspected pneumocystis jiroveci pneumonia. Conclusion: We report poor outcome and severe lymphopenia in most patients treated with thoracic radiotherapy and selumetinib at RP2D in combination, contributing to confirmed/clinically suspected pneumocystis jiroveci pneumonia. These results suggest that this combination should not be pursued in a phase II trial.ClinicalTrials.gov reference: NCT01146756.en
dc.language.isoenen
dc.relation.urlhttps://dx.doi.org/10.1016/j.ctro.2021.02.008en
dc.titlePhase I trial of the MEK inhibitor selumetinib in combination with thoracic radiotherapy in non-small cell lung canceren
dc.typeArticleen
dc.contributor.departmentThe Christie NHS Foundation Trust, United Kingdomen
dc.identifier.journalClinical and Translational Radiation Oncologyen
dc.description.noteen]
refterms.dateFOA2021-04-26T09:08:42Z


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