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    First in human, modular study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced solid malignancies

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    Authors
    Krebs, Matthew G
    Lord, S.
    Kenny, L.
    Baird, R. D.
    MacPherson, I.
    Bahl, A.
    Clack, G.
    Ainscow, E.
    Barrett, A. G.
    Dickinson, P.
    Fuchter, M. J.
    Lehnert, M.
    Ali, S.
    McIntosh, S.
    Coombes, R. C.
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    Affiliation
    Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester, UK
    Issue Date
    2021
    
    Metadata
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    Abstract
    Background CDK7 inhibition is a promising therapeutic strategy in cancer. CDK7 is a key kinase, regulating cell division, transcription and nuclear receptor function, particularly the oestrogen receptor. Methods Tolerability, pharmacokinetics and efficacy of samuraciclib were assessed; including evaluation of ascending doses (M1A), paired tumour biopsy (PB) samples (M1A), effect of food on bioavailability (M4) and a triple-negative breast cancer (TNBC) expansion cohort (M1B). Results M1A recruited 33 patients in 5 cohorts: 120, 240, 360mg and 480 mg once daily (OD), and 180 mg twice daily (BID). 11 further patients were dosed in PB cohorts for pharmacodynamic assessment. M4 recruited 15 patients. M1B recruited 23 patients. At 120 mg, 240 mg and 360mg, most common adverse drug reactions (AE) were: G1-2 nausea, vomiting and diarrhoea. At 480 mg, 3/6 patients experienced a DLT (G3 diarrhoea, G3 oral mucositis, G3 vomiting). At 180mg BD, 1/7 patients experienced a DLT (G4 thrombocytopaenia). 240mg OD and 360 mg OD were determined clinically relevant doses, with 360mg OD as the preliminary recommended phase 2 dose. In fasted patients, median Tmax = 1.5 - 4 hrs and geomean T1/2 ? 75 hrs. Steady-state was achieved within 8 - 15 days. Plasma exposure increased dose proportionally; pharmacologically active exposures were achieved throughout the entire dosing period. Food had no clinically significant effect on exposure. 57% (25/44) of RECIST evaluable patients had evidence of disease control at first post baseline scan (FPBS) observed across the �all comer� cohorts in M1A and M4, including a partial response (PR) in a patient with HR+ breast cancer; PSA reductions were observed in the 4 castrate-resistant prostate cancer patients recruited. Preliminary tumour biopsy data supports tumour target engagement. 20 patients with TNBC were evaluable for RECIST assessment: 12/20 had stable disease at FPBS; 3 have been on treatment > 1 year. Conclusions Samuraciclib has demonstrated an acceptable safety profile with evidence of anti-tumour activity.
    Citation
    Krebs MG, Lord S, Kenny L, Baird RD, MacPherson I, Bahl A, et al. 230MO First in human, modular study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced solid malignancies. Vol. 32, Annals of Oncology. Elsevier BV; 2021. p. S458.
    Journal
    Annals of Oncology
    URI
    http://hdl.handle.net/10541/624701
    DOI
    10.1016/j.annonc.2021.08.513
    Additional Links
    https://dx.doi.org/10.1016/j.annonc.2021.08.513
    Type
    Other
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.annonc.2021.08.513
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