Academic Journal
A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies.
| العنوان: | A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies. |
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| المؤلفون: | Mateo, J, Olmos, D, Dumez, H, Poondru, S, Samberg, NL, Barr, S, Van Tornout, JM, Jie, F, Sandhu, S, Tan, DS, Moreno, V, LoRusso, PM, Kaye, SB, Schöffski, P |
| المساهمون: | Kaye, Stanley Bernard, Mateo Valderrama, Joaquin |
| سنة النشر: | 2018 |
| المجموعة: | The Institute of Cancer Research (ICR): Publications Repository |
| مصطلحات موضوعية: | Leukocytes, Mononuclear, Humans, Neoplasms, Imidazoles, Triazines, Multiprotein Complexes, Protein Kinase Inhibitors, Maximum Tolerated Dose, Dose-Response Relationship, Drug, Half-Life, Adult, Aged, Middle Aged, Female, Male, Young Adult, TOR Serine-Threonine Kinases, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2 |
| الوصف: | Background The kinase activity of mTOR involves 2 multiprotein complexes, (mTORC1-mTORC2). Targeting mTORC1 with rapalogues induces compensatory feedback loops resulting in AKT/ERK activation, which may be abrogated by mTORC2 inhibition. A first-in-human trial evaluating tolerability, pharmacokinetics and pharmacodynamics of the dual TORC1/TORC2 inhibitor OSI-027 was conducted.Methods Dose escalation was pursued for three schedules of administration (three consecutive days per week (S1), once a week (S2) and daily dosing (S3)), until dose-limiting toxicities (DLT) were identified. Expansion cohorts with paired tumour biopsies were initiated based on tolerability and pharmacodynamics.Results One hundred and twenty eight patients with advanced cancer were enrolled. DLT consisted predominantly of fatigue, renal function disturbances and cardiac events. OSI-027 exposure was dose proportional, with Tmax within 4 h and a half-life of ∼14 h. Expansion cohorts were initiated for S1 and S2, as MTD for S3 was overall considered suboptimal. Target modulation in peripheral blood mononuclear cells were observed from 30 mg, but in tumour biopsies 120 mg QD were needed, which was a non-tolerable dose due to renal toxicity. No RECIST responses were recorded, with stable disease >6 months in six (5%) patients.Conclusions OSI-027 inhibits mTORC1/2 in patients with advanced tumour s in a dose-dependent manner but doses above the tolerable levels in S1 and S3 are required for a sustained biological effect in tumour biopsies. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Print-Electronic; 896; application/pdf |
| اللغة: | English |
| تدمد: | 0007-0920 1532-1827 |
| Relation: | British journal of cancer, 2016, 114 (8), pp. 889 - 896; https://repository.icr.ac.uk/handle/internal/2960 |
| DOI: | 10.1038/bjc.2016.59 |
| الاتاحة: | https://repository.icr.ac.uk/handle/internal/2960 https://doi.org/10.1038/bjc.2016.59 |
| Rights: | https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.FF7A6A8F |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00070920 15321827 |
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| DOI: | 10.1038/bjc.2016.59 |