دورية أكاديمية
أعرض في EDS

A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies.

التفاصيل البيبلوغرافية
العنوان: A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies.
المؤلفون: Mateo J; Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK., Olmos D; Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK.; Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain., Dumez H; Department of Oncology, University Hospitals Leuven and KU Leuven, Leuven B-3000, Belgium., Poondru S; Astellas Pharma Global Development, Northbrook, IL 60201, USA., Samberg NL; Astellas Pharma Global Development, Northbrook, IL 60201, USA., Barr S; Astellas Pharma Global Development, Northbrook, IL 60201, USA., Van Tornout JM; Astellas Pharma Global Development, Northbrook, IL 60201, USA., Jie F; Astellas Pharma Global Development, Northbrook, IL 60201, USA., Sandhu S; Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK., Tan DS; Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK., Moreno V; Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK., LoRusso PM; Yale University, New Haven, CT 06520, USA., Kaye SB; Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK., Schöffski P; Department of Oncology, University Hospitals Leuven and KU Leuven, Leuven B-3000, Belgium.
المصدر: British journal of cancer [Br J Cancer] 2016 Apr 12; Vol. 114 (8), pp. 889-96. Date of Electronic Publication: 2016 Mar 22.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-1827 (Electronic) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE
أسماء مطبوعة: Publication: 2002- : London : Nature Publishing Group on behalf of Cancer Research UK
Original Publication: London, Lewis.
مواضيع طبية MeSH: Imidazoles/*therapeutic use , Multiprotein Complexes/*antagonists & inhibitors , Neoplasms/*drug therapy , Protein Kinase Inhibitors/*therapeutic use , TOR Serine-Threonine Kinases/*antagonists & inhibitors , Triazines/*therapeutic use, Adult ; Aged ; Dose-Response Relationship, Drug ; Female ; Half-Life ; Humans ; Imidazoles/pharmacokinetics ; Leukocytes, Mononuclear/drug effects ; Male ; Maximum Tolerated Dose ; Mechanistic Target of Rapamycin Complex 1 ; Mechanistic Target of Rapamycin Complex 2 ; Middle Aged ; Neoplasms/pathology ; Protein Kinase Inhibitors/pharmacokinetics ; Triazines/pharmacokinetics ; Young Adult
مستخلص: 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.
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معلومات مُعتمدة: C51/A6883 United Kingdom Cancer Research UK
المشرفين على المادة: 0 (Imidazoles)
0 (Multiprotein Complexes)
0 (OSI 027)
0 (Protein Kinase Inhibitors)
0 (Triazines)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
تواريخ الأحداث: Date Created: 20160323 Date Completed: 20160824 Latest Revision: 20211203
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC4984800
DOI: 10.1038/bjc.2016.59
PMID: 27002938
قاعدة البيانات: MEDLINE
الوصف
تدمد:1532-1827
DOI:10.1038/bjc.2016.59