A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies.
View/ Open
Date
2016-04Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
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
Research team
Prostate Cancer Targeted Therapy Group
Medicine Drug Development Unit (Kaye)
Language
eng
Date accepted
2016-02-16
License start date
2016-04
Citation
British journal of cancer, 2016, 114 (8), pp. 889 - 896