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A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid
Joaquin Mateo1, David Olmos1,2, Herlinde Dumez3
1Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK.
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.
Insights
The dual mTORC1/2 inhibitor OSI-027 shows dose-dependent inhibition in advanced cancers. However, effective tumor drug levels require non-tolerable doses, limiting its clinical utility.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The mechanistic target of rapamycin (mTOR) pathway, comprising mTORC1 and mTORC2, is crucial in cancer.
- Inhibiting mTORC1 with rapalogues can lead to compensatory AKT/ERK activation.
- Dual mTORC1/2 inhibition may overcome resistance mechanisms.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and pharmacodynamics of the dual mTORC1/2 inhibitor OSI-027 in a first-in-human trial.
- To determine dose-limiting toxicities (DLTs) and establish a maximum tolerated dose (MTD) across different dosing schedules.
- To assess target modulation in patients with advanced cancers.
Main Methods:
- A dose-escalation study was conducted with three administration schedules: S1 (3 days/week), S2 (once a week), and S3 (daily).
- DLTs were identified to guide dose escalation.
- Expansion cohorts with paired tumor biopsies were initiated to evaluate pharmacodynamics.
Main Results:
- 128 patients with advanced cancer were enrolled. Predominant DLTs included fatigue, renal, and cardiac events.
- OSI-027 exposure was dose-proportional with a half-life of approximately 14 hours.
- While target modulation was observed in peripheral blood cells at 30 mg, 120 mg QD was needed for tumor modulation, a dose found to be non-tolerable due to renal toxicity. No RECIST responses were observed, with 5% achieving stable disease >6 months.
Conclusions:
- OSI-027 demonstrates dose-dependent inhibition of mTORC1/2 in patients with advanced cancers.
- Achieving sustained biological effects in tumor biopsies necessitates doses exceeding tolerable levels in schedules S1 and S3.
- The therapeutic window for OSI-027 may be narrow due to toxicity at efficacious doses.
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