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In-Depth Information
values, can be utilized in predicting OSI-906 plasma exposures required for
sustained inhibition of one or both targets in humans.
4.14 OSI-906: Clinical Experience
Phase I studies evaluating OSI-906 as a single agent in advanced solid tumors
commenced in June 2007. Trials were designed to evaluate both continuous
once-daily dosing as well as intermittent dosing at QD 1-3/5/7 schedules every
14 days.
52,53
Based on preclinical data indicating that maintenance of plasma
levels necessary to chronically suppress IGF-1R activity translated to improved
anti-tumor ecacy, OSI-906 was additionally evaluated on a twice a day (BID)
dosing schedule. Preliminary analysis has shown that OSI-906 PK is approxi-
mately dose-proportional.
52,53
The median time to C
max
is 2-4 h after dosing,
and the median terminal half life is 2-4 h. A dose of 300mg OSI-906 admi-
nistered once-daily generates plasma concentrations of OSI-906 in excess of
1 mM for 20-24 h. Preliminary PK data for BID dosing indicates that doses
greater than 75mg lead to plasma concentrations greater than 1 mM following
continuous once-daily treatment.
Intermittent dosing schedules were evaluated, as this may facilitate optimal
combination drug regimens with other agents. Preliminary PK analysis indi-
cates approximately dose-proportional exposure of OSI-906, and doses greater
than 450mg led to plasma concentrations greater than 1 mM for 20-24 h after
dosing. Collectively, these data indicate that, based upon preclinical models,
the predicted ecacious concentration in plasma could be achieved in cancer
patients.
Although the primary goal for the Phase I single-agent studies was to
determine the maximum tolerated dose and recommended Phase II dose, pre-
liminary evidence for anti-tumor activity was observed. Long-term stable dis-
ease greater than 24 weeks was observed for select patients receiving both the
once-daily and intermittent dosing schedules.
52
Additionally, a partial response
was observed for a patient with adrenocortical carcinoma receiving 450mg
OSI-906 administered on an intermittent schedule of QD 1-3 every 14 days.
Preliminary anti-tumor activity in ACC is consistent with the scientific ration-
ale for this being a tumor type driven by IGF-2 signaling.
4.15 Summary
In summary, OSI-906 is a potent, highly selective, and orally bioavailable dual
inhibitor of both IGF-1R and IR. The discovery of OSI-906 was enabled
through the use of rational SBD and empirical medicinal chemistry to optimize
potency and overall drug-like properties, as well as achieving a high degree of
selectivity. A streamlined testing cascade of IGF-1R and IR in vitro and in vivo
models allowed for the assessment of PK, PD, ecacy, and safety. Upon once-
per-day oral dosing, OSI-906 showed robust anti-tumor activity in multiple
mouse xenograft models. The anti-tumor activity correlated with the degree
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