To Assess The Effect Of Ridaforolimus On The Qtc Interval In Patients With Advanced Cancer

e13088 Background: Ridaforolimus (RIDA) (AP23573; MK-8669), a unique rapamycin analog and potent inhibitor of mTOR signaling, is being developed for treatment of solid tumors. We aimed to assess the effect of a single supratherapeutic dose of 100 mg RIDA on the QTc interval in advanced cancer patients. This dose was used to achieve an exposure similar to that following the clinical dose regimen. Methods: This was a partially blind, placebo-controlled, 2-part study of RIDA in advanced cancer patients. In Part 1, 2 days of ECG were performed for QTc assessment in a fixed sequence. On Day 1, patients received a single oral dose of placebo; on Day 2 they received a single oral dose of RIDA 100 mg. Each dose was followed by 24 h of Holter ECG. Blood samples for RIDA were measured at pre- and up to 24 h postdose on Day 2. In Part 2, patients had continued access to RIDA for potential clinical benefit, with only safety data collected. Results: 23 patients (8 males; 15 females) were enrolled. For Day 1 placebo treatment, 22 patients were included in the QTcF data; for Day 2 RIDA treatment, 20 were included in the QTcF data and 21 in the pharmacokinetic data. RIDA 100 mg did not prolong the QTcF interval. Upper bound of the 90% CI of the placebo-adjusted mean QTcF interval change-from-baseline was <10 ms at every time point through 24 h. The largest placebo-corrected RIDA change from baseline QTcF occurred at 10 h postdose, mean difference 3.89 ms, 90% CI (0.60, 7.17). After placebo or 100 mg RIDA administration, only 1 patient had QTcF values >450 ms (on both placebo and RIDA) and none had values >480 ms. Neither placebo nor treatment patients had a QTcF change-from-baseline >30 ms. Exposures after single dose RIDA 100 mg were a geometric mean whole blood AUC0-24 of 1875 h·ng/mL and Cmax of 186 ng/mL, approximating steady state exposure with the clinical dose regimen of 40 mg po QD x 5 consecutive days/week. However, these values do not achieve supratherapeutic exposure. RIDA was generally well tolerated, with no patients discontinued from Part 1 due to drug-related AEs. Conclusions: A single dose of RIDA (100 mg) does not prolong the QTc interval in advanced cancer patients and achieved exposures that approximated steady state exposures at the maximally tolerated clinical dose and regimen.