Results Of A Phase I Trial Combining Ridaforolimus (Mtor Inhibitor) And Mk-0752 (Notch Inhibitor) In Patients With Advanced Solid Tumors.

2601 Background: The PI3K/AKT/mTOR signaling pathway is aberrantly activated in a variety of cancers. Ridaforolimus (R) is an mTOR inhibitor with activity in a broad range of cancers. MK-0752 inhibits the Notch receptor through its significant inhibition of gamma secretase and has evidence of antiangiogenic effects. R + MK-0752 may lead to complementary blockade of the PI3K pathway. Methods: The primary objective of this Phase I dose-escalation study (NCT01295632) was to define the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD); a secondary objective was assessment of antitumor activity. Patients (pts) received a 5-day lead-in of R as monotherapy before beginning combination dosing. Rising doses of R were orally administered 5 days/week. MK-0752 dosing was fixed at 1800 mg given orally once per week. Results: For the 28 treated pts R doses were escalated from 20 to 30 mg/d. The MTD was determined to be 20 mg qd R 5 days/week + 1800 mg weekly MK-0752 (dose level 1). Among the 14 evaluable...