Abstract CT-02: A phase I, open label, dose escalation study of oral mammalian target of rapamycin inhibitor INK128 administered by intermittent dosing regimens in patients with advanced malignancies
Authors: Tabernero Josep , Cervantes Andres , Gordon Michael S. , Chiorean Elena G. , Burris Howard A. , Macarulla Teresa , Perez-Fidalgo Alejandro , Martin Michael , Jessen Katti , Liu Yi , Le Trinh , Rommel Christian , Berk Greg I. , Bui Lynne A. , Infante Jeffrey R. 
Published: August 2012

Abstract
Background: INK128 is an orally bioavailable potent and selective ATP site kinase inhibitor of mammalian target of rapamycin (mTOR) complexes TORC1 and TORC2 that play a crucial role in regulating tumor cell growth, metabolism and motility. INK128 is structurally and mechanistically distinct from rapamycin and rapalogs. mTOR activity is frequently dysregulated in cancer by constitutive mitogen stimuli or oncogenic mutations upstream of TORC1/2. TORC1/2 kinase inhibitors are a promising class of novel anti-cancer agents. Methods: Adult patients (pts) with histologically confirmed advanced solid tumors were enrolled in a typical 3+3 dose escalation Phase I study evaluating 3 intermittent schedules: QW (once weekly), QDx3d QW (3 days on 4 days off), and QDx5d QW (5 days on 2 days off). Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary antitumor activity were evaluated. Pharmacodynamic (PD) endpoints were evaluated in surrogate (peripheral blood cells [PBCs], skin) and tumor tissues for the phosphorylation of TORC1-dependent markers (4EBP1/S6), and TORC2-dependent markers (AKT/PRAS40). Results: To date, 52 pts have been treated in 3 intermittent dosing regimens; 21 in 6 cohorts ranging 7-40 mg QW, 21 in 5 cohorts ranging 6-20 mg QDx3d QW, and 10 in 3 cohorts ranging 7-13 mg QDx5d QW. Dose limiting toxicities of Grade (G) 3 asthenia and G3 mucositis were reported in the 40 mg QW, 20 mg QDx3d QW, and 13 mg QDx5d QW cohorts. The MTD for intermittent dosing has not been reached. All adverse events (AEs) reported have been reversible. The most common (≥20%, n=35) AEs considered possibly related to INK128 reported in all 3 dosing regimens included nausea (51%), hyperglycemia (37%), mucosal inflammation (29%), rash (23%), asthenia (23%), vomiting (26%), and diarrhea (20%). The majority of AEs considered possibly related to INK128 in any regimen were G1 or 2. The only reported G ≥3 AE (≥5%) possibly related to INK128 in 3 regimens was lymphopenia (6%). Comparison across the 3 dosing regimens showed consistent and dose-dependent PK. INK128 was rapidly absorbed with Tmax ranging from 0.5 to 4 h and a mean elimination plasma t1/2 of 8 h. The plasma exposures (Cmax and AUC0-24) following oral doses suggest dose-linear plasma PK. Decreases in p4EBP1 levels were seen in PBCs in all dosing regimens. Skin biopsies showed 60∼100% inhibition of TORC1 (p4EBP1 and pS6) and TORC2 (pPRAS40). Preliminary anti-tumor activity was seen in pts with lung and renal cancer. Conclusions: INK128 is well-tolerated at the doses and schedules tested and shows high oral bioavailability and dose-linear PK across all dosing regimens evaluated with exposures in the range of predicted biological activity. PD biomarker changes are consistent with inhibition of TORC1 and TORC2. Preliminary anti-tumor activity is encouraging in this ongoing study.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr CT-02. doi:1538-7445.AM2012-CT-02