Abstract 5588: A phase I, open label, dose escalation study of an oral mammalian target of rapamycin inhibitor INK128 administered once daily in patients with advanced malignancies
Authors: Infante Jeffrey R. , Tabernero Josep , Burris Howard A. , Macarulla Teresa , Martin Michael , Liu Yi , Jessen Katti , Koczon Ethel , Rommel Christian , Klein Pam M. , Berk Greg I. , Bui Lynne A. , Gordon Michael S. 
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 human cancer by constitutive mitogen stimuli or oncogenic mutations upstream of TORC1 and TORC2. 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 to determine the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity. PD endpoints were evaluated in surrogate (peripheral blood cells [PBCs] and skin) and tumor tissues for the phosphorylation of TORC1-dependent markers (S6/4EBP1), and TORC2-dependent markers (AKT/PRAS40). Results: A total of 25 pts received daily (QD) doses of INK128 in 4 cohorts at 2 mg (n=3), 4 mg (n=7), 6 mg (n=7), and 7 mg (n=8). Dose-limiting toxicities (DLTs) were Grade (G) 3 hyperglycemia, G3 rash, and G4 anemia. The MTD was 6 mg QD with a DLT of G3 rash in 1 out of 6 pts. All AEs reported to date have been reversible. The most common (&gt;20%, n=25) AEs considered possibly related to INK128 included hyperglycemia (88%), rash (52%), nausea (36%), pruritus (36%), diarrhea (32%), dysgeusia (32%), mucosal inflammation (32%), asthenia (24%), blood creatinine increased (24%), decreased appetite (24%), fatigue (24%), and vomiting (24%). The most common G ≥3 AEs (≥10%; n=25) considered possibly related to INK128 were rash (28%) and hyperglycemia (16%). Hyperglycemia was generally well controlled with metformin. INK128 was rapidly absorbed with Tmax of 1 to 4 h with high oral bioavailability. The mean elimination t1/2 ranged from 7 to 11 h and the mean steady-state plasma concentrations (Cmax, ss) ranged from 52 nM to 210 nM across 4 dose levels. Comparisons of plasma exposures (Cmax and AUC0-24 following oral doses suggest dose-linear plasma PK with limited inter-pt variability. PD biomarker measurements in PBCs, skin, and tumor showed dose-dependent TORC1/2 inhibition as evidenced by decreases in p4EBP1, pS6, and PRAS40. Preliminary anti-tumor activity was seen in 24% and 12% of pts experiencing stable disease for ≥4 and ≥6 cycles, respectively. Conclusions: INK128 dosed QD at its MTD of 6 mg has an acceptable tolerability and safety profile in pts with advanced malignancies. INK128 shows high oral bioavailability and dose-linear PK with exposures in the range of predicted biological activity. PD biomarker changes are consistent with inhibition of TORC1 and TORC2. Preliminary antitumor 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 5588. doi:1538-7445.AM2012-5588