Abstract C252: A phase 1, dose-escalation study of MLN0128, an investigational oral mammalian target of rapamycin complex 1/2 (mTORC1/2) catalytic inhibitor, in patients (pts) with advanced non-hematologic malignancies.
Authors: Infante Jeffrey R. , Tabernero Josep , Cervantes Andres , Jalal Shadia , Burris Howard A. , Macarulla Teresa , Perez-Fidalgo J. Alejandro , Neuwirth Rachel , Patel Chirag , Gangolli Esha , Brake Rachael , Sturm Jeffrey , Westin Eric H. , Gordon Michael 
Published: August 2014

Abstract
Background: MLN0128 is an investigational, potent, and highly selective inhibitor of mTORC1/2, which are integral to cell proliferation, angiogenesis, and cellular metabolism. This first-in-human study (NCT01058707) aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of oral MLN0128.
Methods: Pts aged ≥18 years with advanced solid tumors were enrolled in a 3+3 dose-escalation design initially to receive MLN0128 once daily (QD), and then enrolled in escalating intermittent schedules of once weekly (QW), 3 days/week (QDx3d QW), or 5 days/week (QDx5d QW) dosing, in 28-day cycles. Blood samples were collected at multiple timepoints for PK analysis. PD endpoints were evaluated in skin to determine the effect on mTORC1/2-dependent biomarkers. A preclinical PK-efficacy model was generated (Phoenix NLME v1.1) with tumor xenograft efficacy data, and implemented using clinical PK parameters to simulate tumor volume-time curves for various MLN0128 doses/schedules. Response was assessed by RECIST v1.1.
Results: 115 pts received MLN0128 doses in the ranges 2-7 mg QD (n=30), 7-40 mg QW (n=30), 6-20 mg QDx3d QW (n=33), and 7-13 mg QDx5d QW (n=22). Median age was 60 years (range 24-89); 40% were male. The most common tumor types were colorectal (22%), renal (9%), and ovarian (8%) cancer. The MTDs were 6 mg QD, 40 mg QW, 16 mg QDx3d QW, and 10 mg QDx5d QW. Based on the overall safety profiles, the recommended phase 2 doses were 5 mg QD, 40 mg QW, 9 mg QDx3d QW, and 7 mg QDx5d QW. Pts received a median of 2 cycles (range 1-23). The most common drug-related adverse events (AEs) were hyperglycemia (65%), nausea (60%), vomiting (44%), decreased appetite (36%), diarrhea (33%), asthenia (30%), and mucosal inflammation (30%). The most common drug-related grade ≥3 AEs were hyperglycemia (12%), asthenia (9%), and mucosal inflammation (5%). MLN0128 exhibited dose-linear PK with a plasma half-life of ∼8 h, and did not accumulate in plasma with QD dosing. Modeling of preclinical PK-efficacy data and simulation of human tumor volume-time curves using clinical PK parameters suggested potential greater antitumor effect with schedules using more frequent dosing (i.e. QD, QDx5d QW). There was a treatment-related inhibition of mTORC1/2 biomarkers in skin. Two of 10 pts (20%) with renal cancer receiving MLN0128 at 15 and 40 mg QW had a partial response; 5 pts (6%) had stable disease for ≥6 cycles.
Conclusions: Based on the safety profile, PK/PD, simulated tumor volume-time curves, and responses, MLN0128 5 mg QD and 40 mg QW were selected for further evaluation in an expansion phase in pts with renal, endometrial, or urothelial cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C252.
Citation Format: Jeffrey R. Infante, Josep Tabernero, Andres Cervantes, Shadia Jalal, Howard A. Burris, Teresa Macarulla, J. Alejandro Perez-Fidalgo, Rachel Neuwirth, Chirag Patel, Esha Gangolli, Rachael Brake, Jeffrey Sturm, Eric H. Westin, Michael Gordon. A phase 1, dose-escalation study of MLN0128, an investigational oral mammalian target of rapamycin complex 1/2 (mTORC1/2) catalytic inhibitor, in patients (pts) with advanced non-hematologic malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C252.