Abstract CT237: Interim results of a first-in-human phase 1 study of the oral MET kinase inhibitor, LY2801653, in patients with advanced cancer
Authors: Hwang Jimmy , Cohen Roger , Perez Kimberly , Safran Howard , He Aiwu Ruth , Giles Jennifer , Hu Tianle , Moser Brian , Turner Patricia Kellie , Walgren Richard A. , Plimack Elizabeth 
Published: May 2015

Abstract
Background: Aberrant MET signaling, whether due to genetic lesions, transcriptional upregulation, or ligand-dependent autocrine or paracrine mechanisms, plays a role in tumorigenesis and angiogenesis. Amplification of MET has also been demonstrated in tumor cells that have acquired resistance to treatments such as cisplatin, erlotinib, and gefitinib. The purpose of this phase 1 study is to evaluate the safety and tolerability of LY2801653, a type II MET kinase inhibitor, and to determine a recommended Phase 2 dose and schedule that may be safely administered to patients with advanced cancer.
Methods: Patients with a diagnosis of advanced or metastatic solid tumors and whose disease had demonstrated standard treatment failure were enrolled in the study (NCT01285037). Dose escalation was performed using a modified CRM design (Part A). Dose confirmation testing continued in Part B enrolling 4 tumor types -colorectal (CRC), squamous cell carcinoma of the head and neck (HNSCC), cholangiocarcinoma (CCA), and uveal melanoma.
Results: In Part A, 50 patients received daily oral doses of LY2801653 at one of 10 dose levels (3, 6, 5, 10, 20, 40, 80, 120, 160, and 240 mg). Reversible grade 3 elevations of AST/ALT were identified as the dose limiting toxicity and occurred at 240 mg (n=2), 160 mg (n=2) and 120 mg
(n=1). A dose of 120 mg QD was selected for further study (geometric mean AUC0-24hr = 3070 ng*hr/mL, CV=79%, n=9; geometric mean Cmax= 298 ng/mL, CV=67%, n=10). As of 08/20/2013, 30 patients (19 CRC; 5 HNSCC; 6 CCA) have received LY2801653 at 120 mg QD in Part B. Among all treated patients (N=80), the most frequent therapy-related adverse events, all ≤ Grade 3 in severity, were fatigue (23.8%), increased AST (21.3%) or ALT (20%), nausea (15%), limb edema (12.5%), and increased ALP (11.3%). The primary reason for discontinuation was progressive disease (n=48, 60%), and 4 patients discontinued due to treatment related adverse events of fatigue, AST increase, bilirubin increase, or left ventricular systolic dysfunction. In Part A, 9 patients have been treated for ≥4 months, including 1CRC patient (707 days) and 1 squamous cervical cancer patient (566 days). Although the data is still immature in Part B, 4 patients (2 CRC; 1 HNSCC; 1 CCA) have been treated for ≥4 months, all with stable disease and 3 with a reduction in tumor size from baseline.
Conclusions: In dose escalation testing, once daily dosing with LY2801653 demonstrated an acceptable toxicity profile. Single agent testing is ongoing at 120 mg in 4 tumor specific cohorts as well as two additional arms investigating LY2801653 in combination with cetuximab in HNSCC and with cisplatin in CCA.
Citation Format: Jimmy Hwang, Roger Cohen, Kimberly Perez, Howard Safran, Aiwu Ruth He, Jennifer Giles, Tianle Hu, Brian Moser, Patricia Kellie Turner, Richard A. Walgren, Elizabeth Plimack. Interim results of a first-in-human phase 1 study of the oral MET kinase inhibitor, LY2801653, in patients with advanced cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT237. doi:10.1158/1538-7445.AM2014-CT237