Abstract CT305: Phase I studies of a selective cMet inhibitor AZD6094 (HMPL504/volitinib) in patients with advanced solid tumors
Authors: Hua Ye , Shen Lin , Gan Hui , Lickliter Jason , Millward Michael , Xu Jianming , Wang Jian , Sai Yang , Su Weiguo , Frigault Melanie M. , Qi Chuan 
Published: August 2015

Abstract
Background: Volitinib is a selective oral small molecule inhibitor of cMet kinase, which has demonstrated potent in vivo inhibitory effects on a variety of human tumor xenografts.
Methods: Two phase I dose-escalation studies have been conducted in Australia (AU) and China (CN) in parallel to determine the maximum tolerated dose (MTD) or phase II Recommended Dose (P2RD), to evaluate pharmacokinetics (PK) profile, and to assess antitumor activity of Volitinib. Treatment was given orally in 21-day cycles until disease progression or unacceptable toxicity.
Results: By July 2014 both studies completed dose-escalation phase. A total of 61 patients were enrolled (40 in AU and 21 in CN). Patients were treated with daily (QD) volitinib from 100mg to 1000mg or twice daily (BID) from 300 mg to 600mg. Median age at baseline was 63 years, and 60% patients were male in the AU study; whereas median age was 53 years, and 57% patients were male in the CN study. In both studies, the most common treatment related adverse events included nausea, vomiting, fatigue, peripheral edema and decreased appetite, mostly of grade (G) 1/2. Four patients experienced 5 dose limiting toxicities (DLTs) in the AU study: 1 G3 abnormal liver function test at 600mg QD, 1 G3 fatigue at 800mg QD, and 2 G3 fatigues and 1 G3 headache at 1000mg QD. One DLT of G3 fatigue at 600mg BID was reported in the CN study. The MTD for the QD regimen was identified as 800mg whereas the MTD for the BID regimen had not been reached in either study. 500mg BID was determined to be the P2RD as monotherapy based on the favorable benefit/risk profile demonstrated in both studies. In the AU study, 2 patients in the 600mg QD cohort and 1 patient in 1000mg QD cohort achieved partial response (PR). All 3 responders were papillary renal cell carcinoma patients. Two of the 3 responders remain PR with volitinib treatment of approximately 10 and 18 months respectively by July 2014. One CRC patient at 600mg QD achieved a 29% tumor reduction. Tumor sample analysis showed that all responders had both MET gene copy number increase (Chr7 gains or Met gene amplification) and high MET protein expression. Volitinib was rapidly absorbed with Tmax around 2∼4 hours and rapidly eliminated with half-life around 3∼7 hours in both studies. Both Cmax and AUC were roughly dose-proportional up to 800 mg QD and 500 mg BID. No obvious accumulation was found after 21-day of continuous QD or BID dosing. Drug exposure did not show racial difference between Caucasian and Asian patients.
Conclusions: Volitinib was well tolerated up to 800 mg QD and 600 BID with acceptable safety profile. 500mg BID was determined to be the P2RD as monotherapy. Preliminary efficacy data demonstrated promising anti-tumor activity in patients with Met gene copy number increase or high protein expression. Volitinib demonstrated linear PK profile without marked drug accumulation. Further clinical studies are warranted.
Citation Format: Ye Hua, Lin Shen, Hui Gan, Jason Lickliter, Michael Millward, Jianming Xu, Jian Wang, Yang Sai, Weiguo Su, Melanie M. Frigault, Chuan Qi. Phase I studies of a selective cMet inhibitor AZD6094 (HMPL504/volitinib) in patients with advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT305. doi:10.1158/1538-7445.AM2015-CT305