A phase I study to evaluate safety, tolerability, pharmacokinetics, and preliminary antitumor activity of TQ-B3101.

Abstract

e21705 Background: TQ-B3101 is a novel compound, which deacetylated metabolite targets to receptor tyrosine kinases including ALK, ROS1 and MET. Preclinical studies showed TQ-B3101 had a better Inhibition activity and duration compared with equimolar crizotinib. Methods: Patients (pts) with advanced solid tumor failed to standard therapy were enrolled into dose escalation and expansion cohorts. TQ-B3101 was orally administered at doses of 100~300mg QD or 200~350mg BID in a 28-day cycle, then received the same dose until disease progression or intolerable toxicity. Dose escalation was based on dose-limiting toxicities (DLTs) in the first cycle and used “3+3” design to get the maximal tolerated dose (MTD) or recommended phase II dose (RP2D). Other objectives included safety and pharmacokinetics (PK) for all pts, and objective response rate (ORR) for ALK+, ROS1+ and MET amplification pts. Results: As of 20 Dec 2019, 30 pts (median age 51.3, males: 16, females: 14, ALK+: 19, ROS1+: 6, MET amplification: 2, lung cancer: 27, asymptomatic brain metastasis: 8, ECOG PS 1: 30) were enrolled into 7 dose escalation cohorts and 2 dose expansion cohorts (350mg BID/ 300mg BID). One DLT (grade 3 ALT increased) occurred at 350 mg BID. The MTD has not been reached. The most common grade 3 adverse events were neutrophils count decreased (20%), ALT increased (6.67%), leucocyte counts decreased (3.33%) and QT internal prolongation (3.33%). Grade 3 adverse events rate were 40% in 350mg BID cohort and 16.67% in 300mg BID cohort. PK analyses indicated TQ-B3101 metabolized into its deacetylated product rapidly, and exposure (Cmax and AUC) of which generally increased in a dose-proportional manner. Tumor response was evaluated in 24 pts with ALK+/ROS1+/MET amplification. ORR were 62.5% (15/24) in all cohorts, and 87.5% (7/8) in 350mg BID cohort. In 8 pts with brain metastases at baseline, ORR was 62.5% (5/8) . In 22 pts without brain metastases at baseline, the incidence of brain metastasis was 4.55% (1/22). 1 patient with MET amplification is evaluable and the tumor response is PR. Conclusions: TQ-B3101 was well tolerated and showed preliminary antitumor activity in ALK+, ROS1+ and MET amplification pts. Recommended phase II dose (RP2D) might be 300mg BID according longtime safety data. Further anti-tumor research in pts with ROS1+ is under going as multicenter clinical study in China. (NCT03972189). Clinical trial information: NCT03019276.