Vorolanib is an orally available, potent, small molecule VEGFR inhibitor. It was designed based on the sunitinib scaffold with the goals of a shorter half-life to meet the pharmacokinetic (PK)/ pharmacodynamic (PD) requirement of intermittent inhibition and no accumulation in tissues. This first-in-human study (NCT01296581) was designed to determine the maximum tolerated dose (MTD) or the recommended dose, dose-limiting toxicity (DLT), safety, PK, and preliminary antitumor activity of vorolanib.
Patients aged ≥ 18 years with advanced solid tumors were enrolled at the starting dose of 20 mg and escalating doses in an accelerated design. Safety was evaluated in every 4-week cycles, and tumor assessment was performed every 8 weeks using RECIST 1.1. Plasma PK samples and time-matched ECG data were collected.
52 patients received vorolanib in 17 cohorts, with doses ranging from 20mg QD to 800 QD and 140-200 mg BID. During the study, the formulation was changed from capsule to tablet. The most common tumor type was ovarian (19%). No DLT occurred and the MTD was not officially reached. Due to apparent saturation of absorption in the 400 – 800 mg QD range, dose escalation was stopped at 800 mg, and 400 mg QD was chosen as the dose for the expansion cohort. The most common treatment-related adverse events (TRAE) were fatigue, nausea, diarrhea, hair color change, vomiting, rash, peripheral edema and asthenia, mostly grade 1-2. Five patients had a grade 3TRAE, with proteinuria (4%) being the most common. The plasma half-life of vorolanib was approximately 6.5 hours, and no accumulation was observed after 21-days of daily dosing. 1 pt with pancreatic adenocarcinoma receiving vorolanib had a complete response, 1 pt with Hurthle cell carcinoma had a partial response, and 11 pts (20%) had stable disease for ≥ 6 cycles.
Vorolanib was generally well tolerated up to 800 mg QD in patients with advanced solid tumors. Based on the safety profile, PK/PD model and patient responses, 400 mg QD was selected as the single agent dose for advanced cancer patients.
Clinical trial identification
Legal entity responsible for the study
Xcovery Holdings, Inc.
Has not received any funding.
K.N. Moore: Advisory boards: AstraZeneca, Advaxis, Clovis, Tesaro, Immunogen, Genentech/Roche, VBL Therapeutics, Janssen. G. Dukart, K. Harrow, C. Liang: Full time employee and stock options: Xcovery Holdings, Inc. All other authors have declared no conflicts of interest.