Phase I, first-in-human trial of an oral VEGFR tyrosine kinase inhibitor (TKI) x-82 in patients (pts) with advanced solid tumors.

Abstract

Listen

Translate article

3041 Background: VEGFR TKIs have shown benefit in the treatment of various tumor types. Side effects of the TKIs have affected the duration of therapy pts can tolerate, as well as the combinability with chemotherapy. X-82 is a highly potent VEGFR/PDGFR TKI with a smaller volume of distribution and limited tissue accumulation designed to minimize side effects while maintaining target effect. Methods: Pts with advanced solid tumors were enrolled using an accelerated titration scheme followed by 3+3 dose escalation design. X-82 was administered orally once daily (QD) or twice daily (BID) every 28 days. Safety, pharmacokinetic, clinical endpoints and blood-based biomarkers were evaluated. Results: 16 pts were treated across 8 dose levels: 20 (n=1), 40 (n=1), 80 (n=1), 160 (n=1), 300 (n=2), 400 mg QD (n=3), 140 mg BID (n=3) and 200 mg BID (n=4). The most common related adverse events (AEs) by pt were fatigue (4 G1, 1 G2), nausea (3 G1, 1 G2), diarrhea (3 G1), anorexia (1 G1, 1 G2), and vomiting (2 G1). G2 hypertension, resolved with treatment, was experienced by 1 patient. No > G3 related AEs have been reported. Dose proportional exposure was observed with doses up to 160 mg QD, and BID dosing cohorts were added. At 160 mg QD X-82 has plasma concentrations >100 ng/mL for at least 12 hours, the desired exposure predicted preclinically. Preliminary blood biomarker data (n=8) shows >25% decrease in VEGFR1 in 62% of pts and in VEGFR2 in 25% of pts, including pts at 40 and 80 mg cohorts. Efficacy has also been noted, including 1 confirmed complete response lasting 24+ weeks (pancreatic adenocarcinoma), and 6 pts with stable disease lasting 8+ weeks (range 12.1+, 38.3+ weeks), including the pt at 20 mg with SCLC (25.1 weeks). Conclusions: X-82 is a well-tolerated VEGFR/PDFGR TKI designed to minimize side effects while inhibiting target receptors. No MTD has yet been defined, though preliminary biomarker data are encouraging and clinical efficacy has been noted.