Background: Vascular endothelial growth factor receptor (VEGFR) signal transduction mediates glioblastoma (GB) associated neo-angiogenesis. Axitinib is an oral small molecule tyrosine kinase inhibitor with high affinity and specificity for the VEGF-receptors, approved for the treatment of metastatic renal cell carcinoma. Methods: Axitinib (5 mg BID starting dose) vs. best alternative choice of therapy was studied in an open label, randomized, phase II clinical trial in patients (pts) with recurrent GB. Six-month progression-free survival (6mPFS) was the primary endpoint. Results: Between Sep 2011 and Oct 2013, 44 pts who failed surgery, RT and temozolomide were randomized 1:1 at 3 sites. Median age 54y (range 20-79), 33M/11F, WHO-PS 0/1/2/3: 6, 26, 11, and 1 pt. In the control arm 20 pts received bevacizumab and 2 pts received lomustine at standard doses. Axitinib (n=22) was generally well tolerated. Most common axitinib related AEs consisted of dysphonia (3x G2), fatigue (6x G2, 2x G3), hypertension (5x G2), oral hyperesthesia (7x G2, 1x G3), diarrhea (2x G2, 2x G3), and hypothyroidism (3x G2). In 4 pts axitinib dosing was interrupted and subsequently dose reduced because of toxicity; in 4 other pts axitinib was dose escalated to 7 or 10 mg BID (2 pts each). Tumor response by RANO criteria was 28% in the axitinib arm vs. 23% in the control arm (Table). All pts had an increased uptake on 18F-FET PET at baseline. A decrease (-26 to -100%) of SUVmax/background was documented in 6/7 pts on axitinib at the time of response on MRI. Corticosteroids could be stopped in 4/12 and tapered in an additional 5/12 pts in the axitinib arm. After a median follow-up of 10.5 mths, the 6mPFS for axitinib was 22% (95% CI 5-40) vs. 19% (95% CI 2-36) for the control arm. Median PFS and OS were respectively 2.9 vs. 2.6 mths, and 10.3 vs. 7.4 mths for pts treated in the axitinib vs. control arm. Conclusions: Axitinib has single-agent activity and manageable toxicity in pts with recurrent GB. The survival on the axitinib arm was comparable to that on the contemporary control arm. Further evaluation of axitinib for recurrent GB is warranted. Clinical trial information: NCT01562197.

Abbreviations: BOR, best overall tumor response; NE: not evaluable.