Background: Since previous experiments of B with VEGFR tyrosine kinase inhibitors showed overlapping and limiting toxicities, a dose-finding study was designed to explore the safety and feasibility of the combination of a recent VEGFR inhibitor P with B in mRCC treatment-naive patients (pts) or in pts with other advanced refractory solid tumors. Methods: This double center trial was conducted with 3+3+3 escalation doses of P + B. The maximum tolerated dose (MTD) was the highest dosage not expected to cause a dose limiting toxicity (DLT) in more than 2/3, 3/6 or finally 3/9 pts, during the first 8 weeks of treatment. After preliminary DLT results, an approved by IDSMB extension cohort was enrolled and treated at MTD level.The effect of B on steady-state pharmacokinetic (PK) of P was also investigated by comparing PK at day 1 (D1) and D15 (day of B infusion). Results: 25 pts were enrolled with mRCC (n=7) or other advanced refractory solid tumors (n=18). Median age is 62 (41-79), 14 pts are male. At DL2 (n=10) 3 nephrectomized and 2 non-nephrectomized pts experienced DLT, as presented in the Table. In the 6-non-nephrectomized-pt extension cohort at DL1, 3 additional DLT were observed. Mean P AUC at D1 was higher than previously described in phase I P monotherapy (Clin Cancer Res 2009;15:4220). Mean P AUC at steady-state (D15) at both P dose levels was also significantly higher, though without being influenced by B infusion. Conclusions: The MTD of the P + B combination is respectively 400 mg/d and 7.5mg/kg (DL1) in all patients. Final PK analysis showed that there is no influence of B on P PK and that P AUC is higher than previously reported. Clinical trial information: NCT01202032.

* Microangiopathic hemolytic anemia. ^# Nephrectomized pt.