Négrier S, et al. – The combination of pazopanib and bevacizumab was inspected in order to ascertain the maximum tolerated dose (MTD) in metastatic renal cell carcinoma (mRCC) and other advanced solid tumors. In patients without any pre–existing renal or vascular damage, pazopanib with bevacizumab induced angiogenic toxicity. The toxicity profile compromised the development of this combination, even if a marginal efficacy was reported with five (22%) patients in a partial response in different tumor types.

Methods

• Patients received oral pazopanib once daily plus intravenous infusion of bevacizumab every 2 weeks from D15, at one of the four dose levels (DL) planned according to the occurrence of dose limiting toxicities (DLT), in this bicentric phase I trial with a 3 + 3 + 3 dose-escalation design.
• In DL1 and DL2, 400 and 600 mg pazopanib were respectively combined with 7.5 mg/kg bevacizumab, and 600 and 800 mg pazopanib with 10 mg/kg bevacizumab in DL3 and DL4.
• Every 8 weeks, tumor response was evaluated.
• In order to examine pazopanib pharmacokinetics, blood samples were assayed.

Results

• This study recruited twenty five patients including seven mRCC.
• DL1 was given to nine patients and ten received the DL2.
• Data did not indicate any DLT at DL1.
• This study highlighted five DLT at DL2, and 3 DLT in the six additional patients who received the DL1.
• Four (16%) patients exhibited a grade 3 microangiopathic hemolytic anemia syndrome.
• A partial response was achieved by five (22%) patients.
• Higher than those previously reported with pazopanib, the mean (range) plasmatic concentrations of 400 and 600 pazopanib were respectively 283 (139–427) and 494 (227–761) μg.h/mL at Day 1, and 738 (487–989) and 1071 (678–1464) μg.h/mL at Day 15 and were not directly influenced by bevacizumab infusion.