Combinations of vascular endothelial growth factor receptor tyrosine kinase inhibitiors (VEGFR-TKIs) and checkpoint inhibitors have proven to be both active and tox-ic. Tivozanib is a VEGFR-TKI with high specificity and lower incidence of class effect adverse events. In this phase I study we combined tivozanib with nivolumab in patients with metastatic renal cell carcinoma.

Using a standard 3 + 3 design we determined the safety, tolerability, and maximum tolerated dose of tivozanib in combination with nivolumab in patients with metastatic renal cell carcinoma. Tivozanib was administered orally at two dose levels, 1.0 mg and 1.5 mg, once daily for 21 days every 28 day cycle in combination with nivolumab 240 mg every 14 days intravenously.

Six patients were treated. Three were untreated and 3 patients had previously progressed following treatment with sunitinib. The median age was 59; 4 patients were ECOG 0 and 2 ECOG 1; and there were 4 males. No patient had a dose limiting toxicity in cycle 1. The most common adverse events were asthenia seen in 3 patients and diarrhea, stomatitis, arthralgia, and dysphonia, all seen in 2 patients. Hypertension, elevations of liver enzymes, and hand foot syndrome, were seen in one patient each. In cycle 1 no adverse event was higher than grade 2, although one event of grade 3 stomatitis was observed in a later cycle. No immune related adverse events were seen. There was no discernible difference between the two dose cohorts. All patients are ongoing and have started cycle 3. No patient progressed at the end of cycle 2.

As expected from a VEGFR-TKI with high specificity and a preferable toxicity pattern as a single agent, the combination of tivozanib with nivolumab has an adverse event pattern that appears preferable to combinations using other, less specific, VEGR-TKIs. The MTD was not identified. This data is based on limited exposure and should be interpreted with caution. More follow up is forthcoming from these patients, as well as data from an expansion cohort of patients treated at full dose of both agents, 1.5 mg of tivozanib with 240 mg of nivolumab. This dose would be the dose recommended for further studies.