In vivo activity of R1530 (R) alone and in combination with bevacizumab (B) and peginterferon alfa-2a (P) in a renal cell carcinoma (RCC) xenograft model

Abstract

e14629 Background: R1530 is a multikinase inhibitor currently in clinical phase I testing. Its inhibitory profile includes several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. These properties translate into a potent cytotoxicity in a wide range of cancer cell lines in vitro and tumor growth inhibition in human tumor xenografts. Preclinical studies were conducted to evaluate the effects of R alone and in combination with B and P in the Caki-1 RCC xenograft model. Methods: We initially evaluated the antitumor activity of optimal dose (OD) and 1/2 OD R alone and with OD B. This was followed up with testing of OD & 1/2 OD P ± OD B, along with triplets of 1/2 OD P + OD B + 1/2 OD R and OD P + OD B + 1/2 OD R. A final study compared 1/2 OD R to OD R triplets to attempt to increase tumor growth inhibition (TGI) and increase life span (ILS). Results: No doublets or triplets tested showed antagonism or enhanced toxicity. Antitumor activity and survival results are listed below (Table). Conclusions: 1/2 OD R + OD B or OD R + OD B doublets gave better TGI and ILS than monotherapy. Comparing these two doublets, TGI is better in the high dose combination but ILS is equivalent. All TGI and ILS are better in doublet P + B combinations over respective single agent arms except for TGI (but not ILS) for 1/2 OD P vs its correlative doublet with B. The OD P + B doublet gave better TGI and ILS than 1/2 OD P + B doublet. TGI and ILS do not differ between triplets containing OD R + 1/2 OD or OD P or for triplets containing the OD P + 1/2 OD or OD R. Therefore, either agent can be alternatively dose reduced without a loss of tumor response or detriment to survival in this preclinical model of RCC. [Table: see text] [Table: see text]