Abstract B60: Combination of tivozanib (AV‐951) and temsirolimus in patients with renal cell carcinoma (RCC): Preliminary results from a phase 1 trial

Background: Based on preclinical data, a combination of VEGF and mTOR inhibitors (mTORi) may be active in RCC and other tumors. However, it has been difficult to combine VEGF tyrosine kinase inhibitors (TKIs) and mTORi due to toxicity. Clinical trials have demonstrated that VEGF TKI and mTORi can only be combined after reducing the doses of both agents, which may also result in reduced anti‐tumor activity of this drug combination. Tivozanib, a potent VEGF receptor 1, 2 and 3 TKI, has demonstrated antitumor activity in a phase 2 study in RCC and may be easier to combine with mTORi due to its selective adverse event profile (Proceedings of ASCO 2009, Abstract no. 5032). The combination of tivozanib and temsirolimus was tested in a phase 1 study. Methods: Patients (pts) with advanced RCC (with clear cell component) who had failed up to one prior VEGF‐targeted therapy received oral tivozanib (3 wks on, 1 wk off) and intravenous temsirolimus (once weekly). Dose levels tested (tivozanib/temsirolimus) were: 0.5mg/15mg, 1.0mg/15mg, 1.5mg/15mg, 1.5mg/25mg. The goals of the study were to determine the maximum tolerated dose (MTD), safety, dose‐limiting toxicity (DLT), pharmacokinetics (PK) and clinical activity of this drug combination. Results: As of September 1, 2009, 15 pts had been enrolled: 15 males/ 0 females, median age 63 yrs (range 43–70), KPS 100% (11 pts) or 90% (4 pts). Nine (60%) pts had received prior VEGF targeted therapy. The median duration of treatment was 8 wks (range 0–40 wks). Based on preliminary data, treatment‐related AEs seen in ≥20% pts (No. of pts with all grades/grade 3 toxicity) were thrombocytopenia (5/2), fatigue (5/1), mucositis (4/0), rash (3/0) and stomatitis (3/0). There were no DLTs and no grade 4 toxicities. The MTD of this combination was: tivozanib 1.5 mg and temsirolimus 25 mg. Available data suggest lack of PK interaction between the two agents. One pt had a confirmed PR, and 7 pts had stable disease for ≥ 8 wks. Conclusions: The combination of tivozanib with temsirolimus is well tolerated in patients with advanced RCC. Tivozanib is the first VEGF TKI that can be combined with temsirolimus at full doses of both agents. Additional patients are being enrolled in the MTD cohort for an expanded safety assessment, and updated results will be available for presentation. An all oral combination of tivozanib and the mTORi everolimus is also being developed for the treatment of RCC and other tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B60.