Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma

Abstract

Background: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life. Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor.

Patients and methods: Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3+3 dose-escalation design and subsequent expansion cohort.

Results: Of 27 patients treated, 20 patients had received ≥ 1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5mg/d plus temsirolimus 25mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade ≤ 3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. Confirmed partial responses and stable disease were achieved at 23% and 68%, respectively. Pharmacokinetic analyses may suggest lack of an interaction between tivozanib and temsirolimus.

Conclusions: In this small phase Ib study, tivozanib and temsirolimus were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC.

Trial registration: ClinicalTrials.gov NCT00563147.

Keywords: Dose escalation; Maximum tolerated dose; Pharmacokinetics; Renal cell carcinoma; Temsirolimus; Tivozanib.

Conflict of interest statement

Conflict of interest statement

M.N. Fishman has served as a consultant/advisor and/ or received research funding from Altor, Amgen, AVEO, Bayer, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Novartis, Onyx, Pfizer, Prometheus and Roche/Genentech. R.J. Hauke has received research funding from AVEOand Pfizer.B. Esteves, M.M. Cotreau, A.L. Strahs and W.J. Slichenmyer are employees of, and own stock in, AVEO; P. Bhargava is a former employee of AVEO. All remaining authors declare no conflicts of interest.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Fig. 1

Dosing schedule. Tivozanib was administered once daily for 3 weeks, followed by a 1-week break (4 weeks = 1 cycle), and temsirolimus was administered weekly starting on day 8 of cycle 1. Treatment continued for a minimum of 8 weeks (two cycles), but could be continued for up to 1 year for patients achieving response or stable disease. T, temsirolimus.

Fig. 2

Duration of treatment and best response. Response was determined for the 22 patients evaluable for response: five (23%) patients achieved a best response of PR, and 15 (68%) patients achieved a best response of SD. Patient 010 received six cycles of study treatment before the patient’s treatment was interrupted (September 2009) when a suspected abscess appeared in the peripheral lung. He had antimicrobial treatment and resection, showing no malignancy in that area. The mediastinal lymph nodes that were the site of the metastatic RCC were about the same (SD) after the treatment hiatus, and he restarted on treatment (March 2010) following IRB approval. The patient continued study treatment for another 6 months before rolling over to a long-term treatment study. Of the six patients who were NE for response, one patient withdrew prior to tivozanib administration, two patients received

Fig. 3

Tumour response. Maximum changes in tumour size from baseline were determined for the 22 patients evaluable for response.

Fig. 4

Individual and mean (shown in bold) tivozanib (1.5 mg) serum concentration versus time by dose level throughout cycle 1. Although substantial individual variation was observed, there was a clear relationship between tivozanib concentration and dose, and an accumulation of tivozanib to nearly steady-state levels over the 21-d treatment period.