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Phase I pharmacodynamic trial of sequential sunitinib (SU) with bevacizumab (bev) in patients with renal cell carcinoma (mRCC) and other advanced solid malignancies
Abstract   Open access   Peer reviewed

Phase I pharmacodynamic trial of sequential sunitinib (SU) with bevacizumab (bev) in patients with renal cell carcinoma (mRCC) and other advanced solid malignancies

M. R. Harrison, R. Jeraj, H. J. Hammers, M. N. Stein, A. Andrei, S. Perlman, J. Kolesar, R. M. Marnocha, D. B. Alberti, G. Wilding, …
Journal of clinical oncology, Vol.29(15_suppl), pp.e13503-e13503
05/20/2011
DOI: 10.1200/jco.2011.29.15_suppl.e13503
url
https://doi.org/10.1200/jco.2011.29.15_suppl.e13503View
Published (Version of record) Open Access

Abstract

Abstract only Background: VEGF signaling pathway (VSP) inhibition has been clinically validated for the treatment of multiple solid tumors. SU is an oral TKI of primarily VEGFR, PDGFR, and c-Kit, while bev is an IV mAb that binds VEGF. The PET radiotracer [18F]-FLT can be used to measure cellular proliferation. Temporary discontinuation of SU results in a proliferative tumor flare as measured by FLT PET/CT. This flare may be the result of a compensatory increase in the VEGF ligand. Prior studies of SU + bev demonstrated unacceptable toxicity with concurrent administration, especially in mRCC pts. We propose to block the flare with a VEGF ligand binding agent (bev) using a novel sequential strategy, with the goal of attaining a higher clinical response and/or prolonged clinical benefit. We hypothesize that this strategy will minimize overlapping toxicity while achieving flare suppression. Methods: This multicenter phase I study will enroll a maximum of 39 evaluable pts with mRCC or any other advanced solid tumor to evaluate the novel combination of SU with sequential bev dosing. No prior VSP inhibitors will be allowed. Two successive dose-escalation cohorts will be followed by a recommended phase II dose (RP2D) cohort. Each dose-escalation cohort will enroll 6 evaluable pts with mRCC only. SU will be given daily for 4 consecutive wks (d1-28) followed by a 2 wk drug holiday (approved 4/2 schedule). SU will be dose-escalated from 37.5 mg to 50 mg daily if <2/6 pts experience a DLT after 3 cycles of treatment. Bev will be given at a fixed dose of 5 mg/kg IV q6 wks on day 29 only. At each dose level a total of 6 additional evaluable pts (mRCC or other solid tumor) will be enrolled for FLT PET/CT imaging. Once a safe and pharmacodynamically appropriate dose is identified, 15 more evaluable pts with mRCC only will be enrolled in the RP2D cohort for further safety evaluation. Coprimary endpoints are the evaluation of safety/tolerability and assessment of objective response rate in pts with mRCC. Secondary endpoints include characterization of SUV values, tumor perfusion, and ratio of free:bound plasma VEGF at timepoints throughout the SU cycle.

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