Biological and Medical Action of AV-951 in Patients With Advanced Solid Tumors.

Eskens FA, de Jonge MJ, Bhargava P, Isoe T, Cotreau MM, Esteves B, Hayashi K, Burger H, Thomeer M, van Doorn L, Verweij J. "Clin Cancer Res. 2011 Oct"

PURPOSE:

To assess the maximum tolerated dose (MTD)/dose-limiting toxicities (DLTs), safety, pharmacokinetics, and pharmacodynamics of AV-951, a potent and selective oral VEGFR tyrosine kinase inhibitor.
EXPERIMENTAL Design:

Dose ranges of 1.0, 1.5, and 2.0 mg/day AV-951 for 28 days followed by 14 days off medicine had been explored in sufferers with sophisticated sound tumors.

RESULTS:

Forty-one sufferers had been enrolled. Animal data incorrectly predicted toxicity, leading to DLTs in the beginning dose (2.0 mg) consisting of grade three proteinuria and hypertension and grade 3 ataxia. At 1.0 mg, no DLT was observed; At an intermediate dose (1.5 mg), one individual experienced DLT consisting of quality 3 hypertension. This dose was determined as the MTD Of 10 further individuals handled at 1.5 mg, 1 patient every single knowledgeable grade three hypertension and grade 3 tiredness, and two patients skilled grade three and four transaminase elevation. In 12 additional sufferers handled at 1.0 mg, no DLT was observed. Pharmacokinetics shown lengthy absorption time, dose proportional publicity, plus a half-life of 4.7 days. Plasma ranges of VEGF-A and sVEGFR-2 showed dose-dependent increases and decreases, respectively. Dynamic contrast-enhanced magnetic resonance imaging indicated reduction in tumor perfusion. Clinical activity was observed in renal cell cancer, colorectal most cancers, as well as other tumors.

CONCLUSIONS:

AV-951 was well tolerated with manageable unwanted effects. The pharmacokinetics profile uncovered that AV-951 was suitable for as soon as every day dosing. Encouraging and tough medical activity was observed. The suggested day-to-day dose of AV-951 in a 4 week on 2 week off dosing program is 1.5 mg.