796PD - Tivozanib pharmacokinetic (PK)/pharmacodynamic (PD) analysis of blood pressure (BP) and soluble vascular endothelial growth factor receptor 2 (SVEGF...

Date 01 October 2012
Event ESMO Congress 2012
Session Genitourinary tumors, non-prostate (renal cancer)
Topics Renal Cell Cancer
Pharmacology
Presenter Dmitri Nosov
Authors D. Nosov1, R.J. Motzer2, J. Loewy3, L. Hodge3, B. Esteves4, A. Berkenblit4, W. Yin5, K. Dykstra6, T. Hutson7, M. Cotreau5
  • 1Clinical Pharmacology And Chemotherapy, N. N. Blokhin Russian Cancer Research Center, 115478 - Moscow/RU
  • 2Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York/US
  • 3Biostatistics, qPharmetra, Andover/US
  • 4Clinical Research, AVEO Pharmaceuticals, Cambridge/US
  • 5Oncology, AVEO Pharmaceuticals, Inc, Cambridge/US
  • 6President/ceo, qPharmetra, Andover/US
  • 7Gu Center Of Excellence Texas Oncology, Charles A. Sammons Cancer Center / Baylor University Medical Center / Texas AM Health Science Center College of Medicine, DALLAS/US

 

Abstract

Background

Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor of VEGF receptors (VEGFRs) 1, 2, and 3, demonstrating activity against advanced RCC in Phase (Ph) II–III trials. This analysis explored the relationship between tivozanib PK and BP, as hypertension is a mechanism-based adverse event and a potential surrogate of response. The relationship between exposure and sVEGFR2 also was explored.

Methods

Pharmacokinetic, BP, and sVEGRF2 data from tivozanib-treated RCC patients (pts) from a Ph II (n = 21) and a Ph III (n = 259) study were pooled; pts were treated with 1.5 mg tivozanib daily for 21 days followed by a 7-day rest (28-day treatment cycle) in each study. A population PK model of tivozanib was constructed from PK data from Ph I–III studies, to obtain individualized predictions of steady-state values for Cavg. BP was measured at baseline and on Cycle 1 Day 15 (C1D15), C2D1, and C3D1 in the Ph II and Ph III studies, and was binned to the nearest 5 mm Hg. Analysis focused on BP shifts in 5 mm Hg increments. Serum samples for sVEGFR2 (Ph III only) were collected at baseline and on C1D15, C2D1, and C2D22–28. Models of drug exposure as predictors of longitudinal changes in BP and/or sVEGFR2 were constructed by non-linear mixed-effects modeling.

Results

Across pts, there was a statistically significant median 5 mm Hg increase in diastolic BP on C1D15, with similar increases noted on C2D1. There was a curvilinear decrease in sVEGFR2 with time. An Emax model vs time showed a half-maximal effect occurring in 19.4 (SE = 1.7) days, and a maximal 53% (%CV = 4%) decrease in sVEGFR2. There was a statistically significant effect of Cavg on Emax, with the magnitude of Emax increasing 6% per 10 ng/mL increase in Cavg.

Conclusion

PK/PD analysis of data from tivozanib Ph II–III studies showed that pts had a median increase in diastolic BP of 5 mm Hg on C1D15 and C2D1. Levels of serum sVEGFR2 were found to decrease significantly with time, and the effect size increased with tivozanib exposure. Relationships between exposure, BP, and sVEGFR2 and outcome are being explored.

Disclosure

R.J. Motzer: Only disclosure is research funding from AVEO Oncology.

J. Loewy: Consulting fee or honoraria from qPharmetra LLC.

L. Hodge: Consulting or honoraria from qPharmetra LLC.

B. Esteves: AVEO Pharmaceuticals employee with stock options.

A. Berkenblit: AVEO Pharmaceuticals employee with stock options.

W. Yin: AVEO Pharmaceuticals employee with stock options.

K. Dykstra: -Consultancy fee or honorarium: qPharmetra LLC -Fees for participation in review activities such as data monitoring boards, statistical analysis, end point committees and the like: qPharmetra LLC.

T.E. Hutson: - Consultancy or honoraria: AVEO Pharmaceuticals - Consultancy: Pfizer, Bayer, GSK, Novartis – Grants, grants pending: Pfizer, Bayer, GSK, Novartis – Payment for lectures includes service on speakers bureau:Pfizer, Bayer, GSK, Novartis.

M. Cotreau: AVEO Pharmaceuticals employee with stock options.

All other authors have declared no conflicts of interest.