Abstract OT1-2-03: A prospective randomized phase II study to identify predictive biomarkers and mechanisms of resistance in patients with HER2-negative metastatic breast cancer treated with the combination of bevacizumab and paclitaxel
Authors: Foukakis T , Hartman J , Stone-Elander S , Jacobsson H , Bergh J 
Published: August 2014

Abstract
Background
Several phase III trials have evaluated the combination of bevacizumab and chemotherapy in patients with metastatic breast cancer (MBC). These individual studies as well as a meta-analysis indicate high response rates (RR) and increased progression-free survival (PFS), however no significant gain of overall survival (OS) by the addition of bevacizumab to chemotherapy. To date, there are no methods to reliably select patients with MBC that benefit from treatment with bevacizumab.
Trial design
This project is a prospective, randomized, 2-arm, open-label, single-center, phase II trial aiming to identify predictive markers and mechanisms of resistance to bevacizumab in MBC by longitudinal biopsies and functional imaging. The study will be initiated with a non-randomized, feasibility stage including ten patients who will be treated with bevacizumab and paclitaxel, in order to determine the safety of metastatic tumor biopsies during therapy with bevacizumab. In a second phase, 20 patients will be randomized (1:1) between two treatment arms: Paclitaxel 80 mg / m2 weekly with or without bevacizumab 15 mg / kg every 3 weeks.
Mandatory, repeated peripheral blood sampling and fine needle aspiration biopsies (FNAB) will be collected at baseline, at day 4 after the first cycle and at progression. At baseline, a core biopsy will be obtained as well. Patients will also undergo two 18F]-fluoro-L-thymidine (FLT) Positron Emission Tomography (PET)/CT scans (18F-FLT PET/CT), at baseline and at day 4 after the first cycle.
Eligibility criteria
Eligible are patients aged 18-70 years, with newly diagnosed HER2-negative MBC (stage IV or recurrent) that are candidates for chemotherapy (ECOG 0-2), with measurable disease and at least one lesion that is accessible for biopsy. Adequate bone marrow, hepatic and renal function are required, as well as absence of thromboembolic disease, bleeding diathesis or second concurrent malignancy. No previous systemic treatment for MBC is allowed.
Specific aims
1. To assess early therapeutic response to bevacizumab in MBC by whole-exome sequencing and gene expression of serial metastatic biopsies and functional imaging.
2. To identify potential biomarkers present in plasma that can be used for patient selection or for monitoring therapy with bevacizumab in MBC.
3. To explore mutations and gene expression alterations as mechanisms of resistance to bevacizumab in MBC.
Statistical methods
The main objective of the study is exploratory. For most of the planned analyses, each patient will serve as her own control and baseline values of potential biomarkers will be compared in pairs with intra-patient, longitudinal samples, which significantly increases the statistical power.
For the identification of biomarkers, the results of the molecular analyses will be correlated with clinical outcome measurements including RR, PFS, and OS.
Present accrual and target accrual.
The trial was opened for inclusion in May 2013 and one patient has been accrued by June 1st 2013. A total of 30 patients will be included during a period of 2 years.
Contact:
Principal Investigator: Theodoros.Foukakis@ki.se; Study Director: Jonas.Bergh@ki.se.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-2-03.