Abstract OT2-07-02: CNIO-BR-009 trial: Targeting mitochondrial metabolism with ME-344 in breast cancer upon bevacizumab-induced vascular normalization: A phase 0 randomized clinical trial
Authors: Cortes A , Apala JV , Malon D , Guerra J , Gion-Cortes M , Manso L , Hornedo J , Gonzalez-Cortijo L , Mouron S , Quintela-Fandino M 
Published: February 2018

Abstract
Background: Antiangiogenic agents have shown activity in breast cancer; however their use should be optimized. One potential solution is designing rational combinations based on blocking specific mechanisms of resistance. We previously published that tumors exposed to bevacizumab (BEV) can either experience vascular pruning (followed by increased tumor hypoxia) or vascular normalization (followed by a switch to mitochondrial metabolism). FDG-PET can monitor which pattern is occurring as early as 8 days after the first dose (Mol Oncol; 10: 704-18). We have also shown that when vascular normalization occurs, tumors become highly sensitive to mitochondrial inhibitors (Cell Rep 2016; 15: 1-14). ME-344 is a mitocondrial respiration inhibitor that has recently completed phase I. We sought to test the pharmacodynamic effects of ME-344 and its effects in Ki67 and cleaved caspase 3 (CC3) after single-dose BEV in treatment-naive early HER2-negative breast cancer patients, and whether the effects are restricted or not to those patients experiencing vascular normalization as predicted by FDG-PET.
Trial design
Placebo-controlled, two-arm, randomized, multicentric phase 0 trial. Treatment-naive HER2-negative breast cancer patients undergo a breast FDG-PET and a baseline tumor biopsy (frozen and paraffinized cores), followed by a single (15 mg/kg) BEV dose. FDG-PET is repeated on day +8. Patients are then randomized to three ME-344 (10 mg/kg) doses or placebo (days +8, +15 and +22). A second biopsy is then harvested, ending trial procedures. Patients can then follow surgery or neoadjuvant treatment according to their physician's criterion. Serial paraffinized biopsies are used to measure Ki67 and CC3; frozen biopsies are used for measuring mitochondrial activity with SDH enzymo-histochemistry (EHC) and assessing vessel architecture. Toxicity is graded with NCI CTC AE V4.03 criteria.
Eligibility criteria
1) Women &gt;18 year old; 2) diagnosed of HER2-negative breast cancer; 3) patients must be treatment-naive; 4) ECOG 0/1; 5) lack of neuropathy; 6) primary tumor &gt; 1cm .
Specific aims
Primary:
1) To study the effects in cell replication and cell death as a surrogate measure of efficacy of ME-344 added to BEV in treatment-naive breast cancer.
2) To determine if FDG-PET accurately detects patients experiencing vascular normalization early after BEV dosing.
3) To observe the effects of ME-344 in mitochondrial activity at the tumor level by performing SDH EHC.
4) To assess if ME-344 efficacy (measured by changes in CC3 and Ki67) is restricted or not to those patients experiencing vascular normalization and mitochondrial switch.
Secondary:
5) To study the tolerability of the combination of BEV plus ME-344.
Statistical methods
The sample size is calculated on the basis of the expected change in Ki-67 staining in the primary tumors in patients receiving ME-344 (-10% on average). With an α and β errors of 5% and 20% respectively, the minimum number of patients necessary to observe a 10% decrease is 20 per arm. Changes in CC3, KI67, SDH activity and FDG-PET SUV will be compared with intra-subject measurements and Z-scores.
Accrual: 13 of 40 planned patients.
Contact: acsalgado86@gmail.com
Citation Format: Cortes A, Apala JV, Malon D, Guerra J, Gion-Cortes M, Manso L, Hornedo J, Gonzalez-Cortijo L, Mouron S, Quintela-Fandino M. CNIO-BR-009 trial: Targeting mitochondrial metabolism with ME-344 in breast cancer upon bevacizumab-induced vascular normalization: A phase 0 randomized clinical trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-02.