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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 >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 > 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.

Background This trial is based on a combination strategy with two immunostimulatory agents in the search of synergism that may induce responses with long-term clinical benefit in ABC pts. Safety data from the run-in-phase were published in ESMO IO 2018. Here, we report the results from the phase II part of the study. Methods HER2-negative ABC pts previously treated with anthracyclines and taxanes (unless contraindicated), ≤ 4 chemotherapy lines and/or ≥ 2 hormone therapy lines, and irrespective of PD-L1 status, were eligible. Study treatment consisted of 21-day cycles (cy) of P 200mg on day 1 and Gem 1250mg/m2 on days 1 and 8 until progressive disease (PD) or unacceptable toxicity, whatever occurred first. Primary objective was Objective Response Rate (ORR). Results Thirty-six pts were included in the first stage of a Simon’s design. Recruitment was stopped as only 5 pts presented an objective response (partial) (≥ 7 responses needed to continue recruiting pts). Median age was 52 years (range 31-77), 21 pts had triple negative disease, the majority of pts had an ECOG performance status ≤ 1 (n = 35), visceral involvement (n = 28) and ≥ 2 metastatic locations (n = 27). Median number of prior lines (any therapy) for ABC was 4 (range 0-11). Pts received a median of 4.5 cy of Gem and 4 cy of P (same range for both drugs, 1-24). The median relative dose intensity of P and Gem was 100% and 80%, respectively. Treatment discontinuation due to PD was reported on 29 pts. The ORR was 15.2% (95% confidence interval (CI) 5.1-31.9) and the Clinical Benefit Rate was 17% (95% CI 33.5-69.2); median duration of objective response was 4.3 months (mo) (95% CI 2.3-7.4), median Progression-Free Survival was 3.1 mo (95% CI, 2-4.3), and median Overall Survival was 7.9 mo (95% CI 6.5-10.3). Eight pts were on treatment ≥ 6 mo before PD (2 pts on 11.4 and 16.1 mo). Grade (G) ≥ 3 AEs related to the study treatment were reported on 14 pts (39%), being neutropenia the most common G3 (22.2%) and G4 (5.6%) AE. Conclusion P can be safely combined with Gem, the combination did not meet the efficacy objective in terms of ORR but 22.2% pts were on treatment ≥ 6 mo. Clinical trial identification NCT03025880. Legal entity responsible for the study GEICAM Spanish Breast Cancer Group. Funding MSD. Disclosure J. Cruz: Honoraria (self), Advisory / Consultancy: Glaxo; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pharmamar; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer. M. Ramos Vazquez: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer. J. Cortes: Honoraria (self), Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Celgene; Advisory / Consultancy: Cellestia; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Biothera Pharmaceutical; Advisory / Consultancy: Merus; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Erytech; Advisory / Consultancy: Athenex; Advisory / Consultancy: Polyphor; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (institution), Advisory / Consultancy: Servier; Honoraria (self), Honoraria (institution), Advisory / Consultancy: MSD; Advisory / Consultancy: GSK; Honoraria (self): Novartis; Honoraria (self), Honoraria (institution): Eisai; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self): Samsung Bioepis; Honoraria (institution), MedSIR (Stock, patent and intellectual property): Ariad Pharmaceuticals. Baxalta GMBH/Servier Affaires. Bayer Healthcare. Guardanth Health. Piqur Therapeutics. Puma C. Queen Mary University of London. Seagen. All other authors have declared no conflicts of interest.