Randomized Phase 0/I Trial of the Mitochondrial Inhibitor ME-344 or Placebo Added to Bevacizumab in Early HER2-Negative Breast Cancer.

Abstract

PURPOSE:

We previously demonstrated that mitochondrial inhibitors' efficacy was restricted to a metabolic context in which mitochondrial respiration was the predominant energy source, a situation achievable by inducing vascular normalization/hypoxia correction with antiangiogenics. Vascular normalization can be tracked with 2[18F]fluoro-2-deoxy-d-glucose (FDG)-PET. We tested the efficacy of the mitochondrial inhibitor ME-344 or placebo added to bevacizumab in early breast cancer.

PATIENTS AND METHODS:

Treatment-naïve HER2-negative patients with T > 1 cm (any N) underwent a breast-centered 18F-fluorodeoxyglucose (FDG)-PET (day 1) and received a single dose of bevacizumab (15 mg/kg), followed by a second FDG-PET (day 8). Patients were then randomized (1:1) to Arm A (ME-344 10 mg/kg intravenous on days 8, 15, and 21) or Arm B (placebo). Tumors were biopsied on days 0 and 29. Succinate dehydrogenase enzyme histochemistry (SDH-EHC), confocal microscopy of vessel architecture, and HIF1α staining were performed in pre- and posttreatment biopsies to assess the pharmacodynamics, vessel normalization, and tissue re-oxygenation by bevacizumab, respectively.

RESULTS:

ME-344 displayed significant biological activity versus placebo: compared with a 186% increase in Arm B, Ki67 decreased by 23.4% from days 0 to 28 in Arm A (P < 0.001) (N = 42 patients). FDG-PET predicted vascular normalization in about one-third of the patients in each arm, which was confirmed using confocal microscopy and HIF1α staining. In the subgroup with vascular normalization, ME-344 induced a Ki67 decrease of 33.4% (placebo: 11.8 increase). SDH-EHC suggested on-target effects of ME-344.

CONCLUSIONS:

ME-344 has significant biological antitumor activity in HER2-negative breast cancer, particularly after induction of vascular normalization and tissue reoxygenation with bevacizumab.

• Authors: Miguel Quintela-Fandino, Serafín Morales, Alfonso Cortés-Salgado, Luis Manso, Juan V Apala, Manuel Muñoz, Ariadna Gasol Cudos, Joel Salla Fortuny, María Gion, Antonio Lopez-Alonso, Javier Cortés, Juan Guerra, Diego Malón, Eduardo Caleiras, Francisca Mulero, Silvana Mouron
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 1 Pg. 35-45 (01 01 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 31597662 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Isoflavones
• Ki-67 Antigen
• MKI67 protein, human
• Radiopharmaceuticals
• Fluorodeoxyglucose F18
• Bevacizumab
• ME-344
• Succinate Dehydrogenase
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab (administration & dosage)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Female
• Fluorodeoxyglucose F18 (metabolism)
• Humans
• Isoflavones (administration & dosage)
• Ki-67 Antigen (metabolism)
• Middle Aged
• Mitochondria (drug effects)
• Neoplasm Staging
• Patient Safety
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (metabolism)
• Receptor, ErbB-2 (metabolism)
• Succinate Dehydrogenase (metabolism)
• Treatment Outcome