ME-344 in Early HER2-negative Breast Cancer With Antiangiogenic-induced Mitochondrial Metabolism

NCT02806817 | Completed Early Phase 1

• 2 other identifiers: CNIO-BR-0092015-005457-12
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 5

Brief Summary

Prospective, randomized, open label, two arms,, phase 0 clinical trial. HER2-negative breast cancer patients recently diagnosed will be screened for trial participation. A biopsy will be scheduled the week prior to or the same day as the FDG PET. Paraffin-embedded tumor samples will be used to evaluate the stainings of Ki67, cleaved caspase-3 and microvessels, and frozen tumor samples will be used to evaluate SDH staining. The FDG-PET will be followed by the bevacizumab dose (15 mg/kg IV, single dose). After one week, the PET will be repeated in order to detect the patients that have experienced FDG uptake decay. Right after, treatment with ME-344 (arm 1) or no treatment (arm 2) will start. ME-344 will be administered at 10 mg/kg on day 8, 15 and 22. Surgery will be performed on day 28 (thus, 4 weeks after the bevacizumab dose, which is considered a safe window for antiangiogenics). Fragments of the surgical specimen will be collected. Paraffin-embedded tumor sample will be used to repeat (and compare) the stainings of Ki67, cleaved caspase-3 and microvessels, and frozen tumor sample will be used to repeat (and compare) SDH staining. Patients will come off trial in case of consent withdrawal, unequivocal disease progression is observed, unacceptable toxicity occurs, or in case of intercurrent disease or any other condition deemed incompatible with continuation in the clinical trial by the investigator.

Conditions

Breast Cancer; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Early-Stage Breast Carcinoma

Outcome Measures

Primary Outcomes (2)

• Reduction of FDG uptake

  Mitochondrial switch changes from baseline

  1 month

• SDH (succinate dehydrogenase) levels staining

  Mitochondrial switch changes from baseline: glucolisis and studies microvasculature

  1 month

Secondary Outcomes (3)

• Toxicity profile: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0

  8 weeks

• Ki67 changes

  From day 1 to day 8

• Cleaved caspase-3 changes

  From day 1 to day 8

Study Arms (2)

Bevacizumab + ME-344

EXPERIMENTAL

Bevacizumab single dose (15 mg/kg infused IV) on day 1. ME-344 will be administered at 10 mg/kg infused IV over 30 minutes on days 8, 15 and 22 (arm 1). ME-344 will be suspended in 250 mL sterile saline.

Drug: ME-344; Drug: Bevacizumab

Bevacizumab + normal saline

PLACEBO COMPARATOR

Bevacizumab single dose (15 mg/kg infused IV) on day 1. Placebo: will be administered normal saline 250 mL infused IV over 30 minutes on days 8, 15 and 22 (arm 2).

Drug: Bevacizumab; Other: Normal saline

Interventions

ME-344 DRUG

ME-344 is a synthetic small molecule mitochondrial inhibitor based on the isoflavan ring structure. ME-344 is a chiral compound, and is manufactured predominantly as a single stereoisomer that is dextrorotatory. As a stereoisomeric drug with two chiral centers, ME-344 is one of four potential stereoisomers. The current manufacturing process produces a racemic mixture of two of those stereoisomers, which are enantiomers, and ME-344 is separated from the levorotatory enantiomer by chromatography in the final step.

Also known as: small molecule mitochondrial inhibitor

Bevacizumab + ME-344

Bevacizumab DRUG

Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A)

Also known as: Avastin

Bevacizumab + ME-344; Bevacizumab + normal saline

Normal saline OTHER

Use saline as placebo

Bevacizumab + normal saline

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Women older than 18 year-old.
• Treatment-naïve diagnosed early (stage I-III) HER2-negative (histologically confirmed) breast cancer not candidates for neoadjuvant therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Signed informed consent obtained from the subject prior to performing any protocol-related procedures.
• Negative pregnancy test, or confirmed menopause.
• Adequate organ function, according to the following parameters:
• Haemoglobin ≥ 9.0 g/dL.
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (\> 1500 / mm3).
• Platelet count ≥ 100 x 109/L (\>100000 / mm3).
• Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
• AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal.
• Serum creatinine \< 1.5 x institutional upper limit of normal (ULN).
• Cardiac ejection fraction above 45%.
• Life expectancy superior to 6 months.
• Willingness to undergo trial procedures.

You may not qualify if:

• Neuropathy of any kind.
• Diabetes mellitus.
• Presence of intercurrent uncontrolled diseases, including untreated hypertension.
• Participation in another clinical study with an investigational product during the last 4 weeks.
• Patients with presence of concurrent or active malignant disease (other than disease under study) within the last 12 months with the exception of adequately treated in situ carcinomas, basal or squamous cell carcinoma, or nonmelanomatous skin cancer.
• Female subjects who are pregnant, breast-feeding or of reproductive potential who are not employing an effective method of birth control.
• Uncontrolled infection or systemic disease.
• Clinically significant cardiac disease not well controlled with medication (e.g., congestive heart failure, symptomatic coronary artery disease e.g. angina, and cardiac arrhythmias) or myocardial infarction within the last 12 months.
• No concurrent systemic chemotherapy or biologic therapy is allowed.
• Known hypersensitivity to any components of ME-344 or bevacizumab.
• Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated or both).
• History of solid organ transplantation.
• Psychiatric disorder or social or geographic situation that would preclude study participation.
• Inability to comply with the study and follow-up procedures (e.g. tumor biopsies).
• Any other condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.

Sponsors & Collaborators

• Centro Nacional de Investigaciones Oncologicas CARLOS III: lead
• Fundacion CRIS de Investigación para Vencer el Cáncer: collaborator

Study Sites (5)

Hospital Universitario de Fuenlabrada

Fuenlabrada, Madrid, 28942, Spain

Location

H. Arnau de Vilanova Lleida

Lleida, 25198, Spain

Location

Hospital Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Clínica Quirón

Madrid, 28223, Spain

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

ME-344; Bevacizumab; Saline Solution

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2016
• First Posted: June 21, 2016
• Study Start: July 1, 2016
• Primary Completion: October 1, 2018
• Study Completion: November 1, 2018
• Last Updated: July 23, 2019

Record last verified: 2019-07

Locations

ES (5)