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

This study is currently recruiting participants.
See Contacts and Locations
Verified December 2016 by Centro Nacional de Investigaciones Oncologicas CARLOS III
Sponsor:
Collaborator:
Fundación CRIS
Information provided by (Responsible Party):
Centro Nacional de Investigaciones Oncologicas CARLOS III
ClinicalTrials.gov Identifier:
NCT02806817
First received: May 20, 2016
Last updated: December 29, 2016
Last verified: December 2016
  Purpose

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.


Condition Intervention Phase
Breast Cancer Human Epidermal Growth Factor 2 Negative Carcinoma of Breast Early-Stage Breast Carcinoma Drug: ME-344 Drug: Bevacizumab Other: Normal saline Early Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: ME-344 in Early HER2-negative Breast Cancer With Antiangiogenic-induced Mitochondrial Metabolism: a Phase 0 Trial

Resource links provided by NLM:


Further study details as provided by Centro Nacional de Investigaciones Oncologicas CARLOS III:

Primary Outcome Measures:
  • Reduction of FDG uptake [ Time Frame: 1 month ]
    Mitochondrial switch changes from baseline

  • SDH (succinate dehydrogenase) levels staining [ Time Frame: 1 month ]
    Mitochondrial switch changes from baseline: glucolisis and studies microvasculature


Secondary Outcome Measures:
  • Toxicity profile: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 [ Time Frame: 8 weeks ]
    All toxicities will be graded according to NCI CTCAE v4.03

  • Ki67 changes [ Time Frame: From day 1 to day 8 ]
    Antitumor activity: Ki67 changes

  • Cleaved caspase-3 changes [ Time Frame: From day 1 to day 8 ]
    Antitumor activity: Cleaved caspase-3 changes


Estimated Enrollment: 40
Study Start Date: July 2016
Estimated Study Completion Date: June 2018
Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bevacizumab + ME-344

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
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.
Other Name: small molecule mitochondrial inhibitor
Drug: Bevacizumab
Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A)
Other Name: Avastin
Placebo Comparator: Bevacizumab + normal saline
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
Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A)
Other Name: Avastin
Other: Normal saline
Use saline as placebo

Detailed Description:

Antiangiogenic agents are the most widely used biologic agents in oncology and are approved by the Food and Drug Administration (FDA) for use against many different malignancies based on the results of several randomized phase III trials. However, acquired resistance to antiangiogenics is a major problem in cancer therapeutics.

Some signaling nodes have been implicated in therapeutic resistance in preclinical studies. However, a global tumor-reprogramming interrogation based on changes in the delivery of oxygen and nutrients has not been undertaken. The findings link acquired resistance to a powerful anticancer drug class with aberrant cancer metabolism. Under selective pressure, tumor plasticity allows sustained tumor growth in the long term despite exposure to antiangiogenic TKIs, and it renders mitochondrial metabolism essential for survival When one energy source (glycolysis) is pharmacologically limited, the tumors become vulnerable to the inhibition of the other (mitochondrial metabolism). Pharmacological blockers of the nutritional stress regulators can abrogate mitochondrial respiration and tumor growth in this situation, which the investigators have termed "metabolic synthetic lethality".

The investigators hypothesized that in cases in which antiangiogenics lead to hypoxia normalization, chronic high-rate glycolysis is offset and tumors might switch to an alternative metabolic source. If this source is essential for tumor survival, it would open a therapeutic opportunity.

The administration of ME-344 in animals where antiangiogenics have induced a mitochondrial phenotype seems promising. The investigators aim to extend these observations in humans. However, several questions remain, prior to launch a large trial:

  • Which percentage of patients experience a mitochondrial shift when exposed to a given antiangiogenic.
  • In case this happens, whether it is possible to trace this response accurately.
  • What is the benefit of adding ME-344 in those cases showing the mitochondrial shift, and what is the benefit, if any, of adding it in the remainder cases.

For that purpose, investigators will conduct a pilot randomized phase 0 trial, where a cohort of patients will be treated with a single bevacizumab dose prior to surgery and a second cohort with bevacizumab plus ME-344.

The purpose of this clinical trial is to evaluate if the addition of ME-344 to antiangiogenic agents in the cases where the mitochondrial phenotype has been induced will enhance antitumor activity.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Women older than 18 year-old.
  2. Treatment-naïve diagnosed early (stage I-III) HER2-negative (histologically confirmed) breast cancer not candidates for neoadjuvant therapy.
  3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  4. Signed informed consent obtained from the subject prior to performing any protocol-related procedures.
  5. Negative pregnancy test, or confirmed menopause.
  6. 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).
  7. Cardiac ejection fraction above 45%.
  8. Life expectancy superior to 6 months.
  9. Willingness to undergo trial procedures.

Exclusion Criteria:

  1. Neuropathy of any kind.
  2. Diabetes mellitus.
  3. Presence of intercurrent uncontrolled diseases, including untreated hypertension.
  4. Participation in another clinical study with an investigational product during the last 4 weeks.
  5. 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.
  6. Female subjects who are pregnant, breast-feeding or of reproductive potential who are not employing an effective method of birth control.
  7. Uncontrolled infection or systemic disease.
  8. 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.
  9. No concurrent systemic chemotherapy or biologic therapy is allowed.
  10. Known hypersensitivity to any components of ME-344 or bevacizumab.
  11. Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated or both).
  12. History of solid organ transplantation.
  13. Psychiatric disorder or social or geographic situation that would preclude study participation.
  14. Inability to comply with the study and follow-up procedures (e.g. tumor biopsies).
  15. 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02806817

Contacts
Contact: Miguel Quintela, PhD 91.732.80.00 ext 2930 mquintela@cnio.es

Locations
Spain
Hospital Universitario de Fuenlabrada Recruiting
Fuenlabrada, Madrid, Spain, 28942
Contact: Miguel Angel Quintela, PhD    +34-91.732.80.00 ext 2930    mquintela@cnio.es   
Contact: Berta Nasarre    +34-91.600.65.84    bnasarre@ext.cnio.es   
Principal Investigator: Miguel Quintela, PhD         
Sub-Investigator: Juan Antonio Guerra         
Sub-Investigator: Diego Malón         
Sub-Investigator: Laura Rodríguez         
Sub-Investigator: Juan Victor Apala         
Hospital de la Princesa Recruiting
Madrid, Spain, 28009
Contact: Ramón Colomer    91.520.22.00 ext 2276    rcolomer@seom.org   
Contact       oncologiamedica.princesa@outlook.com   
Principal Investigator: Ramón Colomer         
Hospital Ramón y Cajal Recruiting
Madrid, Spain, 28034
Contact: Javier Cortés       jacortes@vhio.net   
Contact: Sara Lavín       sara.lavin@salud.madrid.org   
Principal Investigator: Javier Cortés         
Hospital Clínico San Carlos Recruiting
Madrid, Spain, 28040
Contact: José Ángel García Sáez       jagsaenz@yahoo.com   
Contact: Daniel García Palos       dgarciap@salud.madrid.org   
Principal Investigator: José Ángel Garciá Sáez         
Hospital Universitario 12 de Octubre Recruiting
Madrid, Spain, 28041
Contact: Luis Manso       luis_manso@hotmail.com   
Contact: Ana Cortijo       acortijo.imas12@h12o.es   
Principal Investigator: Luis Manso         
Clínica Quirón Recruiting
Madrid, Spain, 28223
Contact: Miguel Quintela    91.732.8000 ext 2930    mquintela@cnio.es   
Contact: Constanza Pardo    91 452 19 87    constanza.pardo@quironsalud.es   
Principal Investigator: Miguel Quintela         
Sponsors and Collaborators
Centro Nacional de Investigaciones Oncologicas CARLOS III
Fundación CRIS
  More Information

Responsible Party: Centro Nacional de Investigaciones Oncologicas CARLOS III
ClinicalTrials.gov Identifier: NCT02806817     History of Changes
Other Study ID Numbers: CNIO-BR-009
2015-005457-12 ( EudraCT Number )
Study First Received: May 20, 2016
Last Updated: December 29, 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Carcinoma
Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 22, 2017