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Trial record 3 of 3 for:    me-344

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02806817
Recruitment Status : Completed
First Posted : June 21, 2016
Last Update Posted : July 23, 2019
Sponsor:
Collaborator:
Fundacion CRIS de Investigación para Vencer el Cáncer
Information provided by (Responsible Party):
Centro Nacional de Investigaciones Oncologicas CARLOS III

Tracking Information
First Submitted Date  ICMJE May 20, 2016
First Posted Date  ICMJE June 21, 2016
Last Update Posted Date July 23, 2019
Actual Study Start Date  ICMJE July 2016
Actual Primary Completion Date October 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 16, 2016)
  • 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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2016)
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ME-344 in Early HER2-negative Breast Cancer With Antiangiogenic-induced Mitochondrial Metabolism
Official Title  ICMJE ME-344 in Early HER2-negative Breast Cancer With Antiangiogenic-induced Mitochondrial Metabolism: a Phase 0 Trial
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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE
  • Breast Cancer
  • Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
  • Early-Stage Breast Carcinoma
Intervention  ICMJE
  • 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
  • Other: Normal saline
    Use saline as placebo
Study Arms  ICMJE
  • 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.

    Interventions:
    • Drug: ME-344
    • Drug: Bevacizumab
  • 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).
    Interventions:
    • Drug: Bevacizumab
    • Other: Normal saline
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 16, 2016)
40
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE November 2018
Actual Primary Completion Date October 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02806817
Other Study ID Numbers  ICMJE CNIO-BR-009
2015-005457-12 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Centro Nacional de Investigaciones Oncologicas CARLOS III
Study Sponsor  ICMJE Centro Nacional de Investigaciones Oncologicas CARLOS III
Collaborators  ICMJE Fundacion CRIS de Investigación para Vencer el Cáncer
Investigators  ICMJE Not Provided
PRS Account Centro Nacional de Investigaciones Oncologicas CARLOS III
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP