Breast CancerEarly Phase 1NCT02806817
ME-344 in Early HER2-negative Breast Cancer With Antiangiogenic-induced Mitochondrial Metabolism
A Early Phase 1 study testing ME-344, Bevacizumab and Normal saline in people with Breast Cancer and Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, run by Centro Nacional de Investigaciones Oncologicas CARLOS III at 5 sites in Spain.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer, Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, Early-Stage Breast Carcinoma
- What is being tested?
- ME-344, Bevacizumab and Normal saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 5 sitesSpain
- Study dates
- Jul 2016to Nov 2018
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
Spain5 sites
Hospital Universitario de Fuenlabrada
Fuenlabrada, Madrid, 28942
H. Arnau de Vilanova Lleida
Lleida, 25198
Hospital Ramón y Cajal
Madrid, 28034
Hospital Universitario 12 de Octubre
Madrid, 28041
Clínica Quirón
Madrid, 28223
About this study
Official title: ME-344 in Early HER2-negative Breast Cancer With Antiangiogenic-induced Mitochondrial Metabolism: a Phase 0 Trial
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.
Read more
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.
Read the 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.
- Conditions
- Breast Cancer, Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, Early-Stage Breast Carcinoma
- Being tested
- ME-344, Bevacizumab, Normal saline
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ME-344Drug
Also called small molecule mitochondrial inhibitor
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.
BevacizumabDrug
Also called Avastin
Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A)
Normal salineOther
Use saline as placebo
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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). Receives: Drug: Bevacizumab; Other: Normal saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Reduction of FDG uptake
Mitochondrial switch changes from baseline
Measured: 1 month
SDH (succinate dehydrogenase) levels staining
Mitochondrial switch changes from baseline: glucolisis and studies microvasculature
Measured: 1 month
Secondary outcomes (3)
Toxicity profile: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0
All toxicities will be graded according to NCI CTCAE v4.03
Measured: 8 weeks
Ki67 changes
Antitumor activity: Ki67 changes
Measured: From day 1 to day 8
Cleaved caspase-3 changes
Antitumor activity: Cleaved caspase-3 changes
Measured: From day 1 to day 8
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jun 2016 (estimated)
- Study startJul 2016
- Primary completionOct 2018
- Study completionNov 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centro Nacional de Investigaciones Oncologicas CARLOS III
- Sponsor type
- University, hospital or other
- Collaborators
- Fundacion CRIS de Investigación para Vencer el Cáncer
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02806817
- Sponsor's protocol ID
- CNIO-BR-009
- Other IDs
- 2015-005457-12, 2015
- Status last verified
- Jul 2019
- First submitted
- 20 May 2016
- Last updated
- 23 Jul 2019
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 23 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- ME-344 in Early HER2-negative Breast Cancer With Antiangiogenic-induced Mitochondrial Metabolism: a Phase 0 Trial
- ClinicalTrials.gov ID
- NCT02806817
- Acronym / sponsor ID
- CNIO-BR-009
- Conditions
- Breast Cancer, Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, Early-Stage Breast Carcinoma
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Centro Nacional de Investigaciones Oncologicas CARLOS IIIUniversity, hospital or other
- Collaborators
- Fundacion CRIS de Investigación para Vencer el Cáncer
- Study start
- Jul 2016 (actual)
- Primary completion
- Oct 2018 (actual)
- Study completion
- Nov 2018 (actual)
- First posted
- 21 Jun 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Bevacizumab + ME-344 | Experimental | Drug: ME-344, Drug: BevacizumabBevacizumab 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. |
| Bevacizumab + normal saline | Placebo comparator | Drug: Bevacizumab, Other: Normal salineBevacizumab 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- 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.
Key exclusion criteria (15 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ME-344Also: small molecule mitochondrial inhibitorME-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. | Drug | Bevacizumab + ME-344 |
| BevacizumabAlso: AvastinBevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A) | Drug | Bevacizumab + ME-344, Bevacizumab + normal saline |
| Normal salineUse saline as placebo | Other | Bevacizumab + normal saline |
Primary outcome
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
3 secondary outcomes
Toxicity profile: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0
Time frame: 8 weeks
Ki67 changes
Time frame: From day 1 to day 8
Cleaved caspase-3 changes
Time frame: From day 1 to day 8
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jul 2019.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing ME-344, Bevacizumab and Normal saline in people with Breast Cancer and Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, run by Centro Nacional de Investigaciones Oncologicas CARLOS III at 5 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Reduction of FDG uptake (time frame: 1 month). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2019.