Metastatic Breast CancerEarly Phase 1NCT02802098
Abrogation of Chronic Monoclonal Antibody Treatment-induced T-cell Exhaustion With DURVALUMAB in Advanced HER-2 Negative Breast Cancer
A Early Phase 1 study testing Durvalumab and Bevacizumab in people with Metastatic Breast Cancer and Bevacizumab-alone Maintenance Treatment Progression, run by Centro Nacional de Investigaciones Oncologicas CARLOS III at 6 sites in Spain.
Trial summary
This is a single-arm pilot proof of concept, open-label clinical trial. Twenty-five subjects will be enrolled in 6 sites. Metastatic breast cancer patients with disease progression to bevacizumab maintenance treatment will be potential candidates. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Metastatic Breast Cancer, Bevacizumab-alone Maintenance Treatment Progression
- What is being tested?
- Durvalumab and Bevacizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 6 sitesSpain
- Study dates
- May 2016to Jul 2019
- 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
- Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
- Age > 18 years at time of study entry.
- Confirmed diagnosis of advanced/metastatic HER-2 negative breast cancer.
- Patients who progress in their first bevacizumab regimen, with no limit on previous lines of hormone therapy, chemotherapy, or targeted therapies as long as they have not included bevacizumab or other antiangiogens. This first bevacizumab regimen can be in combination with chemotherapy, hormonal therapy or monotherapy in any scheme and disease progression during this treatment. At least 6 weeks (two doses) must have passed with bevacizumab treatment, in order to consider bevacizumab progression. Any disease progression according to RECIST 1.1 criteria will be considered progression during bevacizumab maintenance.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Life expectancy of > 24 weeks.
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- Adequate normal organ and marrow function as defined below:
- Haemoglobin ≥ 9.0 g/dL. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3). Platelet count ≥ 100 x 109/L (>100,000 per mm3). Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
- AST (SGOT) / ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5 x ULN.
- Serum creatinine CL> 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
- Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥ 60 years old and no menses for ≥ 1 year without an alternative medical cause; or history of hysterectomy, or history of bilateral tubal ligation, or history of bilateral oophorectomy or must have a negative serum pregnancy test upon study entry.
- Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
Who cannot join
- Involvement in the planning and/or conduct of the study or in any support activity. Previous enrolment in the present study.
- Participation in another clinical study with an investigational product during the last 4 weeks.
- Any previous treatment with a CTLA-4 inhibitor, PD-1 or PD-L1 inhibitor, including DURVALUMAB.
- History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study drug and of low potential risk for recurrence.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
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- Adequately treated carcinoma in situ without evidence of disease, example cervical cancer in situ.
- Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) other than bevacizumab 28 days prior to the first dose of study drug: 28 days prior to the first dose of study drug for subjects who have received prior TKIs (example erlotinib, gefitinib and crizotinib) and within 6 weeks for nitrosourea or mitomycin C). (If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period may be required.)
- Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction.
- Current or prior use of immunosuppressive medication within 28 days before the first dose of DURVALUMAB, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
- Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy, including proteinuria related to bevacizumab. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (example hearing loss, peripherally neuropathy).
- Any prior Grade ≥3 immune-related adverse event while receiving any previous immunotherapy agent, or any unresolved AE >Grade 1.
- Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
- Active or prior documented inflammatory bowel disease (example Crohn's disease, ulcerative colitis).
- History of primary immunodeficiency.
- History of allogeneic organ transplant.
- History of hypersensitivity to DURVALUMAB or any excipient.
- History of hypersensitivity to the combination agent bevacizumab
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
- Anticoagulation therapy (except low-dose heparin and/or wash out with heparin as needed to maintain a permanent intravenous device) or antiplatelet therapy (except for treatment with doses of aspirin below 325 mg per day)
- History of hemorrhagic or thromboembolic event clinically significant in the last 6 months
- Known hereditary predisposition to bleeding or thrombosis
- Known history of previous clinical diagnosis of tuberculosis.
- History of leptomeningeal carcinomatosis or brain metastasis.
- Receipt of live attenuated vaccination within 30 days of receiving DURVALUMAB.
- Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
- Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids.
- Subjects with uncontrolled seizures
- Inability to comply with the study and follow-up procedures (example tumor biopsies and blood sampling).
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
Spain6 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
Hospital General de Valencia
Valencia, 46014
About this study
Official title: Abrogation of Chronic Monoclonal Antibody Treatment-induced T-cell Exhaustion With DURVALUMAB (MEDI4736) in Advanced HER-2 Negative Breast Cancer: a Pilot Proof-of-concept Trial
This is a single-arm pilot proof of concept, open-label clinical trial. Twenty-five subjects will be enrolled in 6 sites.
Metastatic breast cancer patients with disease progression to bevacizumab maintenance treatment will be potential candidates.
Read more
Bevacizumab maintenance will be considered as six weeks of bevacizumab treatment in monotherapy, with hormonal treatment or combined with chemotherapy in the context of previous bevacizumab plus chemotherapy regimens.
When progression to bevacizumab maintenance treatment occurs, patients will enter the trial and will start receiving DURVALUMAB 10 mg/kg Q2W IV infusion plus bevacizumab 10mg/kg IV infusion every 2 weeks. The patients will undergo a tumor biopsy before the first dose of DURVALUMAB, and after one month of combined treatment - the blood sampling will continue on a monthly basis. The treatment will continue until disease progression.
Read the detailed description
Acquired resistance against chronic administration of the monoclonal antibody antiangiogenic agent like bevacizumab in breast cancer is caused in a fraction of patients by an immune reprogramming. The immune reprogramming can be detected by elevated counts of Tregs in peripheral blood, aberrant pattern of cytokines, and elevated concentrations of kynurenine and immunosuppressive/vasodilator prostaglandins. The addition of DURVALUMAB to a bevacizumab-based treatment would delay or abrogate these changes and be of therapeutic interest in this scenario.
- Being tested
- Durvalumab, Bevacizumab
- Keywords
- Metastatic breast cancer, bevacizumab maintenance, Durvalumab
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DurvalumabDrug
Also called MEDI4736
Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). PD-L1 can be expressed by tumours to evade detection by the immune system through binding to PD-1 on cytotoxic T lymphocytes. Durvalumab blocks the PD-L1 interaction with PD-1, countering the tumour's immune-evading tactics.
BevacizumabDrug
Also called Avastin
Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A)
| Study group | Role | What they receive |
|---|---|---|
| Bevacizumab + Durvalumab | Experimental | Treatment with DURVALUMAB 10 mg/kg Q2W IV infusion plus Bevacizumab 10 mg/ Kg Q2W, IV infusion for a maximum duration of treatment of 12 months. Study treatment should be discontinued prior to 12 months if there is confirmed PD (unless the investigator considers the subject to continue to receive benefit from treatment), initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or if other reasons to discontinue study treatment occur. Receives: Drug: Durvalumab; Drug: Bevacizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
To compare different peripheral blood mononuclear cells subpopulations at baseline or during treatment among patients showing benefit ro not from the combinations
Determine the immunodynamics changes from baseline in peripheral blood and in the tumor of combined administration of DURVALUMAB and the monoclonal antibody bevacizumab in advanced HER-2- negative breast cancer patients that have progressed to bevacizumab-based treatment. From baseline every 4 weeks throughout the study up to progression disease
Measured: throughout the study up to progression disease, an average of 1 year
To determine progression-free survival of the combination
Assessed by RECIST 1.1
Measured: up to 12 weeks
To determine overall survival
Overall survival rate by Kaplan-Meier Analysis
Measured: up to death
Secondary outcomes (1)
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Evaluate safety and toxicity of combination of both DURVALUMAB and bevacizumab
Measured: Throughout study completion, an average of 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2016 (estimated)
- Study startMay 2016
- Primary completionJun 2019
- Study completionJul 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Metastatic 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 25 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
- NCT02802098
- Sponsor's protocol ID
- CNIO-BR-008
- Other IDs
- 2015-005609-34, 2015
- Status last verified
- Jun 2020
- First submitted
- 20 May 2016
- Last updated
- 19 Jun 2020
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
Quintela-Fandino M, Holgado E, Manso L, Morales S, Bermejo B, Colomer R, Apala JV, Blanco R, Munoz M, Caleiras E, Iranzo V, Martinez M, Dominguez O, Hornedo J, Gonzalez-Cortijo L, Cortes J, Gasol Cudos A, Malon D, Lopez-Alonso A, Moreno-Ortiz MC, Mouron S, Manes S. Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial. Breast Cancer Res. 2020 Nov 11;22(1):124. doi: 10.1186/s13058-020-01362-y.
PubMed 33176887
Study at a glance
From the registry record, last updated by the sponsor on 19 Jun 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Abrogation of Chronic Monoclonal Antibody Treatment-induced T-cell Exhaustion With DURVALUMAB (MEDI4736) in Advanced HER-2 Negative Breast Cancer: a Pilot Proof-of-concept Trial
- ClinicalTrials.gov ID
- NCT02802098
- Acronym / sponsor ID
- CNIO-BR-008
- Keywords
- Metastatic breast cancer, bevacizumab maintenance, Durvalumab
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 25 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
- May 2016 (actual)
- Primary completion
- Jun 2019 (actual)
- Study completion
- Jul 2019 (actual)
- First posted
- 16 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.
This is a single-arm pilot proof of concept, open-label clinical trial. Twenty-five subjects will be enrolled in 6 sites.
Metastatic breast cancer patients with disease progression to bevacizumab maintenance treatment will be potential candidates.
Bevacizumab maintenance will be considered as six weeks of bevacizumab treatment in monotherapy, with hormonal treatment or combined with chemotherapy in the context of previous bevacizumab plus chemotherapy regimens.
When progression to bevacizumab maintenance treatment occurs, patients will enter the trial and will start receiving DURVALUMAB 10 mg/kg Q2W IV infusion plus bevacizumab 10mg/kg IV infusion every 2 weeks. The patients will undergo a tumor biopsy before the first dose of DURVALUMAB, and after one month of combined treatment - the blood sampling will continue on a monthly basis. The treatment will continue until disease progression.
Detailed description
Acquired resistance against chronic administration of the monoclonal antibody antiangiogenic agent like bevacizumab in breast cancer is caused in a fraction of patients by an immune reprogramming. The immune reprogramming can be detected by elevated counts of Tregs in peripheral blood, aberrant pattern of cytokines, and elevated concentrations of kynurenine and immunosuppressive/vasodilator prostaglandins. The addition of DURVALUMAB to a bevacizumab-based treatment would delay or abrogate these changes and be of therapeutic interest in this scenario.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Bevacizumab + Durvalumab | Experimental | Drug: Durvalumab, Drug: BevacizumabTreatment with DURVALUMAB 10 mg/kg Q2W IV infusion plus Bevacizumab 10 mg/ Kg Q2W, IV infusion for a maximum duration of treatment of 12 months. Study treatment should be discontinued prior to 12 months if there is confirmed PD (unless the investigator considers the subject to continue to receive benefit from treatment), initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or if other reasons to discontinue study treatment occur. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
- Age > 18 years at time of study entry.
- Confirmed diagnosis of advanced/metastatic HER-2 negative breast cancer.
- Patients who progress in their first bevacizumab regimen, with no limit on previous lines of hormone therapy, chemotherapy, or targeted therapies as long as they have not included bevacizumab or other antiangiogens. This first bevacizumab regimen can be in combination with chemotherapy, hormonal therapy or monotherapy in any scheme and disease progression during this treatment. At least 6 weeks (two doses) must have passed with bevacizumab treatment, in order to consider bevacizumab progression. Any disease progression according to RECIST 1.1 criteria will be considered progression during bevacizumab maintenance.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Key exclusion criteria (30 listed)
- Involvement in the planning and/or conduct of the study or in any support activity. Previous enrolment in the present study.
- Participation in another clinical study with an investigational product during the last 4 weeks.
- Any previous treatment with a CTLA-4 inhibitor, PD-1 or PD-L1 inhibitor, including DURVALUMAB.
- History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study drug and of low potential risk for recurrence.
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 |
|---|---|---|
| DurvalumabAlso: MEDI4736Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). PD-L1 can be expressed by tumours to evade detection by the immune system through binding to PD-1 on cytotoxic T lymphocytes. Durvalumab blocks the PD-L1 interaction with PD-1, countering the tumour's immune-evading tactics. | Drug | Bevacizumab + Durvalumab |
| BevacizumabAlso: AvastinBevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A) | Drug | Bevacizumab + Durvalumab |
Primary outcome
To compare different peripheral blood mononuclear cells subpopulations at baseline or during treatment among patients showing benefit ro not from the combinations
Time frame: throughout the study up to progression disease, an average of 1 year
Determine the immunodynamics changes from baseline in peripheral blood and in the tumor of combined administration of DURVALUMAB and the monoclonal antibody bevacizumab in advanced HER-2- negative breast cancer patients that have progressed to bevacizumab-based treatment. From baseline every 4 weeks throughout the study up to progression disease
To determine progression-free survival of the combination
Time frame: up to 12 weeks
Assessed by RECIST 1.1
To determine overall survival
Time frame: up to death
Overall survival rate by Kaplan-Meier Analysis
1 secondary outcome
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: Throughout study completion, an average of 1 year
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 19 Jun 2020.
- Derived from this study: PubMed 33176887Quintela-Fandino M, Holgado E, Manso L, Morales S, Bermejo B, Colomer R, Apala JV, Blanco R, Munoz M, Caleiras E, Iranzo V, Martinez M, Dominguez O, Hornedo J, Gonzalez-Cortijo L, Cortes J, Gasol Cudos A, Malon D, Lopez-Alonso A, Moreno-Ortiz MC, Mouron S, Manes S. Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial. Breast Cancer Res. 2020 Nov 11;22(1):124. doi: 10.1186/s13058-020-01362-y.
- 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.
6 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 Durvalumab and Bevacizumab in people with Metastatic Breast Cancer and Bevacizumab-alone Maintenance Treatment Progression, run by Centro Nacional de Investigaciones Oncologicas CARLOS III at 6 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 12 inclusion and 30 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 19 Jun 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 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. 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?
To compare different peripheral blood mononuclear cells subpopulations at baseline or during treatment among patients showing benefit ro not from the combinations (time frame: throughout the study up to progression disease, an average of 1 year). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02802098, which also lists 1 linked publication.
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 19 Jun 2020.