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Abrogation of Chronic Monoclonal Antibody Treatment-induced T-cell Exhaustion With DURVALUMAB in Advanced HER-2 Negative Breast Cancer

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. Identifier: NCT02802098
Recruitment Status : Unknown
Verified December 2016 by Centro Nacional de Investigaciones Oncologicas CARLOS III.
Recruitment status was:  Recruiting
First Posted : June 16, 2016
Last Update Posted : September 14, 2017
Fundacion CRIS de Investigación para Vencer el Cáncer
Information provided by (Responsible Party):
Centro Nacional de Investigaciones Oncologicas CARLOS III

Brief 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-alone maintenance treatment will be potential candidates.

Bevacizumab maintenance will be considered as six weeks of bevacizumab treatment in monotherapy after the last dose of chemotherapy in the context of bevacizumab plus chemotherapy first-line regimens.

When progression to bevacizumab-alone maintenance treatment occurs, patients will enter the trial and will start receiving DURVALUMAB 750 mg (equivalent to 10 mg/kg Q2W) IV infusion, if ≥ 30 kg, every 2 weeks together with bevacizumab 15mg/kg IV infusion every 3 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 or for a maximum of 50 weeks.

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Bevacizumab-alone Maintenance Treatment Progression Drug: Durvalumab Drug: Bevacizumab Early Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
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
Study Start Date : May 2016
Estimated Primary Completion Date : May 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Bevacizumab + Durvalumab
Treatment with 750 mg Q2W DURVALUMAB (equivalent to 10 mg/kg Q2W) IV infusion, if ≥ 30 kg, commences on day 1 following confirmation of eligibility into the study and continues on a Q2W schedule + Bevacizumab 10 mg/ Kg Q3W, IV infusion for a maximum duration of treatment of 12 months (maximum of 26 doses, last infusion on week 50). 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.
Drug: Durvalumab
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.
Other Name: MEDI4736

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

Primary Outcome Measures :
  1. Changes Immunodynamics factors: kynurenine, prostaglandin, tryptophan levels [ Time Frame: up to 52 weeks ]
    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

Secondary Outcome Measures :
  1. T-cell exhaustion parameters [ Time Frame: up to 52 weeks ]
    Study the relationship between T-cell exhaustion parameters and failure of monoclonal-antibody-based treatment. From baseline every 4 weeks throughout the study up to progression disease

  2. T-cell exhaustion reversion [ Time Frame: 4 months ]
    Study if the reversion of the phenomenon of T-cell exhaustion by DURVALUMAB induces therapeutic benefit (measured by clinical benefit (CR+PR+SD) at 4 months after inclusion of DURVALUMAB in patients that have progressed to bevacizumab alone)

  3. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Through study completion, an average of 1 year ]
    Evaluate safety of combination of both DURVALUMAB and bevacizumab

Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
  2. Age > 18 years at time of study entry.
  3. Confirmed diagnosis of advanced/metastatic HER-2 negative breast cancer.
  4. Patients previously treated with any regimen containing chemotherapy plus bevacizumab as first line of treatment, switched to maintenance treatment with bevacizumab alone and disease progression during this treatment. At least 6 weeks (two doses) must have passed since the last chemotherapy administration, while in treatment with bevacizumab alone, in order to consider bevacizumab monotherapy as maintenance therapy. Any disease progression according to RECIST 1.1 criteria after this timeframe will be considered progression during bevacizumab maintenance.
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  6. Life expectancy of > 24 weeks.
  7. 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.

  8. 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.
  9. 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.

Exclusion Criteria:

  1. Involvement in the planning and/or conduct of the study or in any support activity. Previous enrolment in the present study.
  2. Participation in another clinical study with an investigational product during the last 4 weeks.
  3. Any previous treatment with a CTLA-4 inhibitor, PD-1 or PD-L1 inhibitor, including DURVALUMAB.
  4. 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.

    Adequately treated carcinoma in situ without evidence of disease, example cervical cancer in situ.

  5. 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.)
  6. Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction.
  7. 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.
  8. 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).
  9. Any prior Grade ≥3 immune-related adverse event while receiving any previous immunotherapy agent, or any unresolved AE >Grade 1.
  10. 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.
  11. Active or prior documented inflammatory bowel disease (example Crohn's disease, ulcerative colitis).
  12. History of primary immunodeficiency.
  13. History of allogeneic organ transplant.
  14. History of hypersensitivity to DURVALUMAB or any excipient.
  15. History of hypersensitivity to the combination agent bevacizumab
  16. 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.
  17. 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)
  18. History of hemorrhagic or thromboembolic event clinically significant in the last 6 months
  19. Known hereditary predisposition to bleeding or thrombosis
  20. Known history of previous clinical diagnosis of tuberculosis.
  21. History of leptomeningeal carcinomatosis or brain metastasis.
  22. Receipt of live attenuated vaccination within 30 days of receiving DURVALUMAB.
  23. 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.
  24. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
  25. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids.
  26. Subjects with uncontrolled seizures
  27. Inability to comply with the study and follow-up procedures (example tumor biopsies and blood sampling).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02802098

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Contact: Miguel Quintela, PhD 91.732.80.00 ext 2930
Contact: Ramón Colomer 91.520.22.00 ext 2276

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Hospital Universitario de Fuenlabrada Recruiting
Fuenlabrada, Madrid, Spain, 28942
Contact: Miguel Angel Quintela, PhD    +34-91.732.80.00 ext 2930   
Contact: Berta Nasarre    +34-91.600.65.84   
Principal Investigator: Miguel Quintela, PhD         
Sub-Investigator: Juan Victor Apala         
Sub-Investigator: Juan Antonio Guerra         
Sub-Investigator: Diego Malón         
Sub-Investigator: Laura Rodríguez         
H. Arnau de Vilanova Lleida Not yet recruiting
Lleida, Spain, 25198
Contact: Serafin Morales         
Hospital Universitario de la Princesa Not yet recruiting
Madrid, Spain, 28006
Contact: Ramón Colomer   
Principal Investigator: Ramón Colomer         
Hospital Ramón y Cajal Recruiting
Madrid, Spain, 28034
Contact: Esther Holgado   
Contact: Sara Lavín   
Principal Investigator: Esther Holgado         
Hospital Clínico San Carlos Withdrawn
Madrid, Spain, 28040
Hospital Universitario 12 de Octubre Recruiting
Madrid, Spain, 28041
Contact: Luis Manso   
Contact: Ana Cortijo   
Principal Investigator: Luis Manso         
Clínica Quirón Recruiting
Madrid, Spain, 28223
Contact: Miguel Quintela   
Contact: Mar Marquez    91 452 19 87/   
Principal Investigator: Miguel Quintela         
Sponsors and Collaborators
Centro Nacional de Investigaciones Oncologicas CARLOS III
Fundacion CRIS de Investigación para Vencer el Cáncer

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Responsible Party: Centro Nacional de Investigaciones Oncologicas CARLOS III Identifier: NCT02802098     History of Changes
Other Study ID Numbers: CNIO-BR-008
2015-005609-34 ( EudraCT Number )
First Posted: June 16, 2016    Key Record Dates
Last Update Posted: September 14, 2017
Last Verified: December 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Centro Nacional de Investigaciones Oncologicas CARLOS III:
Metastatic breast cancer
bevacizumab maintenance

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents, Immunological
Antibodies, Monoclonal
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Immunologic Factors