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

NCT02802098 | Completed Early Phase 1 DMC

• 2 other identifiers: CNIO-BR-0082015-005609-34
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 6

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 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.

Conditions

Metastatic Breast Cancer; Bevacizumab-alone Maintenance Treatment Progression

Keywords

Metastatic breast cancer; bevacizumab maintenance; Durvalumab

Outcome Measures

Primary Outcomes (3)

• 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

  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

  up to 12 weeks

• To determine overall survival

  Overall survival rate by Kaplan-Meier Analysis

  up to death

Secondary Outcomes (1)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  Throughout study completion, an average of 1 year

Study Arms (1)

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.

Drug: Durvalumab; Drug: Bevacizumab

Interventions

Durvalumab DRUG

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.

Also known as: MEDI4736

Bevacizumab + Durvalumab

Bevacizumab DRUG

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

Also known as: Avastin

Bevacizumab + Durvalumab

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Centro Nacional de Investigaciones Oncologicas CARLOS III: lead
• Fundacion CRIS de Investigación para Vencer el Cáncer: collaborator

Study Sites (6)

Hospital Universitario de Fuenlabrada

Fuenlabrada, Madrid, 28942, Spain

Location

H. Arnau de Vilanova Lleida

Lleida, 25198, Spain

Location

Hospital Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Clínica Quirón

Madrid, 28223, Spain

Location

Hospital General de Valencia

Valencia, 46014, Spain

Location

Related Publications (1)

• 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.

  PMID: 33176887 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

durvalumab; Bevacizumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2016
• First Posted: June 16, 2016
• Study Start: May 1, 2016
• Primary Completion: June 1, 2019
• Study Completion: July 1, 2019
• Last Updated: June 19, 2020

Record last verified: 2020-06

Locations

ES (6)