Study to Identify the Impact of Denosumab on the Immune System in Patients With HER2 Negative Breast Cancer

Phase 2WithdrawnNCT03532087

Borstkanker Onderzoek Groep

Overview

The aim of this prospective, randomized, multicenter, open-label, explorative phase II study is to identify the impact of (neo)adjuvant denosumab on the systemic immunity and local immunologic microenvironment in postmenopausal patients with HER2 negative non-metastatic primary breast cancer.

In this study, postmenopausal patients with stage T1c + grade 3, stage II or III, HER2-negative breast cancer, which are planned to undergo surgery followed by adjuvant AC-T chemotherapy, are randomized between no denosumab, denosumab low dosing and denosumab high dosing. Denosumab administration will start one week before surgery and continue until the last chemotherapy cycle.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Conditions

Breast Neoplasms

Interventions

Denosumab 120 mgDRUG

Denosumab 120 mg every 3 weeks.

Denosumab 60 mgDRUG

Denosumab 60 mg every 6 months.

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Postmenopausal, defined as 1 year without menstrual activity, previous bilateral oophorectomy, age older than 60 years or baseline FSH \>20 U/l and estradiol \<110 pmol/l. * Clinical stage T1c + grade 3, stage II or III breast cancer amenable to adjuvant AC-T combination chemotherapy. * Measurable disease (breast and/or lymph nodes). * Histological proven HER2-negative breast cancer in the core biopsy material. * WHO 0-2. * Adequate bone marrow function (within 4 weeks prior to randomization): WBC≥3.0x109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l. * Adequate liver function (within 4 weeks prior to randomization): bilirubin ≤1.5 X upper limit of normal (UNL) range, ALAT and/or ASAT ≤2.5 x UNL, Alkaline Phosphatase ≤5 x UNL. * Adequate renal function (within 4 weeks prior to randomization): the calculated creatinine clearance should be ≥50 ml/min. * Albumin-adjusted serum calcium \> 2.0 mmol/L (8.0mg/dL) * Accessible for treatment and follow-up. * Written informed consent. Exclusion Criteria: * Evidence of distant metastases (M1). * History of breast cancer. * Prior chemotherapy or radiation therapy. * Previous malignancy within 5 years, with exception of a history of a previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix. * Prior or current bisphosphonate or denosumab usage. * Serious other diseases as recent (last 6 months) myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias. * Current active dental problems including dental abscess or infection of the jawbone (maxilla or mandible), non-healed dental or oral surgery, a current or prior diagnosis of osteonecrosis of the jaw or planned invasive dental procedures for the course of the study. * Known hypersensitivity reaction to any of the components of the treatment. * Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.

Locations (8)

Ziekenhuisgroep Twente (Twenteborg ZH Almelo)

Almelo, Netherlands

Gelre ziekenhuizen

Apeldoorn, Netherlands

Zuyderland Medisch Centrum (Heerlen)

Heerlen, Netherlands

Spaarne Gasthuis (Hoofddorp)

Hoofddorp, Netherlands

Outcomes

Primary Outcomes

Change in intratumoral T-cell (CD4, CD8 and Treg) numbers and function between the baseline biopsy and the surgical specimen.

The change will be determined by use of IHC and immunofluorescent stainings.

Time frame: The change can be determined after the surgical specimen is obtained, which is around two weeks after enrolment.

Change in myeloid cell (M1/M2 Macrophage, MDSC, DC) numbers and function between the baseline biopsy and the surgical specimen.

The change will be determined by use of IHC and immunofluorescent stainings.

Time frame: The change can be determined after the surgical specimen is obtained, which is around two weeks after enrolment.

Secondary Outcomes

Shift in activated T effector cell levels.

Shifts will be determined by comparing PBMCs (using flow cytometry) before start treatment, at day of surgery before surgery and 7 days after last chemotherapy administration.

Time frame: Measurements will be done in PBMCs from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.

Shift in regulatory T-cell levels.

Shifts will be determined by comparing PBMCs (using flow cytometry) before start treatment, at day of surgery before surgery and 7 days after last chemotherapy administration.

Time frame: Measurements will be done in PBMCs from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.

Change in functional response of T-cells.

Changes will be determined by comparing PBMCs (using stimulation tests) before start treatment, at day of surgery before surgery and 7 days after last chemotherapy administration.

Time frame: Measurements will be done in PBMCs from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.

Data from ClinicalTrials.gov

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