Clinical trial NCT03532087: Study to Identify the Impact of Denosumab on the Immune System in Patients With HER2 Negative Breast Cancer
Official title: Explorative Trial to Identify the Impact of Denosumab on the Systemic Immunity and Local Immunologic Microenvironment in Postmenopausal Patients With HER2 Negative Breast Cancer
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Breast Neoplasms
Keywords: Breast cancer
Denosumab
Chemotherapy
Immunity
Immune system
PERIDENO
Lead sponsor: Borstkanker Onderzoek Groep
Sponsor class: NETWORK
Collaborators: name: Amgen
First posted: 2018-05-22
Enrollment: 0
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in intratumoral T-cell (CD4, CD8 and Treg) numbers and function between the baseline biopsy and the surgical specimen.
timeFrame: The change can be determined after the surgical specimen is obtained, which is around two weeks after enrolment.
measure: Change in myeloid cell (M1/M2 Macrophage, MDSC, DC) numbers and function between the baseline biopsy and the surgical specimen.
timeFrame: The change can be determined after the surgical specimen is obtained, which is around two weeks after enrolment.
Secondary outcomes:
measure: Shift in activated T effector cell levels.
timeFrame: 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.
measure: Shift in regulatory T-cell levels.
timeFrame: 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.
measure: Change in functional response of T-cells.
timeFrame: 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.
measure: Change in mature and immature myeloid cells (M1/M2 macrophage, MDSC, DC).
timeFrame: 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.
measure: Shift in myeloid cell function.
timeFrame: 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.
measure: Change in stimulation capacity APCs.
timeFrame: 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.
measure: Change in serum levels of RANKL and OPG.
timeFrame: Measurements will be done in serum from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.
measure: Change in serum cytokine levels (TNF-alpha, interleukines, IFN gamma).
timeFrame: Measurements will be done in serum from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.
measure: Correlation of tumor measurements with serum measurements.
timeFrame: Measurements will be done in tumor material and serum from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment and tumor material from baseline and surgery.
measure: Correlation of tumor measurements with PBMCs measurements.
timeFrame: Measurements will be done in tumor material and PBMCs from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment and tumor material from baseline and surgery.
measure: Correlation of serum measurements and PBMCs measurements.
timeFrame: Measurements will be done in PBMCs/serum from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment and tumor material from baseline and surgery.
measure: Toxicity according to NCI CTCAE v4.03.
timeFrame: Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.
measure: Difference in descriptive event free survival (EFS) at 3 years based on immune response.
timeFrame: EFS will be determined after 3 years.
Other outcomes:
Locations:
city: Almelo
country: Netherlands
facility: Ziekenhuisgroep Twente (Twenteborg ZH Almelo)
city: Apeldoorn
country: Netherlands
facility: Gelre ziekenhuizen
city: Heerlen
country: Netherlands
facility: Zuyderland Medisch Centrum (Heerlen)
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis (Hoofddorp)
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Schiedam
country: Netherlands
facility: Fransiscus (Vlietland)
city: Venlo
country: Netherlands
facility: VieCuri Medisch Centrum (Venlo)
city: Zoetermeer
country: Netherlands
facility: 't Lange Land Ziekenhuis
Study officials:
affiliation: Leiden University Medical Center
name: Judith R Kroep, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Gerrit-Jan Liefers, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Sjoerd H van der Burg, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: