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

NCT03532087 | Withdrawn Phase 2

• 2 other identifiers: BOOG-2017-022016-005210-22
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 8

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.

Conditions

Breast Neoplasms

Keywords

Breast cancer; Denosumab; Chemotherapy; Immunity; Immune system; PERIDENO

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

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

Secondary Outcomes (13)

• Shift in activated T effector cell levels.

  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.

  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.

  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 mature and immature myeloid cells (M1/M2 macrophage, MDSC, DC).

  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 myeloid cell function.

  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.

Study Arms (3)

No denosumab

NO INTERVENTION

All patients undergo surgery followed by adjuvant chemotherapy. Patients in this study arm are not additionally treated with denosumab.

Denosumab 120 mg

EXPERIMENTAL

All patients undergo surgery followed by adjuvant chemotherapy. Patients in this study arm are additionally treated with denosumab 120 mg every 3 weeks. First denosumab gift is before surgery, last denosumab gift is together with the last cycle of chemotherapy.

Drug: Denosumab 120 mg

Denosumab 60 mg

EXPERIMENTAL

All patients undergo surgery followed by adjuvant chemotherapy. Patients in this study arm are additionally treated with denosumab 60 mg every 6 months. First denosumab gift is before surgery, last denosumab gift is together with the last cycle of chemotherapy.

Drug: Denosumab 60 mg

Interventions

Denosumab 120 mg DRUG

Denosumab 120 mg every 3 weeks.

Also known as: Xgeva

Denosumab 120 mg

Denosumab 60 mg DRUG

Denosumab 60 mg every 6 months.

Also known as: Prolia

Denosumab 60 mg

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Borstkanker Onderzoek Groep: lead
• Amgen: collaborator

Study Sites (8)

Ziekenhuisgroep Twente (Twenteborg ZH Almelo)

Almelo, Netherlands

Location

Gelre ziekenhuizen

Apeldoorn, Netherlands

Location

Zuyderland Medisch Centrum (Heerlen)

Heerlen, Netherlands

Location

Spaarne Gasthuis (Hoofddorp)

Hoofddorp, Netherlands

Location

Leiden University Medical Center

Leiden, Netherlands

Location

Fransiscus (Vlietland)

Schiedam, Netherlands

Location

VieCuri Medisch Centrum (Venlo)

Venlo, Netherlands

Location

't Lange Land Ziekenhuis

Zoetermeer, Netherlands

Location

Related Publications (1)

• Adams A, Jakob T, Huth A, Monsef I, Ernst M, Kopp M, Caro-Valenzuela J, Wockel A, Skoetz N. Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis. Cochrane Database Syst Rev. 2024 Jul 9;7(7):CD013451. doi: 10.1002/14651858.CD013451.pub2.

  PMID: 38979716 DERIVED

Related Links

• Information PERIDENO study on BOOG website (sponsor).

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Denosumab

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 Officials

• Judith R Kroep, MD PhD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

• Gerrit-Jan Liefers, MD PhD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

• Sjoerd H van der Burg, Prof. Dr.

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2018
• First Posted: May 22, 2018
• Study Start: February 1, 2018
• Primary Completion: February 1, 2021
• Study Completion: June 1, 2023
• Last Updated: January 18, 2020

Record last verified: 2019-07

Locations

NL (8)