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

Primary Purpose

Breast Neoplasms

Status
Withdrawn
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Denosumab 120 mg
Denosumab 60 mg
Sponsored by
Borstkanker Onderzoek Groep
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Breast Neoplasms focused on measuring Breast cancer, Denosumab, Chemotherapy, Immunity, Immune system, PERIDENO

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

  • Ziekenhuisgroep Twente (Twenteborg ZH Almelo)
  • Gelre ziekenhuizen
  • Zuyderland Medisch Centrum (Heerlen)
  • Spaarne Gasthuis (Hoofddorp)
  • Leiden University Medical Center
  • Fransiscus (Vlietland)
  • VieCuri Medisch Centrum (Venlo)
  • 't Lange Land Ziekenhuis

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

No Intervention

Experimental

Experimental

Arm Label

No denosumab

Denosumab 120 mg

Denosumab 60 mg

Arm Description

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

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.

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.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.
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.
Change in mature and immature myeloid cells (M1/M2 macrophage, MDSC, DC).
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.
Shift in myeloid cell function.
Shifts will be determined by comparing PBMCs (using triggering tests) before start treatment, at day of surgery before surgery and 7 days after last chemotherapy administration.
Change in stimulation capacity APCs.
Changes will be determined by comparing PBMCs (using restimulation tests) before start treatment, at day of surgery before surgery and 7 days after last chemotherapy administration.
Change in serum levels of RANKL and OPG.
Changes will be determined by comparing serum before start treatment, at day of surgery before surgery and 7 days after last chemotherapy administration, using ELISA.
Change in serum cytokine levels (TNF-alpha, interleukines, IFN gamma).
Changes will be determined by comparing serum before start treatment, at day of surgery before surgery and 7 days after last chemotherapy administration, using luminex.
Correlation of tumor measurements with serum measurements.
Measurements in tumor and serum will be correlated.
Correlation of tumor measurements with PBMCs measurements.
Measurements in tumor and PBMCs will be correlated.
Correlation of serum measurements and PBMCs measurements.
Measurements in serum and PBMCs will be correlated.
Toxicity according to NCI CTCAE v4.03.
Toxicities are graded according to NCI CTCAE v4.03.
Difference in descriptive event free survival (EFS) at 3 years based on immune response.
After 3 years of follow up, differences in EFS based on immune response will be determined.

Full Information

First Posted
February 5, 2018
Last Updated
January 16, 2020
Sponsor
Borstkanker Onderzoek Groep
Collaborators
Amgen
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1. Study Identification

Unique Protocol Identification Number
NCT03532087
Brief Title
Study to Identify the Impact of Denosumab on the Immune System in Patients With HER2 Negative Breast Cancer
Acronym
PERIDENO
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

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Withdrawn
Why Stopped
Due to new insights
Study Start Date
February 2018 (Anticipated)
Primary Completion Date
February 2021 (Anticipated)
Study Completion Date
June 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Borstkanker Onderzoek Groep
Collaborators
Amgen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Neoplasms
Keywords
Breast cancer, Denosumab, Chemotherapy, Immunity, Immune system, PERIDENO

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
No denosumab
Arm Type
No Intervention
Arm Description
All patients undergo surgery followed by adjuvant chemotherapy. Patients in this study arm are not additionally treated with denosumab.
Arm Title
Denosumab 120 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Denosumab 60 mg
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Denosumab 120 mg
Other Intervention Name(s)
Xgeva
Intervention Description
Denosumab 120 mg every 3 weeks.
Intervention Type
Drug
Intervention Name(s)
Denosumab 60 mg
Other Intervention Name(s)
Prolia
Intervention Description
Denosumab 60 mg every 6 months.
Primary Outcome Measure Information:
Title
Change in intratumoral T-cell (CD4, CD8 and Treg) numbers and function between the baseline biopsy and the surgical specimen.
Description
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.
Title
Change in myeloid cell (M1/M2 Macrophage, MDSC, DC) numbers and function between the baseline biopsy and the surgical specimen.
Description
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 Outcome Measure Information:
Title
Shift in activated T effector cell levels.
Description
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.
Title
Shift in regulatory T-cell levels.
Description
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.
Title
Change in functional response of T-cells.
Description
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.
Title
Change in mature and immature myeloid cells (M1/M2 macrophage, MDSC, DC).
Description
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.
Title
Shift in myeloid cell function.
Description
Shifts will be determined by comparing PBMCs (using triggering 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.
Title
Change in stimulation capacity APCs.
Description
Changes will be determined by comparing PBMCs (using restimulation 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.
Title
Change in serum levels of RANKL and OPG.
Description
Changes will be determined by comparing serum before start treatment, at day of surgery before surgery and 7 days after last chemotherapy administration, using ELISA.
Time Frame
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.
Title
Change in serum cytokine levels (TNF-alpha, interleukines, IFN gamma).
Description
Changes will be determined by comparing serum before start treatment, at day of surgery before surgery and 7 days after last chemotherapy administration, using luminex.
Time Frame
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.
Title
Correlation of tumor measurements with serum measurements.
Description
Measurements in tumor and serum will be correlated.
Time Frame
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.
Title
Correlation of tumor measurements with PBMCs measurements.
Description
Measurements in tumor and PBMCs will be correlated.
Time Frame
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.
Title
Correlation of serum measurements and PBMCs measurements.
Description
Measurements in serum and PBMCs will be correlated.
Time Frame
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.
Title
Toxicity according to NCI CTCAE v4.03.
Description
Toxicities are graded according to NCI CTCAE v4.03.
Time Frame
Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.
Title
Difference in descriptive event free survival (EFS) at 3 years based on immune response.
Description
After 3 years of follow up, differences in EFS based on immune response will be determined.
Time Frame
EFS will be determined after 3 years.

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Judith R Kroep, MD PhD
Organizational Affiliation
Leiden University Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gerrit-Jan Liefers, MD PhD
Organizational Affiliation
Leiden University Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sjoerd H van der Burg, Prof. Dr.
Organizational Affiliation
Leiden University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ziekenhuisgroep Twente (Twenteborg ZH Almelo)
City
Almelo
Country
Netherlands
Facility Name
Gelre ziekenhuizen
City
Apeldoorn
Country
Netherlands
Facility Name
Zuyderland Medisch Centrum (Heerlen)
City
Heerlen
Country
Netherlands
Facility Name
Spaarne Gasthuis (Hoofddorp)
City
Hoofddorp
Country
Netherlands
Facility Name
Leiden University Medical Center
City
Leiden
Country
Netherlands
Facility Name
Fransiscus (Vlietland)
City
Schiedam
Country
Netherlands
Facility Name
VieCuri Medisch Centrum (Venlo)
City
Venlo
Country
Netherlands
Facility Name
't Lange Land Ziekenhuis
City
Zoetermeer
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Links:
URL
https://www.boogstudycenter.nl/studie/287/perideno.html
Description
Information PERIDENO study on BOOG website (sponsor).

Learn more about this trial

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

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