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Evaluation of the Immunological Effects of a Combined Treatment With Radiation and Cyclophosphamide in Metastasized Breast Cancer Patients

Primary Purpose

Radiotherapy, Immunology

Status
Withdrawn
Phase
Early Phase 1
Locations
Belgium
Study Type
Interventional
Intervention
Cyclophosphamide
Stereotactic body radiotherapy
Sponsored by
University Hospital, Ghent
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Radiotherapy

Eligibility Criteria

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

Inclusion Criteria:

  • Histologically proven diagnosis of breast cancer
  • Evidence of metastasized disease on imaging or during clinical examination
  • Progressive disease during last systemic treatment
  • Multiple (≥2) measurable lesions accessible for repeat biopsy, in particular:
  • Skin- or subcutaneous metastases
  • Lymph node metastases cervical, supraclavicular, axillary or inguinal
  • Superficial lesions in the breast or on the thoracic wall
  • Age ≥ 18 years
  • Adequate organ and bone marrow function:
  • ANC > 1500/µL
  • haemoglobin > 9 g/dL (potentially after transfusion)
  • thrombocytes ≥ 100 000/µL
  • total bilirubin ≤ 1.5 X maximum reference value
  • AST ≤ 2.5 X maximum reference value
  • ALT ≤ 2.5 X maximum reference value
  • creatinin ≤ 1.5 X maximum reference value
  • Informed consent
  • Chemotherapy or targeted therapy should be stopped for at least 1 month before the start of cyclophosphamide. Hormone therapy can be continued if it was not changed in the last 3 months

Exclusion Criteria:

  • Life expectancy of less than 3 months or Karnofsky performance status < 70
  • New line of systemic therapy planned
  • Concomitant treatment with other experimental drugs
  • Local therapies (radiation, surgery, topical anti-cancer treatment, intralesional therapy, laser treatment) at the target lesion(s) less than 4 weeks before the start of cyclophosphamide. Biopsy is allowed.
  • Chemotherapy or targeted therapy < 4 weeks before the start of cyclophosphamide
  • Hormone therapy change within the last 3 months
  • Uncontrolled coagulation disorders
  • Patients receiving therapeutic anticoagulants that cannot be stopped temporarily for repeat biopsy. Aspirin or anti-aggregants are allowed.
  • Patients with a known immune-deficiency disorder or receiving immune-suppressive treatment
  • Known allergy or intolerance for cyclophosphamide
  • Pregnant or breastfeeding
  • Women in the reproductive age not using a medically accepted method of contraception
  • Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study
  • Patient unlikely to comply with the protocol; i.e. uncooperative attitude, inability to return for follow-up visits, and unlikely to complete the study

Sites / Locations

  • University Hospital - Radiotherapy Department

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Cyclophosphamide

Arm Description

Outcomes

Primary Outcome Measures

Identification of the immunological effects, in peripheral blood and tumor biopsies, of the combined treatment with radiation and cyclophosphamide
Biopsies will be divided for 1) flowcytometric analysis (CD4 and CD8 tumor infiltrating lymphocytes, Tregs, dendritic cell subsets) and 2) immune histochemistry (CD8 tumor infiltrating lymphocytes, Foxp3+ Tregs). Immunomonitoring in peripheral blood by flow-cytometric analysis of leukocyte subsets involved in tumor-related immune responses: NK and T-cell subsets, dendritic cell subsets and myeloid-derived suppressor cells. Cytokine secretion patterns will be investigated using FACS and ELISA. Immune monitoring: Before the first session of radiation, 4 weeks after radiotherapy and 3 months after radiotherapy.

Secondary Outcome Measures

Evaluation of the clinical/radiographical response of irradiated metastases
Evaluation of the clinical response of irradiated metastases will be done by monthly photographic documentation of all skin lesions. Evaluation of the radiographical response of irradiated metastases by 3-monthly imaging.
Evaluation of the response of non-irradiated metastases (the so-called "abscopal effect").
Evaluation of the "abscopal effect" will be done by using the RECIST criteria and the immune related response criteria (irRC) 3 months post-radiotherapy.

Full Information

First Posted
April 24, 2015
Last Updated
July 7, 2021
Sponsor
University Hospital, Ghent
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1. Study Identification

Unique Protocol Identification Number
NCT02441270
Brief Title
Evaluation of the Immunological Effects of a Combined Treatment With Radiation and Cyclophosphamide in Metastasized Breast Cancer Patients
Official Title
Evaluation of the Immunological Effects of a Combined Treatment With Radiation and Cyclophosphamide in Metastasized Breast Cancer Patients
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Withdrawn
Why Stopped
Study was never started.
Study Start Date
April 2015 (undefined)
Primary Completion Date
May 15, 2018 (Actual)
Study Completion Date
May 15, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Ghent

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
In metastasized of locally advanced breast cancer patients, local problems often occur like skin metastases, ulcerations or lymph node metastases. These problems are related to a worse quality of life, while overall survival is generally in the order of months to years. Treatment of these lesions is challenging, especially after failure of first or second line systemic therapy. Local treatments, like radiation, are able to give short-term palliation, but the effect is often disappointing in the long run. Therefore, the search for new therapeutic strategies like the combination of local and systemic treatments is emerging. Recent investigations clearly show that radiation is capable of inducing a systemic anti-tumor response. Both in mouse models and in patients, it was reported that irradiating one metastasis can slow down the growth of other non-irradiated metastases. This effect is called the "abscopal effect" and is immune-mediated. There are also several chemotherapeutics that are capable of influencing the immune response like cyclophosphamide. Cyclophosphamide is a known inducer of immunogenic cell death, which leads to the activation of dendritic cells and thus the presentation of antigens. In this pilot study the investigators wish to identify the immunological effects of combined treatment with radiation and cyclophosphamide in breast cancer patients. Five patients with metastasized breast carcinoma will be treated with the combined treatment and the immunological effects will be monitored using repeat blood draws and biopsies. These effects will be correlated to the clinical response.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Radiotherapy, Immunology

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cyclophosphamide
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Type
Radiation
Intervention Name(s)
Stereotactic body radiotherapy
Primary Outcome Measure Information:
Title
Identification of the immunological effects, in peripheral blood and tumor biopsies, of the combined treatment with radiation and cyclophosphamide
Description
Biopsies will be divided for 1) flowcytometric analysis (CD4 and CD8 tumor infiltrating lymphocytes, Tregs, dendritic cell subsets) and 2) immune histochemistry (CD8 tumor infiltrating lymphocytes, Foxp3+ Tregs). Immunomonitoring in peripheral blood by flow-cytometric analysis of leukocyte subsets involved in tumor-related immune responses: NK and T-cell subsets, dendritic cell subsets and myeloid-derived suppressor cells. Cytokine secretion patterns will be investigated using FACS and ELISA. Immune monitoring: Before the first session of radiation, 4 weeks after radiotherapy and 3 months after radiotherapy.
Time Frame
1.5 years
Secondary Outcome Measure Information:
Title
Evaluation of the clinical/radiographical response of irradiated metastases
Description
Evaluation of the clinical response of irradiated metastases will be done by monthly photographic documentation of all skin lesions. Evaluation of the radiographical response of irradiated metastases by 3-monthly imaging.
Time Frame
1.5 years
Title
Evaluation of the response of non-irradiated metastases (the so-called "abscopal effect").
Description
Evaluation of the "abscopal effect" will be done by using the RECIST criteria and the immune related response criteria (irRC) 3 months post-radiotherapy.
Time Frame
1.5 years

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically proven diagnosis of breast cancer Evidence of metastasized disease on imaging or during clinical examination Progressive disease during last systemic treatment Multiple (≥2) measurable lesions accessible for repeat biopsy, in particular: Skin- or subcutaneous metastases Lymph node metastases cervical, supraclavicular, axillary or inguinal Superficial lesions in the breast or on the thoracic wall Age ≥ 18 years Adequate organ and bone marrow function: ANC > 1500/µL haemoglobin > 9 g/dL (potentially after transfusion) thrombocytes ≥ 100 000/µL total bilirubin ≤ 1.5 X maximum reference value AST ≤ 2.5 X maximum reference value ALT ≤ 2.5 X maximum reference value creatinin ≤ 1.5 X maximum reference value Informed consent Chemotherapy or targeted therapy should be stopped for at least 1 month before the start of cyclophosphamide. Hormone therapy can be continued if it was not changed in the last 3 months Exclusion Criteria: Life expectancy of less than 3 months or Karnofsky performance status < 70 New line of systemic therapy planned Concomitant treatment with other experimental drugs Local therapies (radiation, surgery, topical anti-cancer treatment, intralesional therapy, laser treatment) at the target lesion(s) less than 4 weeks before the start of cyclophosphamide. Biopsy is allowed. Chemotherapy or targeted therapy < 4 weeks before the start of cyclophosphamide Hormone therapy change within the last 3 months Uncontrolled coagulation disorders Patients receiving therapeutic anticoagulants that cannot be stopped temporarily for repeat biopsy. Aspirin or anti-aggregants are allowed. Patients with a known immune-deficiency disorder or receiving immune-suppressive treatment Known allergy or intolerance for cyclophosphamide Pregnant or breastfeeding Women in the reproductive age not using a medically accepted method of contraception Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study Patient unlikely to comply with the protocol; i.e. uncooperative attitude, inability to return for follow-up visits, and unlikely to complete the study
Facility Information:
Facility Name
University Hospital - Radiotherapy Department
City
Ghent
ZIP/Postal Code
9000
Country
Belgium

12. IPD Sharing Statement

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Evaluation of the Immunological Effects of a Combined Treatment With Radiation and Cyclophosphamide in Metastasized Breast Cancer Patients

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