Primary objective• Determine the change in intratumoral T-cell (CD4, CD8 and Treg) and Myeloid cell (M1/M2 Macrophage, MDSC, DC) numbers and function between the baseline biopsy and the surgical specimen.Secondary objectives• PBMC before start…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in intratumoral T-cell (CD4, CD8 and Treg) and Myeloid cell (M1/M2
Macrophage, MDSC, DC) numbers and function between the baseline biopsy and the
surgical specimen.
Secondary outcome
• PBMC before start treatment (t=1), at day of surgery before surgery (t=2) and
7 days after last denosumab administration (t=3):
o Shift in activated T effector cell levels (Ki67, HLA-DR, CD45RO, CD25, CD69,
PD-1, TIM-3 and NKG-2A);
o Shift in regulatory T-cell levels (CD3, CD4, CD25, CD127, CD45RA, Foxp3,
helios, CTLA-4 and Ki67);
o Change in functional response of T-cells (stimulation with recall antigens).
o Change in mature and immature myeloid cells (M1, M2,MDSC, DC).
o Shift in myeloid cell function (IL-10 and IL-12 production after LPS or
anti-CD40 triggering).
o Change in stimulation capacity APCs (MLR + cytokine production after
restimulation).
• Serum before start treatment (t=1), at day of surgery before surgery (t=2)
and 7 days after last denosumab administration (t=3):
o Change in serum levels for RANKL, OPG by ELISA; TNF-alpha, IL-1-beta, IL-6,
IL-7,IL-10, IL-15, IL-12, IFN gamma by luminex.
• Tumor:
o Correlation of tumor (biopsy and resection material) (intratumoral T-cell and
Myeloid cell numbers), serum cytokine levels and PBMC immunologic parameters.
• Toxicity according to NCI CTCAE v4.03.
• Difference in descriptive event-free survival (EFS) at 3 year based on immune
response.
Background summary
See page 11 and 12 of the protocol for a more detailed background of the study.
Breast cancer (BC) is the most common cancer in women worldwide, with nearly
1.7 million new cases worldwide and in the Netherlands more than 14.000
patients were diagnosed in 2012. Recent data show that the addition of
bisphosphonates (BP) to (neo)adjuvant systemic therapy has an anti-tumor effect
in postmenopausal patients with early BC. The vicious cycle between tumor cells
and osteoclasts is interrupted by BP as well as by the bone targeting agent
denosumab which is a humanized monoclonal antibody against receptor activator
of nuclear factor kappa-B ligand (RANKL). Denosumab was superior to zoledronate
in preventing skeletal related events with favorable safety and convenience in
patients with bone metastases, including advanced BC patients.
In the ABCSG-18 trial, a randomized phase III trial in 3,425 postmenopausal
patients treated with adjuvant aromatase inhibitor (AI) with or without
denosumab 60 mg q6 months, the primary aim was met with a significant reduction
in AI-induced fractures in the denosumab arm. Noteworthy, at SABCS 2015 the
disease free survival (DFS) data was improved for patients that were treated
with additional densosumab. Survival data of this ABSCG-18 trial and data about
the antitumor effect of denosumab 120 mg every month of the D-CARE trial
(NCT01077154) are awaited. These exciting efficacy findings are expected to
change clinical practice. Understanding the mechanism behind the antitumor
effect denosumab, including the role of oestrogen deficiency and
immune-modulatory effects on T-cells and myeloid cells, are essential in order
to predict efficacy and select those patients that benefit most.
RANKL, Receptor activator of nuclear factor kappa-B ligand (RANK) and
Osteoprotegrin (OPG) interaction is important for the activation of adaptive
immunity in a similar way as the CD40-CD40L axis. The two pathways - with minor
differences - can substitute for each other. Blockade of RANKL probably does
not affect activation of adaptive immunity (due to the unaffected CD40-CD40L
signaling pathway) but may show only impact on the negative effects of
RANKL-RANK signaling. We expect that denosumab modulates the systemic (and
local) immune response.
Study objective
Primary objective
• Determine the change in intratumoral T-cell (CD4, CD8 and Treg) and Myeloid
cell (M1/M2 Macrophage, MDSC, DC) numbers and function between the baseline
biopsy and the surgical specimen.
Secondary objectives
• PBMC before start treatment, at day of surgery and 7 days after last
denosumab administration:
o Determine the shift in T-cell (activated T effector cells and regulatory T
cells) levels and function in PBMC samples.
o Determine the change in mature and immature myeloid cells (M1, M2, MDSC, DC).
o Determine the shift in myeloid cell function (IL-10 and IL-12 production
after LPS or anti-CD40 triggering).
o Determine the change in stimulation capacity APCs (MLR + cytokine production
after restimulation).
• Serum before start treatment, at day of surgery and 7 days after last
denosumab administration:
o Determine the change in RANKL, OPG by ELISA; TNF-alpha, IL-1-beta, IL-6,
IL-7, IL-10, IL-15, IL-12, IFN gamma by luminex.
• Tumor
o Correlate tumor (biopsy and resection material), serum and PBMC immunologic
parameters.
• Toxicity according to NCI CTCAE v4.03.
• Determine the descriptive difference in event-free survival (EFS) at 3 year
based on immune response.
Study design
A prospective, randomized, multicenter, open-label, phase II, explorative
intervention study.
Intervention
Randomization between:
- Denosumab 60 mg q6 months
- Denosumab 120 mg q3 weeks
- No denosumab
Study burden and risks
The patients risks will be the side-effects of investigational drug as
described in this protocol and the patient information leaflet, and the risks
and discomfort accompanying denosumab injections and blood sampling.
Furthermore, since denosumab needs to be administered in the hospital and extra
blood samples will have to be taken (four times in total) this subsequently
requires some (maximal 3x) extra hospital visits. The benefit might be that
patients are treated with an agent which possibly possesses anti-tumor
activity. All patients contribute in the knowledge about developing new
strategies in anti-cancer therapies.
IJsbaanpad 9-11
Amsterdam 1076 CV
NL
IJsbaanpad 9-11
Amsterdam 1076 CV
NL
Listed location countries
Age
Inclusion criteria
• Postmenopausal, defined as 1 year without menstrual activity, previous bilateral oophorectomy, age older than 60 years or baselineFSH >20 U/l and estradiol <110 pmol/l.
• Clinical stage T1c + grade 3/4, stage II or III breast cancer amenable to adjuvant AC-T or ddAC-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>=3.0x10^9/l, neutrophils >=1.5 x 10^9/l, platelets >=100 x 10^9/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 invasive 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.
• Serious other diseases as recent (last 6 months) myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias.
• Prior or current bisphosphonate or denosumab usage.
• Osteoporosis as demonstrated on dexa vfa scan, defined as T <= 2.5 and/or a vertebral fracture.
• 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
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-005210-22-NL |
| ClinicalTrials.gov | NCT03532087 |
| CCMO | NL62335.058.17 |