This study has been transitioned to CTIS with ID 2024-515080-54-00 check the CTIS register for the current data. Primary objectiveTo determine the pathological complete response rate per cohort
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective
To determine the pathological complete response rate per cohort
Secondary outcome
Secondary objectives
• To establish whether short-term pre-operative nivolumab either as monotherapy
or in combination with ipilimumab or novel IO combinations is safe in early BC
patients
• To assess the proportion of clinical and radiological responses as measured
by imaging
• To assess the proportion of pathological responses (pCR, residual cancer
burden)
• To correlate parameters of systemic immune suppression in early BC with
intratumoral immune landscape and with responses seen in patients
• To correlate changes in tumor fragments (ex vivo model system, developed by
Daniela Thommen) upon nivolumab either as monotherapy or in combination with
ipilimumab or novel IO combinations with changes in the on-treatment biopsy
• To explore the putative predictive value of upcoming biomarkers such as but
not limited to: CD8, IFNy gene signature, mutational load, homologous
recombination deficiency (HRD)
• To evaluate 3-year, 5-year and 10-year overall and event free survival rate
Background summary
The absolute benefit in terms of overall survival of adjuvant chemotherapy in
early breast cancer (BC) is relatively low (±10%), at the cost of substantial
toxicity. Therefore, the identification of BC patients who could benefit from
more targeted treatment approaches that improve outcome, thereby preventing the
toxicity of chemotherapy, is of high priority for breast cancer management.
Data in lung cancer has now revealed that PD1-blockade is in general less toxic
compared to chemotherapy. Promising activity of anti-PD(L)1 treatment has been
observed in patients with metastatic BC, leading to the motivation of this
study to investigate which patients with primary breast cancer might benefit
from anti-PD1. In order to improve quality of life for BC patients,
de-escalating or omitting chemotherapy might be an attractive future strategy
for those tumors responding to immunotherapy.
Study objective
This study has been transitioned to CTIS with ID 2024-515080-54-00 check the CTIS register for the current data.
Primary objective
To determine the pathological complete response rate per cohort
Study design
This trial has an adaptive design (Simon*s two stage) and therefore the number
of patients is defined for stage I and stage II. 90 patients in stage I (6
cohorts with 15 patients each). Depending on the results in stage I, in stage
II 31 additional patients will be needed per cohort, so if all cohorts show
promising results in stage I a total of (6*(15+31)) 276 patients will be
included (funding for full stage I available).
Intervention
This study is a pre-operative window of opportunity phase II multiple-cohort
trial in TNBC and luminal B-like early BC
Separate cohorts will be opened in this trial, LumB and TNBC tumors will be
divided in separate cohorts.
The following cohorts will start in this trial:
• Cohort IA (n=15, LumB) and 1B (n=15, TNBC) will be treated pre-surgically for
4 weeks (in waiting time for surgery) with nivolumab (2 courses 240mg flat dose
day 1 and day 15).
• Cohort 2A (n=15, LumB) and 2B (n=15, TNBC) will be treated pre-surgically for
4 weeks (in waiting time for surgery) with nivolumab (2 courses 240 mg flat
dose day 1 and day 15) and one single dose ipilimumab 1 mg/kg day 1.
• Cohort 2B (n=15, TN, high TIL) will be treated pre-surgically for 6 weeks
(in waiting time for surgery) with nivolumab (2 courses 240 mg flat dose day 1
and day 21) and 2 courses ipilimumab 1 mg/kg day 1 en 21
New cohorts with novel IO in combination with nivolumab can be added if safety
data are available and signals for efficacy are convincing in breast cancer or
other cold tumors, e.g. resulting in cohort 3A (n=15, LumB) and 3B(n=15, TNBC),
and an addition of 30 patients in total in stage I.
• Cohort 3B (n=15, TNBC) will include only TIL-high breast tumors of patients
with cT1c-T2N0 disease and patients will be treated pre-surgically for 6 weeks
with nivolumab (240 mg flat dose) and ipilimumab (1mg/kg) at day 1 and day 21.
Each therapy cycle will be 3 weeks and after 6 weeks patients will be scheduled
for surgery.
• Cohort 4B (n=15, TNBC cT1b-cT2N0, TIL upper-intermediate 30-49%) will be
treated pre-surgically for 8 weeks with nivolumab (480mg)/relatlimab (480mg) at
day 1 and day 29. Each cycle will be 4 weeks and after 8 weeks patients will be
scheduled for surgery.
• Cohort 5B (n=15, TNBC cT1b-cT2N0, TIL high >=50%) will be treated
pre-surgically for 8 weeks with nivolumab (480mg)/relatlimab (480mg) at day 1
and 29. Each cycle will be 4 weeks and after 8 weeks patients will be scheduled
for surgery.
Study burden and risks
The subjects' load will consist of taking an extra biopsy, extra blood tests,
physical examination and the possibility of side effects of the therapy. The
reported side effects for Nivolumab in pre-operative clinical trials are low
(see page 9 protocol) and the specific combination of Nivolumab combined with a
broad knowledge of side effects in patients, leads to a low chance of side
effects for patients in the BELLINI study. In order to be able to give better,
personalized, therapy to patients with a primary breast tumor in the future,
where we try to prevent over-treatment with chemotherapy and additional side
effects, participation of the subjects and the additional burden is justified.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
• Resectable primary breast cancer stage I-III. Nodal status must be examined
by ultrasound, fine needle aspiration, sentinel node biopsy, or FDG-PET scan
(cohort 3B, 4B and 5B4: PET-CT mandatory).
- Patients indicated for neoadjuvant chemotherapy will also be eligible,
whereby a new dedicated biopsy is performed before the beginning of the
chemotherapy. Adjuvant systemic treatment is allowed if indicated according to
local guidelines.
• Tumor size at least 5 mm (minimum cT1b) as determined by MRI
• TNBC defined as ER<10%, HER2-negative OR luminal B defined as ER>=10%,
HER2-negative with either Ki67>=20% or PR <=20% OR grade 3. HER2 negative is
defined as an IHC score of <2 or 2+ with a negative ISH.
- For TNBC patients: TIL>=5%
- For LumB breast cancer patients: TIL>=1%
- For cohort 3B: N0 status, TNBC and TIL >=1%
- For cohort 4B: N0 status, TNBC and TIL >=30-49%
- For cohort 5B: N0 status, TNBC and TIL >=50%
• Age >=18
• WHO performance status <=1
Exclusion criteria
• evidence or suspicion of metastatic disease. Evaluation of the presence of
distant metastases may include chest X-ray, liver ultrasound, isotope
bone-scan, CT-scan of chest and abdomen and/or FDG-PET scan, according to local
procedures;
• other prior invasive malignancy 1) in the breast or 2) localized in the near
proximity of the breast, that was treated with radiotherapy at the
localization of the new breast tumor;
• Concurrent ipsilateral or contralateral disease of the primary or a secondary
tumor is allowed, as long as the other lesions is not a distant metastasis.
• Locoregional recurrences are not allowed. Second primary tumors are allowed
in the study;
• occult breast cancer;
• previous anti-cancer hormone therapy or chemotherapy;
• prior treatment with checkpoint inhibitors (including anti- PD1, -PD-L1,
-CTLA-4 - LAG3);
• concurrent anti-cancer treatment, neoadjuvant therapy or another
investigational drug;
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| EU-CTR | CTIS2024-515080-54-00 |
| EudraCT | EUCTR2018-004188-30-NL |
| ClinicalTrials.gov | NCT03815890 |
| CCMO | NL67890.031.18 |