Pre-operative Trial for Breast Cancer With Nivolumab in Combination With Novel IO

Study Overview
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Brief Summary
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To determine whether short-term pre-operative nivolumab either as monotherapy or in combination with low dose doxorubicin or novel IO combinations can induce immune activation in early BC.

Detailed Description
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The investigators aim to test the activity of nivolumab monotherapy in primary breast tumors in a pre-operative window of opportunity trial. As the data of the investigators generated in the TONIC trial (metastatic TNBC) indicate that low dose doxorubicin may 'prime' the tumor microenvironment (TME) resulting in higher response rates on nivolumab, in addition, cohorts for treatment with nivolumab plus low dose doxorubicin will be opened. Given the emerging data on other immunomodulatory strategies, this platform study allows opening additional cohorts for promising novel immune-oncology (IO) drugs for which a strong efficacy signal has been seen without drug safety issues. The investigators will study the TME and systemic host factors with specific emphasis on immunosuppressive processes that can potentially be targeted by novel IO agents to further optimize BC immunotherapy.

Official Title
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Pre-operative Phase II Trial for Breast Cancer With Nivolumab in Combination With Novel IO (BELLINI Trial)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Ipilimumab
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent 18 years or older at moment of inclusion; Female gender; WHO performance status 0 or 1; Resectable primary breast cancer stage I-III. Nodal status must be examined by ultrasound, fine needle aspiration, sentinel node biopsy, or FDG-PET scan. The tumors must be: at least 10 mm (minimum cT1c) 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, TN and TIL ≥50% 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; evidence of a concurrent contralateral or ipsilateral second primary infiltrating breast cancer. Evaluation of the presence of a concurrent second primary breast cancer may include mammography, breast ultrasound and/or MRI breast; other malignancy except carcinoma in situ and basal-cell and squamous carcinoma of the skin, unless the other malignancy was treated ≥5 years ago with curative intent without the use of chemotherapy or radiotherapy previous radiation therapy or chemotherapy; prior treatment with checkpoint inhibitors (including anti- PD1, -PD-L1, -CTLA-4); concurrent anti-cancer treatment, neoadjuvant therapy or another investigational drug;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Separate cohorts will be opened in this trial. LumB and TNBC tumors will be divided in separate cohorts.More cohorts, e.g. combining nivolumab and novel IO, can open after the start of this trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1A; LumB<br>Nivolumab | Drug: Nivolumab<br>* 2 courses 240 mg flat dose<br>|
| Experimental: 1B; TNBC<br>Nivolumab | Drug: Nivolumab<br>* 2 courses 240 mg flat dose<br>|
| Experimental: 2A; LUMB<br>Nivolumab and ipilimumab | Drug: Nivolumab<br>* 2 courses 240 mg flat dose<br>Drug: Ipilimumab<br>* single dose ipilimumab (1mg/kg) at day 1<br>|
| Experimental: 2B; TNBC<br>Nivolumab and ipilimumab | Drug: Nivolumab<br>* 2 courses 240 mg flat dose<br>Drug: Ipilimumab<br>* single dose ipilimumab (1mg/kg) at day 1<br>|
| Experimental: 3B; TNBC, High TIL<br>Nivolumab and ipilimumab | Drug: Nivolumab<br>* 2 courses 240 mg flat dose<br>Drug: Ipilimumab<br>* two courses ipilimumab (1mg/kg) at day 1 and 21<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune activation after pre-operative nivolumab | measuring the tumor-associated CD8 and expression of genes induced by IFNy after pre-operative immunotherapy | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events according to NCI Common Toxicity Criteria version 5.0 | Adverse events in all regimens will be graded according to NCI Common Toxicity Criteria version 5.0. | up to 3 weeks after surgery, an average of 6 months | 
| Radiological response rate | The percentage of patients having a complete response, partial response or stable disease per cohort assessed by MRI | At 4 weeks | 
| Pathological response rate | The percentage of patients having a complete response or residual cancer burden per cohort | up to 3 weeks after surgery, an average of 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pre-operative, triple negative and Luminal B, resectable, stage I-III