Immune Induction Strategies to Improve Response to Immune Checkpoint Blockade in Triple Negative Breast Cancer (TNBC) Patients

Study Overview
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Brief Summary
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This is a single center non-blinded randomized multi-cohort non-comparative phase II trial with a Simon's two-stage design.

Detailed Description
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In the first stage, 13 evaluable patients will be accrued per cohort. Evaluable is defined as: at least one administration of nivolumab and availability of paired biopsies for immunohistochemistry (for induction treatment cohorts pre-induction and pre-nivolumab biopsies). If there are 1 or no responses observed in these 13 patients, the cohort will be stopped. Otherwise, 21 additional patients will be accrued for a total of 34.

Official Title
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Immune Induction Strategies to Improve Response to Immune Checkpoint Blockade in Triple Negative Breast Cancer (TNBC) Patients: the TONIC-2 Trial

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Cisplatin
* Drug: Low dose doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic or incurable locally advanced triple negative breast cancer (ER < 10%, HER2 IHC 0,1+ or 2+ with no amplification) Metastatic lesion accessible for histological biopsy 18 years or older Maximum of three lines of chemotherapy for metastatic disease and with evidence of progression of disease. Treatment with low-dose doxorubicin in the palliative setting is not allowed. WHO performance status of 0 or 1 Measurable or evaluable disease according to RECIST 1.1 Disease Free Interval (defined as time between first diagnosis or locoregional recurrence and first metastasis) longer than 1 year Subjects with brain metastases are eligible if these are not symptomatic and free of progression of at least 4 weeks A maximum dosage of 360 mg/m2 of anthracyclines and no previous anthracycline-related cardiac toxicity. In case of radiation in the cardiac area, hypertension, diabetes mellitus or hypercholesterolemia, the left ventricular ejection fraction must be 50% or higher. Adequate bone marrow, kidney and liver function Exclusion Criteria: uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris known history of leptomeningeal disease localization history of having received other anticancer therapies within 2 weeks of start of the study drug history of immunodeficiency, autoimmune disease, conditions requiring immunosuppression (>10 mgl daily prednisone equivalents) or chronic infections. prior treatment with immune checkpoint inhibitors. active other cancer history of uncontrolled serious medical or psychiatric illness current pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients are randomized between experimental cohorts and a control cohort.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Control group<br>no induction treatment, nivolumab 240 mg flat-dose, every 2 weeks | Drug: Nivolumab<br>* 240 mg flat-dose, every 2 weeks. From 20 weeks onwards, nivolumab will be administered every 4 weeks with a flat-dose of 480 mg starting from week 20 onwards<br>|
| Experimental: Cisplatin induction<br>Cisplatin 40mg/m2, weekly for two weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks | Drug: Nivolumab<br>* 240 mg flat-dose, every 2 weeks. From 20 weeks onwards, nivolumab will be administered every 4 weeks with a flat-dose of 480 mg starting from week 20 onwards<br>Drug: Cisplatin<br>* 40mg/m2, weekly for two weeks<br>|
| Experimental: Low dose doxorubicin induction<br>Low dose doxorubicin 15mg flat dose, weekly for 8 weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks | Drug: Nivolumab<br>* 240 mg flat-dose, every 2 weeks. From 20 weeks onwards, nivolumab will be administered every 4 weeks with a flat-dose of 480 mg starting from week 20 onwards<br>Drug: Low dose doxorubicin<br>* 15mg flat dose, weekly for 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Time from randomization to date of first tumor progression | assessed monthly until progression or date of death; median 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | complete response or partial response according to iRECIST and RECIST1.1 | assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months | 
| Clinical benefit rate | Beneficial response (complete response, partial response or stable disease) according to RECIST 1.1 and iRECIST | assessed at week 6, 12 and 20 and every 8 weeks thereafter; assessed up to 120 months | 
| Overall survival | time from nivolumab initiation to death from any cause | assessed monthly until date of death; median 12 months | 
| Toxicity of all study regimens | adverse events will be graded according to NCI Common Toxicity Criteria v 5.0 | assessed until 100 days after of treatment end | 
| Progression Free Survival after 6 cycles | the number of patients free of progression after 6 cycles of nivolumab | time from nivolumab initiation to tumor progression or death from any cause; assessed up to 120 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Triple negative, Metastatic disease