Nivolumab After Induction Treatment 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 non-comparative phase II trial. The first stage of the trial consists of five arms ( with induction treatment followed by nivolumab, 1 with no induction treatment before nivolumab). For the second stage, the number of arms will be reduced based on the results obtained in the first stage.

Detailed Description
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Triple negative breast cancer (TNBC) patients have a relatively high relapse rate and upon relapse the median overall survival is less than a year. No targeted therapies are currently available for this subgroup. Compared to other breast cancer subtypes, the percentage of tumor-infiltrating lymphocytes (TILs) is significantly higher in TNBC. Given the durable responses induced by the immune checkpoint inhibitor nivolumab in other advanced solid cancers, immunotherapeutic approaches, such as blockade of PD-1 by nivolumab may be the key to treat TNBC. Moreover, since classical anticancer agents can stimulate immune effector cells, the investigators hypothesize that short-term induction treatment with radiation, doxorubicin, cyclophosphamide or cisplatin induces an anticancer immune response resulting in synergistic activity with nivolumab.

Official Title
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Adaptive Phase II Randomized Non-comparative Trial of Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients: TONIC-trial

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Nivolumab
* Radiation: Radiation therapy
* Drug: Low dose doxorubicin
* Drug: Cyclophosphamide
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic triple negative breast cancer with confirmation of Estrogen Receptor (ER) and HER2 negativity on a histological biopsy of a metastatic lesion 18 years or older Metastatic lesion accessible for histological biopsy (Mandatory biopsies: pre-induction treatment, post-induction treatment, 6-weeks. Optional biopsies: 12-weeks, at progression, of irradiated site). The pre-induction treatment biopsy has to contain sufficient tumor content (≥100 tumor cells); subjects with samples that have insufficient tumor content will require re-biopsy prior to induction treatment. Interval between last treatment and pre-induction biopsy has to be at least 14 days One, two or three line(s) of chemotherapy for metastatic disease and with progression of disease on last treatment regimen Evaluable disease according to RECIST 1.1 Metastatic lesion accessible for radiation with 1x20 Gray or 3x8 Gray Subjects with brain metastases are eligible if these are not symptomatic. Subjects who received prior treatment for brain metastases should be free of progression on magnetic resonance imaging (MRI) for at least 4 weeks after treatment is completed and prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. WHO performance status of 0 or 1 Adequate bone marrow function Adequate hepatic function Adequate renal function Signed written informed consent 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 an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody live vaccine within 30 days of planned start of study therapy. active other cancer positive test for hepatitis B surface virus surface antigen (HBsAg) or hepatitis history of uncontrolled serious medical or psychiatric illness any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Radiation therapy<br>Radiotherapy on metastatic lesion | Drug: Nivolumab<br>* nivolumab 3 mg/kg, every 2 weeks after induction treatment<br>Radiation: Radiation therapy<br>* 20 Gy to metastatic lesion<br>|
| Active Comparator: Low dose doxorubicin<br>15mg flat dose, once weekly for 2 weeks | Drug: Nivolumab<br>* nivolumab 3 mg/kg, every 2 weeks after induction treatment<br>Drug: Low dose doxorubicin<br>* 15 mg flat dose, once weekly for 2 weeks<br>|
| Active Comparator: Cyclophosphamide<br>metronomic schedule, 50mg daily orally for 2 weeks | Drug: Nivolumab<br>* nivolumab 3 mg/kg, every 2 weeks after induction treatment<br>Drug: Cyclophosphamide<br>* metronomic schedule, 50 mg daily orally for 2 weeks<br>|
| Active Comparator: Cisplatin<br>40mg/m2, weekly for 2 weeks | Drug: Nivolumab<br>* nivolumab 3 mg/kg, every 2 weeks after induction treatment<br>Drug: Cisplatin<br>* 40 mg/m2, weekly for 2 weeks<br>|
| Active Comparator: No induction treatment<br> | Drug: Nivolumab<br>* nivolumab 3 mg/kg, every 2 weeks after induction treatment<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 todate of first tumor progression | assessed monthly until progression; median 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | complete response or partial response at 12 weeks and 6 months | At 12 weeks and 6 months | 
| Clinical benefit rate | Beneficial response (complete response, partial response or stable disease) at 6 months | At 6 months | 
| Toxicity of all study regimens | adverse events will be graded according to NCI Common Toxicity Criteria v 4.0 | assessed until 100 days after of treatment end | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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triple negative, metastatic