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

Phase 2

Recruiting

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

Detailed Description: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Low dose doxorubicin induction	Low dose doxorubicin	Low dose doxorubicin 15mg flat dose, weekly for 8 weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks
Control group	Nivolumab	no induction treatment, nivolumab 240 mg flat-dose, every 2 weeks
Cisplatin induction	Nivolumab	Cisplatin 40mg/m2, weekly for two weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks
Cisplatin induction	Cisplatin	Cisplatin 40mg/m2, weekly for two weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks
Low dose doxorubicin induction	Nivolumab	Low dose doxorubicin 15mg flat dose, weekly for 8 weeks, after 2 weeks followed by nivolumab 240 mg flat-dose, every 2 weeks

Primary Outcome Measures

Name	Time	Method
Progression free survival	assessed monthly until progression or date of death; median 12 months	Time from randomization to date of first tumor progression

Secondary Outcome Measures

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