Pembrolizumab and Oral Metronomic Cyclophosphamide in Patients With Chest Wall Breast Cancer

This is a Phase II single center, open-label, non-randomized study in patients with locally recurrent, inoperable, and/or metastatic inflammatory breast cancer with lymphangitic spread to the chest wall. Patients will be treated with pembrolizumab administered as an intravenous infusion at 200 mg in 21-day treatment cycles and oral cyclophosphamide (CTX) 50 mg per day in metronomic administration as a 21 days cycle. Forty-six patients will be required for the study. The study will be open to participants with histologically confirmed, inoperable, locally recurrent and/or metastatic breast cancer (mBC) with lymphangitic spread to the chest wall (chest wall disease), which had received one or more prior cytotoxic treatment. Key exclusion criteria consist of prior anti-PD1, anti-CTLA-4 or other immune pathway-targeted therapy. Patients with autoimmune diseases and/or receiving drugs who interfere with the immune system will not be eligible. Patients will be monitored carefully for the development of adverse experiences and will be monitored for clinical and/or radiographic evidence of disease progression according to usual standards of clinical practice. Adverse experiences will be evaluated according to criteria outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. For individual patients that experience dose-limiting toxicities, criteria for dose modification of pembrolizumab and CTX are outlined in details in the protocol. Treatment with pembrolizumab and metronomic chemotherapy will continue until documented disease progression, unacceptable adverse events (as reported by the site), intercurrent illness that prevents further administration of treatment, Investigator's decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or procedure requirements, completion of 24 months of treatment with pembrolizumab, or administrative reasons requiring the cessation of treatment. Subjects who attain complete response (CR) confirmed by central radiology review may consider stopping trial treatment after receiving at least 24 weeks of treatment. Subjects who discontinue treatment after 24 months of therapy for reasons other than disease progression or intolerability or who discontinue treatment after attaining a CR may be eligible for up to one year of retreatment after they have experienced radiographic disease progression. The decision to retreat will be at the discretion of the Investigator, only if no cancer treatment was administered since the last dose of pembrolizumab, the subject still meets the safety parameters listed in the Inclusion/Exclusion criteria and the trial remains open. Primary Objective: assessment of the efficacy of pembrolizumab and metronomic cyclophosphamide according to immune-related RECIST (irRECIST) criteria in patients with chest wall breast cancer. Primary endpoint will be objective response (confirmed CR or PR as best overall response) based on irRECIST criteria and also based on evaluable disease. Secondary objectives: duration of response (DoR); time to progression (TTP); progression-free survival (PFS); overall survival (OS). Exploratory Objectives: responses according to levels of PD-L1, measured by immunohistochemistry IHC in unresectable locoregional lesion. Responses according to levels of tumor infiltrating lymphocytes. Responses according to ER status. Responses according to FISH ratio and HER2 copy number. Tumor dynamics during the disease course as well as emergence of new clones (i.e.: resistance mechanisms) by determination of circulating tumor DNA (ctDNA). Sequencing of material from tumor biopsies to determine molecular profiles of responders and non-responders. Evaluation of efficacy by immune-related RECIST (irRECIST) (i.e.: irORR, irDoR, irPFS, irDCR). Through analysis of peripheral blood transcriptome in patients treated with pembrolizumab and cyclophosphamide therapy (P and CTX) combination therapy the investigators aim at: 1. Defining baseline peripheral blood gene signatures associated with treatment responsiveness (pre-treatment biomarkers); 2. Defining molecular perturbations associated with the administration P and CTX combination therapy and their relationship with immune-related adverse events (post-treatment predictive biomarkers) and clinical outcome.