Background: Long-term follow-up of neoadjuvant studies demonstrates poor clinical outcomes in patients with TNBC who do not achieve pathologic complete response, with only 35% remaining free of recurrence at 10 years. The addition of adjuvant capecitabine in the CREATE-X study prolonged disease free survival and overall survival (OS) in patients with HER2 negative breast cancer with residual invasive disease, with more striking benefit in patients with TNBC. Checkpoint inhibitors have not been approved in breast cancer yet, but recent studies suggest a benefit in combination with chemotherapy and low burden of disease. In the current study, we will evaluate the role of chemoimmunotherapy in the adjuvant setting for patients with TNBC with residual disease after neoadjuvant therapy. We will also investigate the role of the peripheral immunoscore (PIS) in predicting the benefit of immune checkpoint inhibition with or without chemotherapy.

Trial design: OXEL is a pilot open-label three arm randomized study of nivolumab, capecitabine or the combination as adjuvant therapy for 45 patients with residual TNBC after adequate neoadjuvant chemotherapy. Patients enrolled will be randomly assigned to 1 of 3 treatment arms: nivolumab 360 mg iv q3weeks for x 6 cycles; capecitabine 1250mg/m2 po bid D1-D14 q3 weeks x 6 cycles; nivolumab 360mg iv q3weeks + capecitabine 1250mg/m2 po bid D1-D14 q3 weeks x 6 cycles.

Main eligibility criteria: Patients ≥18 years of age with TNBC and ≥1cm of residual disease in the breast and/or node positive disease; receipt of neoadjuvant taxane +/- anthracycline, or platinum, and having completed definitive resection of primary tumor, with no prior use of capecitabine, fluorouracil or immunotherapy, and with no active autoimmune disease or chronic use of systemic steroids.

Specific aims: The primary endpoint is assessing the immunologic effects of capecitabine, nivolumab or the combination in the adjuvant setting by PIS. Additional endpoints include toxicity assessment, distant recurrence free survival (DRFS) and OS at 3-years, association between changes in PIS and circulating tumor DNA at different timepoints with clinical outcome variables and characterization of the immune contexture in residual tumors.

Statistical methods: The study is designed to assess the change in PIS at 6 weeks from baseline in each arm. The sample size of 15 per arm (45 total for 3 arms) will provide preliminary results. A sample size of 15 per arm will have 85% power to detect an effect size of 1 (the difference of the change in PIS from baseline to week 6 between two arms divided by the standard deviation) at 5% significance level.

Present accrual and target accrual: The Institutional Review Board at Georgetown University Medical Center has approved the study. Clinicaltrials.gov NCT03487666. Enrollment of the first patient is expected in July 2018 with a total of 45 patients planned to be recruited. Recruitment sites are MedStar Georgetown University Hospital, MedStar Washington Hospital Center, Hackensack University Medical Center. This trial is supported by Bristol-Meyers Squibb, P30CA051008-25 from NCI, Inivata and the Nina Hyde Center for Breast Cancer Research.

Citation Format: Khoury K, Isaacs C, Gatti-Mays ME, Donahue RN, Schlom J, Wang H, Gallagher C, Graham D, Warren R, Dilawari A, Swain SM, Pohlmann PR, Lynce F. Nivolumab or capecitabine or combination therapy as adjuvant therapy for triple negative breast cancer (TNBC) with residual disease following neoadjuvant chemotherapy: The OXEL study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-04-01.