OXEL: Immune Checkpoint or Capecitabine or Combination Therapy as Adjuvant Therapy for TNBC With Residual Disease

This pilot study will provide preliminary data regarding the role of PIS in predicting the benefit of immune checkpoint inhibition with or without chemotherapy for high risk patients with TNBC and residual disease after effective neoadjuvant chemotherapy.


Eligibility Criteria:
Inclusion criteria:

1. Biopsy proven TNBC:

   * ER- and PR- defined as ≤5% cells stain positive
   * HER2 negativity defined as:

     * IHC 0, 1+ without in situ hybridization (ISH) HER2/neu chromosome 17 ratio OR
     * IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number \< 6 signals/cells
2. Residual disease of 1.0 cm at least of the primary tumor and/or node positive disease (at least ypN1)
3. Patients must have completed neoadjuvant chemotherapy; patients must NOT have received capecitabine as part of their neoadjuvant therapy regimen. Acceptable preoperative regimens include an anthracycline or a taxane, or both. Participants who received preoperative therapy as part of a clinical trial may enroll. Participants may not have received adjuvant chemotherapy after s urgery prior to randomization. . Carboplatin-containing neoadjuvant chemotherapy is also allowed). Patients who cannot complete all planned neoadjuvant treatment cycles for any reason are considered high risk and therefore are eligible for the study if they have residual disease.
4. Recovery of all toxicities from previous therapies to at least grade 1, except alopecia and ≤ grade 2 neuropathy which are allowed.
5. Must have completed definitive resection of primary tumor and have no evidence of unresected or metastatic disease at the time of study entry

   * Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however patients with positive margins may enroll if the treatment team believes no further surgery is possible and patient has received radiotherapy; patients with margins positive for lobular carcinoma in situ (LCIS) are eligible
   * Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable
   * Sentinel node biopsy post neoadjuvant chemotherapy (i.e. at the time of definitive surgery) is allowed; axillary dissection is encouraged in patients with lymph node involvement, but is not mandatory
6. ECOG PS 0-2
7. Patients must not be planning to receive concomitantly other biologic therapy, hormonal therapy, other chemotherapy, surgery or other anti-cancer therapy except radiation therapy while receiving treatment on this protocol.
8. At the time of registration (randomization), patients must have the following laboratory results (obtained within 28 days prior to registration):

   1. A serum TSH prior to registration to obtain a baseline value.
   2. Patients must have adequate bone marrow function as evidenced by all of the following:

      * ANC ≥ 1,500 microliter (mcL);
      * Platelets ≥ 100,000/mcL;
      * Hemoglobin ≥ 9 g/dL.
   3. Patients must have adequate hepatic function as evidenced by the following:

      * Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (except Gilbert's Syndrome, who must have a total bilirubin \< 3.0 mg/dL), and
      * SGOT (AST) or SGPT (ALT) and alkaline phosphatase ≤ 2.5 x IULN.
   4. Patients must have adequate renal function as evidenced by ONE of the following:

      * Serum creatinine ≤ IULN OR
      * Measured or calculated creatinine clearance ≥ 60 mL/min.
   5. Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to registration and within 24h prior to the start of nivolumab. In addition, women of childbearing potential must agree to have a pregnancy test every 4 weeks while on nivolumab.
9. Signed ICF
10. Age ≥18

Exclusion criteria:

1. Stage IV disease
2. Receipt of adjuvant chemotherapy
3. Diagnosis of other invasive cancer except for adequately treated cervix cancer or skin cancer, or more than 5 years since other diagnosis of invasive cancer without current evidence of disease
4. Previous exposure to capecitabine, fluorouracil or immunotherapy with anti-PD1, anti-PDL1, anti-CTLA4 or similar drugs.
5. Active autoimmune disease that has required systemic treatment in the past 2 years; replacement therapy is not considered a form of systemic therapy
6. TB, active hepatitis B, active hepatitis C or other active infection. Patients who have completed curative therapy for HCV are eligible. Patients with known HIV infection are eligible if they meet each of the following 3 criteria: CD4 counts ≥ 350 mm3; serum HIV viral load of \< 25,000 IU/ml and treated on a stable antiretroviral regimen.
7. History of (non-infectious) pneumonitis that required steroids or evidence of active pneumonia
8. Uncontrolled disease
9. Chronic use of systemic steroids
10. Live vaccine within 30 days prior to registration.
11. Incapacity to provide consent or to follow clinical trial procedures
12. Pregnancy, lactation, or planning to be pregnant

Patients with microsatellite unstable tumors will not be excluded as immunotherapy as adjuvant therapy is not standard for these patients but we will prospective collect this data.