Leflunomide in Previously Treated Metastatic Triple Negative Cancers

Inclusion Criteria:

* Women with histologically confirmed HER2-negative metastatic and/or locally advanced, inoperable breast cancer on a prior biopsy performed as a component of standard of care. The biopsy site may include the primary tumor, regional lymph node, or metastatic site if accessible to biopsy.
* Age ≥ 18.
* Prior treatment for metastatic breast cancer:
* ≤ 3 prior chemotherapies for metastatic disease and up to 2 prior antibody drug conjugate regimens (eg, sacitizumab govitecan, trastuzumab deruxtecan). Patients with ER-positive breast cancer (ER\>10%) must have had progressive disease after at least 1 prior line of CKD4/6 inhibitor, and also a PIK3CA inhibitor if known to have a somatic PIK3CA activating mutation (by tumor or ctDNA assay) sensitive to the PIK3CA inhibitor alpelisib.
* Prior immunotherapy is permitted and does not count as chemotherapy.
* The use denosumab or zoledronic is permitted.
* History of previously treated brain metastases with ≥ 4 weeks after definitive surgery and gamma knife/whole brain radiation and not taking steroids.
* ≥ 4 weeks from last oral or IV chemotherapy, small molecule inhibitor, a biologic agent, surgery or radiation.
* Performance status 0-2.
* Adequate organ and marrow function as defined below:

  * leukocytes ≥ 3,000/mcL
  * Absolute neutrophil count ≥ 1,000/mcL
  * platelets ≥ 100,000/mcl
  * total bilirubin within institutional upper limit of normal. (≤ ULN)
  * AST (SGOT)/ALT (SPGT) ≤ 3 x ULN (3xULN if liver mets)
  * Creatinine ≤ ULN
  * A negative serum or urine pregnancy test within 3 days of receiving Day 1 Cycle 1 of leflunomide.
* Women of child-bearing potential and men must agree to use adequate contraception before study entry, for the duration of study participation and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
* Recommended methods of birth control are: The consistent use of an approved hormonal contraception such as an intrauterine device (IUD), Double barrier methods (Diaphragm with spermicidal gel or condoms with contraceptive foam), Sexual abstinence (no sexual intercourse) or Sterilization. The use of hormonal forms of birth control is controversial in TNBC and as such women enrolled in the trial are permitted to use birth control pills or depot Provera, only after a documented discussion by the treating physician as too the uncertain risks of hormonal birth control methods in the TNBC population. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 months).
* Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

* Patients who have had chemotherapy or radiotherapy within ≥ 2 weeks before entering the study or those who have not recovered from adverse events due to agents administered more than ≥ 4 weeks earlier.
* Patients may not be receiving any other investigational agents.
* The known history human immunodeficiency virus, acute and chronic Hepatitis B or C, or acute or previously treated tuberculosis.
* Patients with untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to leflunomide or teriflunomide.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Patients must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.