A Phase II Study of Nivolumab in Combination With Cabozantinib for Metastatic Triple-negative Breast Cancer

Inclusion Criteria: * Participants must have histologically or cytologically confirmed invasive breast cancer, with metastatic disease. Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation. * Estrogen-receptor and progesterone-receptor expression both \<10% by immunohistochemistry (IHC) and human epidermal growth factor receptor 2 (HER2) negative by IHC or non-amplified as determined by the current American Society of Clinical Oncology (ASCO)/CAP (College of American Pathologists) criteria. If patient has more than one histological result, the most recent one has to be considered for inclusion. * Participants must have measurable disease by RECIST version 1.1 * Participants must agree to undergo a research biopsy, if tumor is safely accessible, at baseline and 7-14 days prior to Cycle 3 Day 1. Participants for whom newly-obtained samples cannot be provided (e.g. inaccessible or participant safety concern) may submit an archived specimen. Note: After the first 6 participants undergo biopsy on cabozantinib, we will review their adverse event profiles to ensure no more than a 20% rate of grade 3 or higher bleeding or wound healing complications occur. If more than 2 patients (\>20%) have safety concerns, we will reassess the safety of collecting the research biopsies. Full review of all grade (including grade 1 and 2) may also prompt changes and will be reviewed by the study team. Exelixis may be consulted if necessary. * Prior chemotherapy: Participants may have received 0-3 prior chemotherapeutic regimens for metastatic breast cancer and must have been off treatment with chemotherapy for at least 14 days prior to registration. Participants should also be adequately recovered from acute toxicities of prior treatment. * Prior biologic therapy: Patients must have discontinued all biologic therapy at least 14 days prior to registration. * Prior radiation therapy: Patients may have received prior radiation therapy in either the metastatic or early-stage setting. Radiation therapy must be completed per the following timelines: * Radiotherapy to the thoracic cavity or abdomen within 4 weeks prior to registration. * Radiotherapy to bone lesions within 2 weeks prior to registration. * Radiotherapy to any other site within 4 weeks prior to registration. * In all cases, there must be complete recovery and no ongoing complications from prior radiotherapy. * The subject is ≥18 years old. * ECOG (Eastern Cooperative Oncology Group) performance status ≤1(Karnofsky ≥60%, see Appendix A) * Participants must have normal organ and marrow function as defined below: * absolute neutrophil count ≥1,000/microliter (mcL) * platelets ≥100,000/mcL * hemoglobin ≥ 9 g/dl * total bilirubin ≤1.5 × institutional upper limit of normal (ULN) (or 2.0 x ULN in patients with documented Gilbert's Syndrome) * Aspartate aminotransferase (AST) / Alanine transaminase (ALT) ≤2.5 × institutional ULN or ≤ 3 × institutional ULN for participants with documented liver metastases * creatinine \<1.5 ×institutional ULN OR creatinine clearance ≥40 mL/min (using Cockcroft-Gault formula) for participants with creatinine levels above institutional ULN. * Urine protein/creatinine ratio (UPCR) ≤1 * Female subjects of childbearing potential must have a negative pregnancy test at screening * Childbearing potential is defined as: participants who have not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause) and has not undergone surgical sterilization (removal of ovaries and/or uterus). * Female and male participants of childbearing potential must agree to use an adequate method of contraception. Contraception is required starting with the first dose of study medication through 150 days (5 months) after the last dose of study medication . Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, established and proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. * Participants on bisphosphonates may continue receiving bisphosphonate therapy during study treatment. * The participant is capable of understanding and complying with the protocol and has signed the informed consent document Exclusion Criteria: * Major surgery within 12 weeks before the first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment. Minor surgery (including uncomplicated tooth extractions) within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment. No clinically relevant ongoing complications from prior surgery are not eligible. * The participant has tumor in contact with, invading, or encasing major blood vessels or radiographic evidence of significant cavitary pulmonary lesions. * The subject has pathologic evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib; * Concurrent administration of other anti-cancer therapy within 14 days of starting protocol therapy and during the course of this study. * The participant has received another investigational agent within 14 days of the first dose of study drug. * The participant has received a prior c-Met inhibitor * Has received prior therapy with an anti-programmed cell death-1 (PD-1), anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including pembrolizumab, ipilimumab, and any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) * Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Participants with a history of treated central nervous system (CNS) metastases are eligible. Treated brain metastases are defined as those having no evidence of progression for ≥ 1 month after treatment, and no ongoing requirement for corticosteroids, as ascertained by clinical examination and brain imaging (magnetic resonance imaging or CT scan) completed during screening. Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥2 weeks prior to registration. Treatment for brain metastases may include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician. Participants with CNS metastases treated by neurosurgical resection or brain biopsy performed within 2 months before day 1 will be excluded. * The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders including: * Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening; * Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) \> 150 mm Hg systolic or \> 100 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment; * Any history of congenital long QT syndrome; * Any of the following within 6 months before the first dose of study treatment: * unstable angina pectoris; * clinically-significant cardiac arrhythmias; * stroke (including transient ischemic attack (TIA), or other ischemic event); * myocardial infarction; * GI disorders particularly those associated with a high risk of perforation or fistula formation including: * Tumors invading the GI tract, active peptic ulcer disease, active inflammatory bowel disease (eg, Crohn's disease), active diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction * Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization, Note: Complete healing of an intra-abdominal abscess must be confirmed prior to randomization * Other clinically significant disorders that would preclude safe study participation; * Corrected Fridericia's QT interval (QTcF) interval \>500 msec Note: Three ECGs must be performed for eligibility determination. If the average of these three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard. * Thromboembolic events requiring therapeutic anticoagulation. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors), platelet inhibitors (eg, clopidogrel) are prohibited. Note: Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low molecular weight heparin (LMWH) are permitted (in subjects who are on a stable dose of LMWH for at least 6 weeks before the first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor). Note: Subjects with a venous filter (eg vena cava filter) are not eligible for this study). * Individuals with a history of different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years or are deemed by the investigator to be at low risk for recurrence of that malignancy. * Participant has an active infection requiring IV antibiotics * Patient has a medical condition that requires chronic systemic steroid therapy or on any other form of immunosuppressive medication. For example, participants with autoimmune disease that requires systemic steroids or immunosuppression agents should be excluded. Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. * The participant is known to be positive for the human immunodeficiency virus (HIV), HepBsAg, or Hepatitis C virus (HCV) RNA. HIV-positive participants on combination antiretroviral therapy are ineligible. * Known hypersensitivity to any of the components of cabozantinib or nivolumab. * The participant has received a live vaccine within 28 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, bacille Calmette-Guerin (BCG), and typhoid vaccine. The use of the inactivated seasonal influenza vaccine (Fluzone®) is allowed. * The subject has experienced any of the following: * Clinically significant gastrointestinal bleeding within 6 months before the first dose of study treatment * Clinically significant hemoptysis within 3 months of the first dose of study treatment * Any other signs indicative of pulmonary hemorrhage within 3 months before the start of study treatment * The participant is unable to swallow oral dosage forms. * The participant is pregnant or breastfeeding