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

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being
studied.

The FDA (the U.S. Food and Drug Administration) has not approved the combination of Nivolumab
and Cabozantinib as a treatment for any disease.

The FDA has not approved Cabozantinib for this specific disease but it has been approved for
other uses. The FDA (the U.S. Food and Drug Administration) has not approved nivolumab for
this specific disease but it has been approved for other uses.

Cabozantinib has been used in some phase I studies and information from those other research
studies suggests that cabozantinib may help to shrink or stabilize breast cancer.

Cancers are recognized by the immune system, and under some circumstances, the immune system
may control or even eliminate tumors. An antibody is a natural protein made by the immune
system that binds other proteins and molecules to fight infection and its ill effects.
Antibodies stimulating the immune system have been developed for treatment of human cancers.
Nivolumab is an experimental antibody drug that may make the immune response more active
against cancer.

In this research study, the investigators are looking at how the participant's type of breast
cancer responds to the combination of cabozantinib and nivolumab.

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 HER2 negative by IHC or non-amplified as determined by
the current ASCO-CAP 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 C3D1. 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 performance status ≤1(Karnofsky ≥60%, see Appendix A)

- Participants must have normal organ and marrow function as defined below:

- absolute neutrophil count ≥1,000/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)

- AST(SGOT)/ALT(SGPT) ≤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 eligibile.

- 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-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,

- Complete healing of an intra-abdominal abscess must be confirmed prior to
randomization

- Other clinically significant disorders that would preclude safe study participation;

- QTcF interval >500 msec

- 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.

- Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose
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).

- 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.

- The participant is known to be positive for the human immunodeficiency virus (HIV),
HepBsAg, or 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, 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

- Hemoptysis of >0.5 teaspoon (2.5 mL) of red blood within 3 months before 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