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Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- Participants must have a histologically confirmed diagnosis of metastatic papillary
renal cell carcinoma (PRCC), either type 1 or type 2. (NOTE: A designation of type 1
or type 2 should be made by the local pathologist if possible but is not required).
Mixed histologies which contain type 1 or type 2 along with any other RCC
histology/histologies will be allowed provided that they contain a papillary
component

- Participants must have measurable disease per RECIST 1.1 criteria. All measurable
lesions must be assessed by CT or MRI within 28 days prior to registration. All
non-measurable lesions must be assessed by CT or MRI, or nuclear medicine bone scan
within 42 days prior to registration. The CT from a combined positron emission
tomography (PET)/CT may be used to document only non-measurable disease unless it is
of diagnostic quality. If there is clinical suspicion for bone metastases at the
time of enrollment (at the discretion of the investigator), bone scan must be
performed at baseline (within 42 days prior to registration)

- Participants with new or progressive brain metastases (active brain metastases) must
not require immediate central nervous system (CNS) specific treatment at the time of
study registration or anticipated during the first cycle of therapy. Patients with
leptomeningeal disease are excluded from enrolling

- Participants with measurable disease, per RECIST version (v)1.1, must be present
outside the CNS

- Participants must have no history of intracranial hemorrhage or spinal cord
hemorrhage

- Participants must not have undergone stereotactic radiotherapy within 7 days prior
to initiation of study treatment, whole-brain radiotherapy within 14 days prior to
initiation of study treatment, or neurosurgical resection within 28 days prior to
initiation of study treatment

- Participants must not have ongoing requirements for corticosteroids as therapy for
CNS disease

- Participants, if needed, must receive a stable dose of anti-convulsant therapy

- Participants must not have cavitating pulmonary lesions

- Participants must not have uncontrolled pleural effusions, pericardial effusions, or
ascites requiring recurrent drainage procedures (once monthly or more frequently).
Participants with indwelling catheters (e.g., PleurX [registered trademark]) are
allowed

- Participants must not have tumor invading the gastrointestinal (GI) tract or
evidence of endotracheal or endobronchial tumor within 28 days prior to registration

- Participants must not have evidence of tumor invading or encasing any major blood
vessels

- Participants must not have had major surgery within 28 days prior to registration,
and participants must have recovered from any adverse effects of surgery

- Participants must not have had prior treatment with cabozantinib for any reason

- Participants must not have had prior treatment or adjuvant therapy with PD-1/PD-L1
checkpoint inhibitors for any reason within the past 6 months

- Participants must not have received more than one prior systemic therapy for
advanced or metastatic renal cell carcinoma with the exception of another VEGF
inhibitor Food and Drug Administration (FDA)-approved for advanced RCC (i.e.,
pazopanib, bevacizumab, sorafenib or axitinib). If a participant develops metastatic
disease within six months of discontinuation of adjuvant therapy, this will
constitute one prior systemic therapy for advanced or metastatic RCC. If a patient
develops metastatic disease and more than six months has elapsed since
discontinuation of adjuvant therapy, this will not constitute prior systemic therapy
for advanced or metastatic RCC

- Participants must not take within 14 days prior to registration, nor plan to take
while on protocol treatment, any strong CYP3A4 inhibitors (e.g. boceprevir,
cobicistat, danoprevir, elvitegravir/RIT, fluvoxamine, indinavir, itraconazole,
ketoconazole, lopinavir/RIT, nefazodone, nelfinavir, posaconazole, ritonavir,
telaprevir, telithromycin, tipranavir/RIT, or voriconazole,); Please refer to
https://drug-interactions.medicine.iu.edu/MainTable.aspx for the updated CYP3A4
inhibitors or inducers

- Participants must not take within 14 days prior to registration, nor plan to take
while on protocol treatment, any strong CYP3A4 inducers (e.g. avasimibe, phenytoin,
rifampin, rifabutin); Please refer to
https://drug-interactions.medicine.iu.edu/MainTable.aspx for the updated CYP3A4
inhibitors or inducers

- Participants must complete all prior radiation therapy at least 14 days prior to
registration. Participants must have recovered to =< grade 1 from all associated
toxicities at the time of registration unless the toxicity is determined to be not
clinically significant by the registering investigator

- Participants must not be receiving or planning to receive any other investigational
agents at time of registration

- Participants must not have been diagnosed with a clinically significant autoimmune
disease, exceptions such as diabetes, eczema, and vitiligo are allowed. Other
non-clinically significant autoimmune diseases are allowed if approved by the
registering investigator

- Participants must not be on steroid doses > 10 mg prednisone equivalent. Replacement
steroid doses for adrenal insufficiency will be allowed. Also, short duration
steroid therapy to prevent allergic reactions are acceptable (e.g. prior to CT
imaging)

- Participants must be >= 18 years of age

- Participants must have a complete physical examination and medical history within 28
days prior to registration

- Participants must have a Zubrod performance status of 0-2

- White blood count (WBC) >= 2 x 10^3/uL (within 28 days prior to registration)

- Absolute neutrophil count (ANC) >= 1.5 x 10^3/uL (within 28 days prior to
registration)

- Platelet count >= 100 x 10^3/uL (within 28 days prior to registration)

- Lymphocyte count >= 0.5 x 10^3/uL (within 28 days prior to registration)

- Hemoglobin (>= 9 g/dL) (within 28 days prior to registration). Participants may be
transfused to meet this criterion

- Total serum bilirubin =< 1.5 x the institutional upper limit of normal (ULN) unless
history of Gilbert's disease (within 28 days prior to registration). Participants
with history of Gilbert's disease must have total bilirubin =< 5 x institutional ULN

- Aspartate aminotransferase (AST) must be =< 3 x the institutional ULN unless the
liver is involved with the tumor, in which case serum transaminase (SGOT) must be =<
5 x the institutional ULN (within 28 days prior to registration)

- Alanine aminotransferase (ALT), must be =< 3 x the institutional ULN unless the
liver is involved with the tumor, in which case serum transaminase (SGPT) must be =<
5 x the institutional ULN (within 28 days prior to registration)

- Participants must have serum creatinine =< 2 x the institutional ULN OR creatinine
clearance (either measured or calculated) > 30 mL/min and obtained within 28 days
prior to registration

- Participants must not have any clinical evidence of congestive heart failure (CHF)
(specifically, New York Heart Association [NYHA] class III [moderate] or class IV
[severe]) at the time of registration

- Participants must not have known history of congenital long QT syndrome and must not
have experienced unstable angina pectoris, clinically significant cardiac
arrhythmias, or stroke (transient ischemic attack [TIA] or other ischemic event)
within 90 days prior to registration

- Participants must not have experienced myocardial infarction or thromboembolic event
requiring anticoagulation within 90 days of registration, unless clinically stable
with ongoing medical management

- Participants must have urine protein < 3+ within 28 days prior to registration. If
urine protein is 3+ or greater, then urine protein by 24-hour collection must show
less than 3 grams of protein

- Participants must have documented blood pressure of systolic blood pressure (SBP) <
150 mm Hg or diastolic blood pressure (DBP) < 100 mm Hg within 14 days prior to
registration

- Participants with known human immunodeficiency virus (HIV) must be on effective
anti-retroviral therapy at registration and have undetectable viral load within 6
months of registration

- Participants with evidence of chronic hepatitis B virus (HBV) infection must have
undetectable HBV viral load while on suppressive therapy within 6 months prior to
registration, if indicated

- Participants with a history of hepatitis C virus (HCV) infection must have been
treated and cured. Participants currently being treated for HCV infection must have
undetectable HCV viral load within 6 months prior to registration

- Participants must be able to take oral medications (i.e., swallow pills whole).
Participants must not have gastrointestinal tract disease resulting in an inability
to take oral medication or a requirement for IV alimentation, prior surgical
procedures that could in the opinion of the treating investigator affect absorption,
or active peptic ulcer disease. Participants with intractable nausea or vomiting are
not eligible

- Participants must not have had any clinically-significant GI bleeding within 3
months prior to registration and participants must not have a GI disorder which (at
the discretion of the investigator) bears a high risk of perforation or fistula
(e.g. Crohn's disease)

- Participants must not have had hemoptysis of >= (2.5 mL) of red blood, and do not
demonstrate any other signs indicative of pulmonary hemorrhage within 3 months prior
registration

- Participants with a prior or concurrent malignancy whose natural history or
treatment does not have the potential to interfere with the safety or efficacy
assessment of the investigational regimen are eligible for this trial

- Participants must not be pregnant or nursing, due to VEGF therapy being toxic to
embryogenesis. Individuals who are of reproductive potential must have agreed to use
an effective contraceptive method with details provided as a part of the consent
process. A person who has had menses at any time in the preceding 12 consecutive
months or who has semen likely to contain sperm is considered to be of "reproductive
potential." In addition to routine contraceptive methods, "effective contraception"
also includes refraining from sexual activity that might result in pregnancy and
surgery intended to prevent pregnancy (or with a side-effect of pregnancy
prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal
ligation/occlusion, and vasectomy with testing showing no sperm in the semen

- Participants must not be on warfarin, at therapeutic doses. Low dose aspirin for
cardio-protection (per local applicable guidelines) and low molecular weight heparin
(LMWH) are allowed

- Participants must be offered the opportunity to participate in specimen banking.
With participant consent, specimens must be collected and submitted via the
Southwest Oncology Group (SWOG) Specimen Tracking System

- Participants must be informed of the investigational nature of this study and must
sign and give informed consent in accordance with institutional and federal
guidelines

- NOTE: For participants with impaired decision-making capabilities, legally
authorized representatives may sign and give informed consent on behalf of
study participants in accordance with applicable federal, local, and Central
Institutional Review Board (CIRB) regulations

- As a part of the OPEN registration process for OPEN access instructions) the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has
been entered in the system