Nivolumab Plus Ipilimumab in Patients With Renal Medullary Carcinoma

Study Drug Administration:

During the combination phase of this study, each study cycle is 21 days (3 weeks). During the
maintenance phase of this study, each study cycle is 28 days (4 weeks).

If you are found to be eligible to take part in this study, during the combination phase, you
will receive nivolumab by vein over about 60 minutes and ipilimumab by vein over about 90
minutes on Day 1 of Cycles 1-4. After that,the maintenance phase begins. During the
maintenance phase, you will receive nivolumab alone by vein over about 60 minutes on Day 1 of
each cycle.

Length of Study Participation:

You may receive the study drugs in combination for up to 4 cycles. After that, you may
receive nivolumab alone for up to 2 years or until the disease gets worse, whichever comes
first. You will no longer be able to take the study drugs if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

Treatment Beyond Progression (Worsening):

If the disease appears to be getting worse or the tumors appear to be getting larger, you may
still be able to receive nivolumab alone or in combination with ipilimumab if you and your
doctor decide it is in your best interest. This is because sometimes the disease appears to
get worse but the study drug(s) are actually working.

However, there are risks of continuing to receive the study drug(s). For example, the disease
may actually be getting worse and may reach the point that you are no longer able to receive
other treatments. You are still at risk for side effects due to the study drug(s). This could
also delay starting other treatments.

If you choose to receive the study drug(s) after the disease appears to get worse, you will
continue to have study visits as described above. The study doctor will discuss this option
with you.

Study Visits:

On Day 1 of all cycles:

- You will have a physical exam.

- Blood (about 5 teaspoons) will be drawn for routine testing.

- Your blood oxygen level will be tested by a clip on your finger.

At Weeks 6, 12, and then every 8 weeks after that (Weeks 20, 28, 36 and so on):

- You will have an MRI and/or CT scan. If needed, you may also have bones/skeletal survey
or bone scan. A bone/skeletal survey is a series of X-rays.

- Blood (about 1 teaspoon) and urine will be drawn for routine testing.

End-of-Treatment Visit:

About 30 days and 90 days after your last dose of study drug(s):

- You will have a physical exam.

- Your blood oxygen level will be tested by a clip on your finger.

- If you stopped taking the study drugs because of a side effect and depending on when
your last scan was, you will have an MRI and/or CT scan. If needed, you may also have an
x-ray or bone scan.

Long-Term Follow-Up:

You will be called by a member of the study staff every 3 months to ask how you are doing and
if you have started any new anti-cancer treatments. This information may be collected from
your medical record instead. If called, this phone call should take about 5-10 minutes.

Inclusion Criteria:

1. Patients must give written informed consent prior to initiation of therapy, in keeping
with the policies of the institution. Patients with a history of major psychiatric
illness must be judged able to fully understand the investigational nature of the
study and the risks associated with the therapy.

2. Patients with locally advanced or metastatic RMC histologically confirmed by expert
pathology review and loss of SMARCB1 staining by immunohistochemistry. Patients with
advanced or metastatic unclassified renal cell carcinoma with medullary phenotype (a
rare SMARCB1 negative RMC variant occurring in individuals without sickle
hemoglobinopathies) are also eligible. The Principal Investigator (PI) is the final
arbiter in questions related to eligibility.

3. Patients will be eligible regardless of whether they have had prior nephrectomy or
still have their primary tumor in-situ.

4. Patients must have at least one measurable site of disease, defined as a lesion that
can be accurately measured in at least one dimension (longest diameter to be recorded)
and measures >/= 15 mm with conventional techniques or >/= 10 mm with more sensitive
techniques such as magnetic resonance imaging (MRI) or spiral computerized tomography
(CT) scan. If the patient has had previous radiation to the marker lesion(s), there
must be evidence of progression since the radiation.

5. Patients should be willing to provide a newly obtained fresh core biopsy of a tumor
lesion. Not required if there is a recently obtained fresh specimen on an IRB approved
correlated trial up to 6 weeks (42 days) prior to initiation of treatment on Day 1.

6. Patients can be either naïve for any previous systemic treatment or have had any
number of prior systemic therapies. However, patients must not have received prior
anticancer therapy with anti-PD1, anti-PD-L1, or anti-CTLA-4 immune checkpoint
inhibitors.

7. There must be evidence of progression on or after last treatment regimen received.
NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair,
subject is considered to be ambulatory for the purpose of assessing their performance
status.

8. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

9. Consent to MD Anderson companion laboratory protocol 2014-0938.

10. Age (at the time of consent): >/= 18 years

11. Within 14 days of the first dose of the study drugs, patients must have adequate organ
and marrow function prior to study entry as defined below: 1) Hemoglobin >/=9 g/dl
(treatment allowed); 2) Absolute neutrophil count >/= 1000/mcL; 3) Platelets
>/=75,000/μL; 4) Total Bilirubin institutional ULN, except in known hepatic metastasis, wherein may be Serum Creatinine dialysis); May receive transfusion; Without growth factor support (filgrastim or
pegfilgrastim) for at least 14 days; If creatinine is not <1.5×ULN, then calculate by
Cockcroft-Gault methods or local institutional standard and CrCl must be >30
mL/kg/1.73 m²

12. INR and PTT warfarin is allowed if target INR dose of low molecular weight (LMW) heparin for > 2 weeks (14 days) at the time of
enrollment.

13. Patients with controlled brain metastases are allowed on protocol if they had solitary
brain metastases that was surgically resected or treated with radiosurgery or Gamma
knife, without recurrence or edema for 1 month (4 weeks).

14. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to
the start of the study drug.

15. Women must not be breastfeeding.

16. WOCBP must agree to follow instructions for method(s) of contraception from the time
of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of
study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post
treatment completion.

17. Men who are sexually active with WOCBP must agree to follow instructions for method(s)
of contraception for the duration of treatment with study drug (s) plus 5 half-lives
of study drug (s) plus 90 days duration of sperm turnover) for a total of 5 months
post-treatment completion.

18. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
from contraceptive requirements. However WOCBP must still undergo pregnancy testing as
described in these sections.

Exclusion Criteria:

1. Patients must not have any other malignancies within the past 2 years except for in
situ carcinoma of any site, or adequately treated (without recurrence post-resection
or post-radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of
the skin.

2. Patients currently receiving anticancer therapies or who have received anticancer
therapies (including chemotherapy and targeted therapy) within 2 weeks (14 days) prior
to study Day are excluded. Patients who have completed palliative radiation therapy
more than 14 days prior to the first dose of the combination ipilimumab plus nivolumab
are eligible.

3. Patients, who have had a major surgery or significant traumatic injury (injury
requiring > 4 weeks (28 days) to heal) within 4 weeks (28 days) of start of study
drug, patients who have not recovered from the side effects of any major surgery
(defined as requiring general anesthesia) or patients that are expected to require
major surgery, other than cytoreductive nephrectomy +/- retroperitoneal lymph node
dissection, during the course of the study.

4. Patients who have organ allografts.

5. Known or suspected autoimmune disease. Patients with a history of inflammatory bowel
disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders
such as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic
Lupus Erythematosus or autoimmune vasculitis [e.g., Wegener's Granulomatosis] are
excluded from this study. Patients with a history of Hashimoto's thyroiditis only
requiring hormone replacement, Type I diabetes, or psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external trigger
are allowed to participate.

6. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).

7. Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test or
positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV
antibody test indicating acute or chronic infection. If hepatitis C antibody test is
positive then active infection has to be confirmed by hepatitis C RNA testing for the
patient to be excluded.

8. Any underlying medical condition, which in the opinion of the Investigator, will make
the administration of study drug hazardous or obscure the interpretation of adverse
events, such as a condition associated with frequent diarrhea, uncontrolled nausea or
vomiting

9. Patients must not have received prior anticancer therapy with anti-PD1, anti-PD-L1, or
anti- CTLA-4 immune checkpoint inhibitors.

10. Patients receiving any concomitant systemic therapy for renal cell cancer are
excluded.

11. Patients must not be scheduled to receive another experimental drug while on this
study.

12. Patients who are on high dose steroid (e.g., > 10mg prednisone daily or equivalent) or
other more potent immune suppression medications (e.g., infliximab). Topical, inhaled,
intraarticular, ocular, or intranasal corticosteroids (with minimal systemic
absorption) are allowed. A brief course (<48 hours) of systemic corticosteroids for
prophylaxis (eg, from contrast dye allergy) is permitted. Physiological corticosteroid
replacement therapy for adrenal insufficiency is also permitted.

13. Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as: a) Symptomatic
congestive heart failure of New York heart Association Class III or IV; b) Unstable
angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6
months of start of study drug, serious uncontrolled cardiac arrhythmia or any other
clinically significant cardiac disease; c) Severely impaired lung function as defined
as 02 saturation that is 92% or less at rest on room air; d) Uncontrolled diabetes as
defined by fasting serum glucose >1.5 x ULN; e) Systemic fungal, bacterial, viral, or
other infection that is not controlled (defined as exhibiting ongoing signs/symptoms
related to the infection and without improvement) despite appropriate antibiotics or
other treatment; f) Known active or symptomatic viral hepatitis or chronic liver
disease. Uncontrolled adrenal insufficiency

14. Patients must not have history of other diseases, metabolic dysfunction, physical
examination finding, or clinical laboratory finding giving reasonable suspicion of a
disease or condition that contraindicates the use of ipilimumab or nivolumab or that
might affect the interpretation of the results of the study or render the subject at
high risk from treatment complications.

15. Patients should not receive immunization with attenuated live vaccines within one week
(7 days) of study entry or during study period; Note: Seasonal influenza vaccines for
injection are generally inactivated flu vaccines and are allowed; however intranasal
influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not
allowed.

16. Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases.

17. Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods as defined above. If
barrier contraceptives are being used, these must be continued throughout the trial by
both sexes. Hormonal contraceptives are not acceptable as a sole method of
contraception.

18. Any patients who cannot be compliant with the appointments required in this protocol
must not be enrolled in this study.