Nivolumab and Ipilimumab With 5-azacitidine in Patients With Myelodysplastic Syndromes (MDS)

Study Groups

If you are found to be eligible to take part in this study, you will be assigned to 1 of 6
study cohorts, based on when you join this study and on what treatments you have already
received. Participants who have already received treatments called hypomethylating agents
will be in Cohorts 1-3. Participants who have not received treatment will be in Cohorts 4-6:

- If you are in Cohort 1, you will receive nivolumab.

- If you are in Cohort 2, you will receive ipilimumab.

- If you are in Cohort 3, you will receive nivolumab and ipilimumab.

- If you are in Cohort 4, you will receive azacitidine and nivolumab.

- If you are in Cohort 5, you will receive azacitidine and ipilimumab.

- If you are in Cohort 6, you will receive azacitidine, nivolumab, and ipilimumab.

Study Drug Administration:

Study cycles for Cohorts 1-3 will be 3-4 weeks long. Study cycles for Cohorts 4-6 will be 4
weeks long.

If you receive nivolumab, you will receive it by vein over about 1 hour on Days 1 and 15. If
you receive ipilimumab, you will receive it by vein over about 90 minutes on Day 1. If you
receive azacitidine, you will receive it by vein over about 10-40 minutes for 5 days every 4
weeks, then receive the other drug(s) as described above on Days 6 and/or 20 of each cycle.

If you are in Cohorts 1-3 and the doctor thinks it is in your best interest, you may begin to
receive azacitidine after Cycle 6.

Study Visits:

One (1) time each week during Cycle 1, and then one time during every cycle after that:

- You will have a physical exam.

- Blood (about 2-3 teaspoons) will be drawn for routine tests.

These tests may be done more often if your doctor thinks it is needed.

If the doctor thinks it is needed, on Day 21 or 28 of Cycles 1 (depending on to which cohort
you are assigned) and then every 3 months, you will have a bone marrow aspiration to check
the status of the disease and for cytogenetic testing.

If you can become pregnant, you will have a urine or blood (about 1 teaspoon) pregnancy test
every 6 weeks.

Length of Treatment:

You may continue taking the study drug(s) for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drug(s) 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.

Follow-up Visits:

If you can become pregnant, you will have a urine or blood (about 1 teaspoon) pregnancy test
30 and 70 days after you have stopped taking the study drugs.

There are additional laboratory research studies that you may be eligible for that may help
researchers learn more about the disease. You will be given separate consent forms for these
studies that explain their goals and risks.

Inclusion Criteria:

1. Patients with MDS (up to 20% blasts) of any risk as defined as: a. Previously
untreated; b. Previously treated with HMA agent. Patients need to have relapsed or
progressed after any number of cycles of HMA therapy. Patients that do not respond to
HMA therapy will also be allowed in the study. Relapse or progression will be measured
by IWG 2006 criteria. No response will be lack of clinical benefit after at least 6
cycles of HMA therapy.

2. Age 18 years or older.

3. Adequate organ function: creatinine and ALT
4. ECOG performance status
5. Females of childbearing potential must have a negative serum or urine beta human
chorionic gonadotrophin (beta-hCG) pregnancy test result within 24 hours prior to the
first dose of treatment and must agree to use an effective contraception method to
avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo
five half-lives) after the last dose of investigational drugs. Females of non-
childbearing potential are those who are postmenopausal greater than 1 year or who
have had a bilateral tubal ligation or hysterectomy.

6. Males who have partners of childbearing potential must agree to use an effective
contraceptive method during the study and a period of 31 weeks after the last dose of
investigational drug.

7. Patients or their legally authorized representative must provide written informed
consent.

Exclusion Criteria:

1. History of another primary invasive malignancy unless definitively treated or unless
in remission for at least 2 years. Patients with non-melanoma skin cancers or with
carcinomas in situ are eligible regardless of the time from diagnosis (including
concomitant diagnoses).

2. Any major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy,
experimental therapy within 2 weeks prior to the first dose of the study drugs.

3. Patients with any other known concurrent severe and/or uncontrolled medical condition
(e.g. uncontrolled diabetes; cardiovascular disease including congestive heart failure
NYHA Class III or IV, myocardial infarction within 6 months, and poorly controlled
hypertension; chronic renal failure; or active uncontrolled infection) which, in the
opinion of the investigator could compromise participation in the study.

4. Patients unwilling or unable to comply with the protocol.

5. History of pneumonitis.

6. Patients who are on high dose steroid (equivalent of prednisone more than 10 mg a day)
or immune suppression medications.

7. Patients with autoimmune diseases (e.g., rheumatoid arthritis, systemic progressive
sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [e.g.,
Wegener's Granulomatosis]).

8. Patients with a history of Inflammatory Bowel Disease such as Crohn's disease and
ulcerative colitis.

9. Patients known to be positive for hepatitis B surface antigen expression or with
active hepatitis C infection (positive by polymerase chain reaction or on antiviral
therapy for hepatitis C within the last 6 months). Patients with history of HIV
disease are also excluded from the study.

10. Current therapy with other systemic anti-neoplastic or anti-neoplastic investigational
agents.

11. Females who are pregnant or lactating.

12. For hypomethylating failure cohorts, treatment for MDS with any other drug not being
an HMA with the following exceptions: Prior treatment with growth factors and/or
lenalidomide is allowed for any cohort.

13. For hypomethylating failure cohorts only, more than 4 months since last cycle of HMA.

14. Prior treatment with allogeneic stem cell transplantation.