Ipilimumab and Decitabine in Treating Patients With Relapsed or Refractory Myelodysplastic Syndrome or Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of
combination decitabine and ipilimumab for relapsed or refractory myelodysplastic syndrome
(MDS) or relapsed or refractory acute myeloid leukemia (AML) in patients who are post
allogeneic hematopoietic stem cell transplant (allo-HCT).

II. To determine the MTD or RP2D of combination decitabine and ipilimumab for relapsed or
refractory MDS or relapsed or refractory AML in patients who are transplant naive.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To determine the overall response rate
(ORR) including complete remission (CR) and complete remission with incomplete count recovery
(CRi) for AML following 2003 International Working Group (IWG) response criteria.

III. To determine the ORR including CR, partial remission, marrow CR, hematologic improvement
for MDS using 2006 IWG criteria.

IV. To determine the overall survival and progression free survival at 1 year. V. To
determine the duration of remission. VI. To determine the incidence and severity of acute
graft-versus-host disease (GVHD) in the post allo-HCT cohort.

VII. To determine the incidence and severity of chronic graft-versus-host disease (GVHD) in
the post allo-HCT cohort.

EXPLORATORY OBJECTIVES:

I. To measure the absolute lymphocyte count (ALC) prior to treatment and during treatment.

II. To evaluate the genome for evidence of clonal evolution among longitudinal samples (prior
to treatment, during treatment, and at relapse if relevant) from individual patients.

III. To evaluate the histopathologic findings of immune response using immunohistochemistry.

IV. To determine the immune response in the AML tumor microenvironment by using flow
cytometry and single cell mass cytometry to evaluate T cell subsets.

OUTLINE: This is a dose-escalation study of ipilimumab.

ARM A (PATIENTS POST ALLO-HCT):

PRIMING PHASE: Patients receive decitabine intravenously (IV) over 60 minutes on days 1-5 out
of 28 days.

INDUCTION PHASE: Patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab IV
over 90 minutes on day 1. Treatment repeats every 28 days for up to 4 courses in the absence
of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab
IV over 90 minutes on day 1. Treatment repeats every 4 or 8 weeks for up to 4 courses in the
absence of disease progression or unacceptable toxicity.

ARM B (TRANSPLANT NAIVE PATIENTS):

PRIMING PHASE: Patients receive decitabine IV over 60 minutes on days 1-5 out of 28 days.

INDUCTION PHASE: Patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab IV
over 90 minutes on day 1. Treatment repeats every 28 days for up to 4 courses in the absence
of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Patients receive decitabine IV over 60 minutes on days 1-5 and ipilimumab
IV over 90 minutes on day 1. Treatment repeats every 4 or 8 weeks for up to 4 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 52
weeks (1 year).

Inclusion Criteria:

- Subjects with evidence of relapsed or refractory acute myeloid leukemia (AML) OR
treatment naive AML who are 75 years or older OR relapsed or refractory
myelodysplastic syndrome (MDS)

- For subjects with relapsed AML: evidence of >= 5% blasts in the bone marrow; or
reappearance of blasts in the peripheral blood; or development of extramedullary
disease (according to 2003 IWG criteria) who relapse after:

- Allogeneic hematopoietic stem cell transplant, or

- After one cycle of standard cytotoxic chemotherapy or two cycles of any
hypomethylating agent-based therapy

- For subjects with refractory AML: =< 2 prior induction regimens (example:
patients who receive 7+3 followed by 5+2 would count as one induction regimen) or
a minimum of two cycles of any hypomethylating agent-based therapy

- For subjects with treatment-naive AML: must be 75 years and older with de novo or
secondary AML to be considered eligible

- For subjects with relapsed MDS: disease recurrence after CR, partial remission
(PR) or hematologic improvement with bone marrow blasts >= 5% who relapse after:

- Allogeneic hematopoietic stem cell transplant, or

- After four cycles of any hypomethylating agent-based therapy

- For subjects with refractory MDS: disease progression at any time after
initiation of hypomethylating agent treatment or persistent bone marrow blasts >=
5% despite a minimum of four cycles of hypomethylating agent therapy

- Allowed prior allogeneic hematopoietic stem cell transplantation (allo-HCT) regardless
of stem cell source; patients must be at least 3 months post allo-HCT (at time of
treatment start); mismatched transplantations would be allowed

- Patients must be off systemic immunosuppressive medications > 2 weeks prior to
treatment start; if patients are in systemic corticosteroids and must be on a dose of
prednisone 5 mg/day or less (or equivalent), then patients must be on this reduced
dose for > 1 week prior to treatment start; topical steroids are allowed

- If post allo-HCT, then patient must have baseline donor T cell chimerism of >= 20%
(from peripheral blood); evaluation can be made within 4 weeks of treatment start

- No limitations on prior therapies

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Total bilirubin =< 1.5 x local institutional upper limit of normal (ULN)

- If elevated total bilirubin is due Gilbert's disease or disease-related hemolysis
then total bilirubin =< 3.0 x local institutional ULN

- Aspartate aminotransferase (AST) or serum glutamic oxaloacetic transaminase (SGOT) =<
3.0 x local institutional ULN

- Alanine aminotransferase (ALT) or serum glutamic pyruvic transaminase (SGPT) =< 3.0 x
local institutional ULN

- Serum creatinine =< 2.0 x local institutional ULN

- Negative serum pregnancy test for women who are of child bearing potential (test must
be repeated if performed > 72 hours from treatment start); women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry and for the duration of study
participation; should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, she should inform her treating physician
immediately; men treated or enrolled on this protocol must also agree to use adequate
contraception prior to the study, for the duration of study participation, and 4
months after completion of study drug administration

- Patients with known active human immunodeficiency virus (HIV) infection; patients with
chronic HIV with a CD4 > 250, undetectable viral load by polymerase chain reaction
(PCR), without opportunistic infection, and on a stable regimen of highly active
anti-retroviral therapy (HAART) therapy would be eligible

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Participants who have had chemotherapy or radiotherapy within 2 weeks prior to
treatment start or those who have not recovered from adverse events due to agents
administered more than 2 weeks prior to treatment start; hydroxyurea is allowed for
symptomatic leukocytosis during screening, lead in, and cycle 1 only if clinically
necessary; a total white blood cell (WBC) count < 25 x 10^9/L prior to first dose of
decitabine on trial is required; prior leukapheresis and/or prior or concurrent
treatment with hydroxyurea to achieve this level are allowed

- Prior hypomethylating agent (HMA) therapy is allowed, however this study excludes
patients with progression or relapse that occur while receiving HMA-based therapy
within 12 weeks prior to treatment start on study. Disease progression is defined as
either: (1) patients with prior MDS who progress to AML (defined by the presence of >=
20% blasts in peripheral blood or bone marrow) on HMA-based therapy; OR (2) patients
with AML with evidence of progressive disease according to European Leukemia Net [ELN]
2017 criteria) (e.g. > 50% increase in marrow blasts over baseline or > 50% increase
in peripheral blasts to > 25 x10^9/L (> 25,000/uL) (in absence of differentiation
syndrome)

- (Note: Patients who relapse post-transplant who received HMA treatment prior to
transplant are eligible for study)

- Donor lymphocyte infusion within 8 weeks prior to treatment start if post-transplant

- For patients that are post-transplant, ineligible patients include those with a
history of overall grade III or IV (severe) acute GVHD at any time even if resolved

- Patients with a history of prior treatment with anti-CTLA-4, anti-PD 1 antibody, or
anti-PDL1 antibody

- Participants who are receiving any other investigational agents

- Participants with known central nervous system (CNS) involvement with leukemia or who
are receiving intrathecal chemotherapy that is either prophylactic or therapeutic;
history of CNS involvement that has been completely treated (no longer receiving
intrathecal chemotherapy) will be allowed

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements; any other prior or ongoing condition, in the opinion of the
investigator, that could adversely affect the safety of the patient or impair the
assessment of study results; as patients with AML and MDS are prone to infections, if
patients are actively being treated with appropriate antibiotics or antifungal therapy
with clinical evidence of infection control, then they will be considered eligible for
study

- Autoimmune disease: Patients who are not eligible include those with a history of
inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are
excluded from this study, as are patients with a history of symptomatic disease (e.g.,
rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus
erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); CNS or motor
neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and
Myasthenia Gravis, multiple sclerosis); patients with a history of autoimmune disease
(specifically including: diabetes mellitus, vitiligo, hashimoto's thyroiditis) who are
asymptomatic, do not require immune suppression or steroids, and do not have
threatened vital organ function from these conditions may be considered after
discussion with the principal investigator (PI)

- No concurrent active malignancies are allowed on study for >= 2 years prior to
treatment start with the exception of currently treated basal cell or squamous cell
carcinoma of the skin, or carcinoma in-situ of the cervix or breast

- Patients with known active hepatitis B virus (HBV) infection should be excluded;
however, if a patient has HBV history with an undetectable HBV load by polymerase
chain reaction (PCR), no liver-related complications, and is on definitive HBV
therapy, then he/she would be eligible for study

- Patients with known active hepatitis C virus (HCV) infection; patients with a history
of HCV infection who received definitive therapy and has an undetectable viral load by
PCR would be eligible

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with ipilimumab