Lirilumab and Azacitidine in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of
lirilumab in combination with 5-azacytidine (azacitidine) in patients with
refractory/relapsed acute myeloid leukemia (AML). (Part A, Lead-In Phase) II. To determine
the overall response rate (ORR) of lirilumab in combination with 5-azacytidine in patients
with refractory/relapsed AML. (Part B, Phase II)

SECONDARY OBJECTIVES:

I. To determine the duration of response, disease-free survival (DFS), and overall survival
(OS) of patients with refractory/relapsed AML treated with this combination.

II. To determine the safety of lirilumab in combination with 5-azacytidine in patients with
refractory/relapsed AML.

TERTIARY OBJECTIVES:

I. To study immunological and molecular changes in the peripheral blood and bone marrow in
response to lirilumab and 5-azacytidine therapy.

II. To determine induction of hypomethylation and deoxyribonucleic acid (DNA) damage during
therapy with this combination and its correlation with response.

OUTLINE:

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 1 hour as
determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and up to 90 days.

Inclusion Criteria:

- Patients with AML or biphenotypic or bilineage leukemia who have failed at least one
prior therapy; patients with AML should have failed prior therapy or have relapsed
after prior therapy

- Patients should not be eligible or able to receive approved therapy of confirmed
clinical benefit in this patient population

- Patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML)
who received therapy for the MDS or CMML and progress to AML are eligible at the time
of diagnosis of AML regardless any prior therapy for AML; the World Health
Organization (WHO) classification will be used for AML

- Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy (e.g.
FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is allowed

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

- Total bilirubin =< 2 times upper limit of normal (x ULN) (=< 3 x ULN if considered to
be due to leukemic involvement or Gilbert's syndrome)

- Aspartate aminotransferase or alanine aminotransferase =< 2.5 x ULN (=< 5.0 x ULN if
considered to be due to leukemic involvement)

- Serum creatinine =< 2 x ULN or glomerular filtration rate (GFR) >= 50

- Patients must provide written informed consent

- In the absence of rapidly progressing disease, the interval from prior treatment to
time of initiation of 5-azacytidine and lirilumab will be at least 2 weeks OR at least
5 half-lives for cytotoxic/noncytotoxic agents; use of one dose of cytarabine (up to 2
g/m^2) is allowed prior to the start of study therapy or hydroxyurea for patients with
rapidly proliferative disease is allowed before the start of study therapy and while
the patient is on active study treatment, as needed, for clinical benefit and after
discussion with the principal investigator (PI); concurrent therapy for central
nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease
is permitted

- Females must be surgically or biologically sterile or postmenopausal (amenorrheic for
at least 12 months) or if of childbearing potential, must have a negative serum or
urine pregnancy test within 72 hours before the start of the treatment

- Women of childbearing potential must agree to use an adequate method of contraception
during the study and until 30 days after the last treatment; males must be surgically
or biologically sterile or agree to use an adequate method of contraception during the
study until 30 days after the last treatment; women are considered post-menopausal and
not of child bearing potential if they have had 12 months of natural (spontaneous)
amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of
vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without
hysterectomy) or tubal ligation at least six weeks ago; in the case of oophorectomy
alone, only when the reproductive status of the woman has been confirmed by follow up
hormone level assessment is she considered not of child bearing potential

Exclusion Criteria:

- Patients with known allergy or hypersensitivity to lirilumab, 5-azacytidine, or any of
their components; patients who have previously been treated with lirilumab in
combination with 5-azacytidine will be excluded

- Patients with a known history of severe interstitial lung disease or severe
pneumonitis or active pneumonitis that is uncontrolled in the opinion of the treating
physician

- Patients with a known history of any of the following autoimmune diseases are
excluded: (a) patients with a history of inflammatory bowel disease (including Crohn's
disease and ulcerative colitis) (b) patients with a history of rheumatoid arthritis,
systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune
vasculitis [e.g., Wegener's granulomatosis])

- Patients with organ allografts (such as renal transplant) are excluded

- Patients with allogeneic stem cell transplantation within the last 6 months or
patients with active graft-versus-host disease (GVHD) will be excluded

- Ongoing immunosuppressive therapy, including cyclosporine and tacrolimus; patients who
are on high dose steroid; Note: Subjects may be using systemic corticosteroids (daily
doses =< 10 mg of prednisone or equivalent) or topical or inhaled corticosteroids

- Patients with symptomatic CNS leukemia or patients with poorly controlled CNS leukemia

- Active and uncontrolled disease/(active uncontrolled infection, uncontrolled
hypertension despite adequate medical therapy, active and uncontrolled congestive
heart failure New York Heart Association [NYHA] class III/IV, clinically significant
and uncontrolled arrhythmia) as judged by the treating physician

- Patients with active and uncontrolled human immunodeficiency virus (HIV) infection
will be excluded; however, patients with well controlled HIV infection will be
considered

- Patients known to be positive for hepatitis B by surface antigen expression; known to
have active hepatitis C infection (positive by polymerase chain reaction or on
antiviral therapy for hepatitis C within the last 6 months)

- Any other medical, psychological, or social condition that may interfere with study
participation or compliance, or compromise patient safety in the opinion of the
investigator

- Patients unwilling or unable to comply with the protocol

- Pregnant or breastfeeding

- Acute promyelocytic leukemia (APL)