A Phase I/II Study of Nivolumab in Combination with 5-azacytidine in pediatric patients with relapsed/refractory acute myeloid leukemia

This is a phase I/II Study of Nivolumab in Combination with 5-azacytidine in pediatric
patients with relapsed/refractory acute myeloid leukemia

Inclusion Criteria:

Age Patients must be ≥ 1 and ≤30 years of age.

Diagnosis

1. Relapsed or refractory AML with ≥5% blasts (by morphology) in the bone marrow.

- 1st or greater relapse, OR

- Failed to go into remission (i.e. refractory) after first or greater relapse,
OR

- Failed to go into remission from original diagnosis after two or more induction
attempts.

2. Relapsed or refractory AML with ≤ 5% blasts (by morphology) and MRD positive disease
(M1/MRD+): Two serial marrows demonstrating stable or rising MRD ≥ 0.1 % (i.e. not
declining). MRD will be determined by multiparameter flow cytometry using
AML-associated phenotype markers, or real-time quantitative PCR for AML-associated
genetic lesions

3. Patients may have CNS 1 or 2 or other sites of extramedullary disease. No cranial
irradiation is allowed during the protocol therapy.

4. Patients with secondary AML are eligible.

5. Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are
excluded.

6. Patients with Down Syndrome will be eligible and will be included as an observation
cohort

Performance Level Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for
patients ≤ 16 years of age.

Prior Therapy Patients must have fully recovered from the acute toxic effects of all
prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

A. Myelosuppressive chemotherapy

1. Prior chemotherapy Patients must have fully recovered from the acute toxic effects
of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this
study. At least 14 days must have elapsed since the completion of the cytotoxic
therapy, except Intrathecal chemotherapy.

2. Cytoreduction with hydroxyurea Hydroxyurea can be initiated and continued for up to
24 hours prior to the start of day 1 nivolumab and azacytidine. It is recommended to
use hydroxyurea in patients with significant leukocytosis (WBC > 50,000/L) to
control blast count before initiation of systemic protocol therapy.

B. Hematopoietic stem cell transplant: Patients who have experienced their relapse after
a HSCT are eligible provided they have no evidence of active GVHD, no past history of
grade 3 or greater GVHD, and are at least 100 days post-transplant at the time of
enrollment. Patients should be off immune suppression for at least 2 weeks (excluding
physiologic replacement steroids).

C. Hematopoietic growth factors: It must have been at least 7 days since the completion
of therapy with GCSF or other growth factors at the time of enrollment. It must have been
at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).

D. Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic
agent. For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse events
are known to occur. The duration of this interval must be discussed with the study chair

E. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after
the last dose of monoclonal antibody. (i.e. Gemtuzumab = 36 days)

F. Immunotherapy: At least 42 days after the completion of any type of immunotherapy,
e.g. tumor vaccines or CAR T-cells.

G. XRT: XRT is prohibited during protocol therapy. No washout period is necessary for
radiation given to non-CNS chloromas; ≥ 90 days must have elapsed if prior TBI or
craniospinal XRT.

Renal and hepatic function

Patients must have adequate renal and hepatic functions as indicated by the following
laboratory values:

A. Adequate renal function defined as: Patient must have a calculated creatinine
clearance or radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on
age/gender in the chart below:

B. Adequate Liver Function Defined as: Direct bilirubin < 1.5 x upper limit of normal
(ULN) for age or normal, AND alanine transaminase (ALT) < 5 x ULN for age. The hepatic
requirements are waived for patients with known or suspected liver involvement by
leukemia. This must be reviewed by and approved by the study chair or vice chair.

Adequate Cardiac Function Defined as: Shortening fraction of ≥ 27% OR ejection fraction
of ≥ 50%.

Reproductive Function A. Female patients of childbearing potential must have a negative
urine or serum pregnancy test confirmed within 24 hours prior to first dose.

B. Female patients with infants must agree not to breastfeed their infants while on this
study.

C. Male and female patients of child-bearing potential must agree to use an effective
method of contraception approved by the investigator during the study and for a minimum
of 7 months after study treatment. Women of childbearing potential (WOCBP) receiving
nivolumab will be instructed to adhere to contraception for a period of 5 months after
the last dose of nivolumab. Men receiving nivolumab and who are sexually active with
WOCBP will be instructed to adhere to contraception for a period of 7 months after the
last dose of nivolumab.

Informed Consent Patients and/or their parents or legal guardians must be capable of
understanding the investigational nature, potential risks and benefits of the study. All
patients and/or their parents or legal guardians must sign a written informed consent.
Age appropriate assent will be obtained per institutional guidelines. To allow
non-English speaking patients to participate in this study, bilingual health services
will be provided in the appropriate language when feasible.

Protocol Approval All institutional, FDA, and OHRP requirements for human studies must be
met.

Exclusion Criteria:

Patients will be excluded if they have a known allergy or hypersensitivity to nivolumab
or AZA used in the study.

Patients will be excluded if they have a systemic fungal, bacterial, viral or other
infection that is exhibiting ongoing signs/symptoms related to the infection without
improvement despite appropriate antibiotics or other treatment. The patient needs to be
off pressors and have negative blood cultures for 48 hours.

Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
radiation therapy, or immunotherapy during the study period.

Patients will be excluded if they have significant concurrent disease, illness,
psychiatric disorder or social issue that would compromise patient safety or compliance
with the protocol treatment or procedures, interfere with consent, study participation,
follow up, or interpretation of study results.

Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are
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 who have previously been treated with nivolumab will be excluded.

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 known Human Immunodeficiency Virus seropositivity will be excluded.

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).

Pregnant or breastfeeding.

Acute promyelocytic leukemia (APL).

CNS 3 disease.

Patients who have experienced their relapse after a HSCT and are less than 100 days
post-transplant at the time of enrollment, have active GVHD at time of enrollment, have
past history of grade 3 or greater GVHD, Patients on immune suppression (excluding
physiologic replacement steroids).