Avelumab 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 avelumab
in combination with azacitidine (5-azacytidine) in patients with refractory/relapsed acute
myeloid leukemia (AML). (Phase IB)

II. To determine the overall response rate (ORR) defined as complete remission (CR)/complete
remission with incomplete platelet recovery (CRp)/complete remission with incomplete count
recovery (CRi)/partial remission (PR)/hematologic improvement (HI)/morphologic leukemia free
state (MLFS) of avelumab in combination with 5-azacytidine in patients with
refractory/relapsed AML. (Phase II

SECONDARY OBJECTIVES:

I. To determine the number of patients achieve > 50% reduction in blasts on therapy with this
combination.

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

TERTIARY OBJECTIVES:

I. To study immunological and molecular features at baseline and at predefined time-points
on-therapy with avelumab and azacytidine in the peripheral blood and bone marrow to include
quantify immune ligand expression by the AML blasts and AML stromal components
(myeloid-derived suppressor cells [MDSCs] and mesenchymal stem cells [MSCs]) including
4-1BBL, ICOSL, PD-L1, PD-L2, OX-40L, CD137L.

II. To study immunological and molecular features at baseline and at predefined time-points
on-therapy with avelumab and azacytidine in the peripheral blood and bone marrow to determine
the quantitative expression of positive and negative co-stimulatory molecules on individual
T-lymphocyte subsets including 4-1BB, CTLA-4, ICOS, PD-1, OX40, LAG-3 and TIM-3.

III. To study immunological and molecular features at baseline and at predefined time-points
on-therapy with avelumab and azacytidine in the peripheral blood and bone marrow to identify
the immunophenotype of tumor-infiltrating T-lymphocytes (TILs) pre- and post-therapy with the
combination: CD8+, CD4+ effector, or CD4+ regulatory.

IV. To develop a micro-array based gene expression profile (GEP) predictor of response to
anti-PDL1 and epigenetic therapy in AML.

V. To determine the correlation of responses to the combination with baseline cytogenetic and
molecular abnormalities

OUTLINE: This is a phase Ib, dose-escalation study of avelumab followed by a phase II study

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 10-40 minutes on
days 1-7 or on days 1-5 and 8-9. Patients also receive avelumab IV over 60 minutes on days 1
and 14 for 4 courses (or until complete response) and on day 1 for subsequent courses.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity

After completion of study treatment, patients are followed up every 3-6 months for up to 5
years.

Inclusion Criteria:

- Patients with AML who are refractory (up to salvage 2) or relapsed (up to 2nd
relapse); for patients with prior myelodysplastic syndrome (MDS) or chronic
myelomonocytic leukemia (CMML) or myeloproliferative neoplasm (MPN) who transformed to
AML, therapy received for MDS, CMML, or MPN is NOT considered as prior therapy 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 =< 1.5 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)

- Estimated creatinine clearance >= 30 mL/min according to the Cockcroft-Gault formula
(or local institutional standard method)

- 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 avelumab will be at least 14 days OR at least
5 half-lives for cytotoxic/noncytotoxic agents, whichever is longer; the toxicity from
prior therapy should have resolved to grade =< 1, however alopecia and sensory
neuropathy grade =< 2 is acceptable; the half-life for the therapy in question will be
based on published pharmacokinetic literature (abstracts, manuscripts, investigator
brochures, or drug-administration manuals) and will be documented in the protocol
eligibility document; use of hydroxyurea for patients with rapidly proliferative
disease is allowed before the start of study therapy and will not require a washout;
concurrent therapy for central nervous system (CNS) prophylaxis or continuation of
therapy for controlled CNS disease is permitted; patients with CNS disease or leukemic
brain metastasis must have been treated locally and be clinically stable for at least
2 weeks prior to enrollment and have no ongoing neurological symptoms that are related
to the CNS disease (sequelae that are a consequence of the treatment of the CNS
disease are acceptable)

- 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 3 months after the last treatment; males must be surgically
or biologically sterile or agree to use an adequate method of contraception during the
study until 3 months after the last treatment; adequate methods of contraception
include:

- Total abstinence when this is in line with the preferred and usual lifestyle of
the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception

- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment;
in case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment

- Male sterilization (at least 6 months prior to screening); for female patients on
the study, the vasectomized male partner should be the sole partner for that
patient

- Combination of any of the two following (a+b or a+c or b+c)

- a. Use of oral, injected or implanted hormonal methods of contraception or
other forms of hormonal contraception that have comparable efficacy (failure
rate < 1%), for example hormone vaginal ring or transdermal hormone
contraception

- b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

- c. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal
suppository In case of use of oral contraception, women should have been
stable on the same pill before taking study treatment

- Note: oral contraceptives are allowed but should be used in conjunction with a
barrier method of contraception due to unknown effect of drug-drug interaction

- 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 a known allergy or hypersensitivity to avelumab, 5-azacytidine, or any
of their components; known severe hypersensitivity reactions to monoclonal antibodies
(grade >= 3 National Cancer Institute [NCI] Common Terminology Criteria for Adverse
Events [CTCAE] version [v] 4.03), any history of anaphylaxis, or uncontrolled asthma
(that is, 3 or more features of partially controlled asthma)

- Patients with a known history of severe interstitial lung disease or severe
pneumonitis or active pneumonitis/pneumonia or pulmonary pathology that is not well
controlled in the opinion of the treating physician and/or principal investigator (PI)

- Patients who have previously been treated with avelumab (or another PD1/PDL1
inhibitor) in combination with 5-azacytidine will be excluded

- Persisting toxicity related to prior therapy of grade > 1 NCI-CTCAE v 4.03; however,
alopecia and sensory neuropathy grade =< 2 is acceptable

- Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent: a) subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid
disease not requiring immunosuppressive treatment are eligible; b) subjects requiring
hormone replacement with corticosteroids are eligible if the steroids are administered
only for the purpose of hormonal replacement and at doses =< 10 mg or 10 mg equivalent
prednisone per day; c) administration of steroids through a route known to result in a
minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are
acceptable

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

- Patients who are < 90 days post allogeneic stem cell transplant will be excluded;
patients beyond 90 days post-allogeneic stem cell transplant with active uncontrolled
graft versus host disease (GVHD) > grade 1 will be excluded; patients who are on a
stable dose of immunosuppressive therapy (tacrolimus, cyclosporine, or other) for > 2
weeks will be eligible but those with recent increase in the immunosuppressive
medication dose within last 2 weeks to control GVHD will not be included; Note:
subjects may be using systemic corticosteroids or topical or inhaled corticosteroids
post allogeneic stem cell transplant; patients requiring >= 1 mg/kg prednisone for
GVHD management at the time of screening will not be eligible until the prednisone can
be weaned to < 1 mg/kg; such patients should be monitored for at least 14 days and if
no flare of GVHD requiring re-escalation of steroids or additional interventions for
the GVHD they will be eligible

- 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 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)

- 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

- All other significant diseases (for example, inflammatory bowel disease, uncontrolled
asthma), which, in the opinion of the investigator, might impair the subject's
tolerance of trial treatment

- Patients unwilling or unable to comply with the protocol

- Pregnant or breastfeeding

- Known alcohol or drug abuse within the last 1 year

- Vaccination within 4 weeks of the first dose of avelumab and while on trial is
prohibited except for administration of inactivated vaccines

- Acute promyelocytic leukemia (APL)

- Subject has a history of other malignancies prior to study entry, with the exception
of: adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
breast; basal cell carcinoma of the skin or localized squamous cell carcinoma of the
skin; previous malignancy confirmed and surgically resected (or treated with other
modalities) with curative intent or completed definitive therapy (chemotherapy,
radiation, others) for the malignancy at least 1 year prior to the date of screening