High Dose Cytarabine Followed by Pembrolizumab in Relapsed/Refractory AML

Primary Objective

1. Estimate the objective overall rate of CR (CR+CRi) for age-adjusted HiDAC (age <60 years:
2 gm/m2 IV Q12hours days 1-5; age >60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by
pembrolizumab 200 mg IV on day 14 in relapsed and refractory AML patients

Secondary Objectives

1. Estimate the rate of unacceptable toxicity associated with HiDAC followed by
pembrolizumab as induction therapy

2. Estimate the objective overall response rates (PR+CR+CRi) for HiDAC followed by
pembrolizumab.

3. Characterize the toxicity associated with HiDAC followed by pembrolizumab as induction
therapy

4. Characterize the toxicity associated with pembrolizumab 200 mg IV Q3weeks when used as
monotherapy maintenance after an initial response to induction phase HiDAC followed by
pembrolizumab

5. Estimate the relapse-free survival (RFS) and progression-free survival (PFS) of patients
receiving maintenance pembrolizumab

6. Estimate the overall survival (OS) of patients who received induction phase treatment.

Inclusion Criteria:

1. Willing and able to provide written informed consent for the trial

2. > 18 years and < 70 years of age on day of signing informed consent

3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

4. Have histologically or cytologically confirmed recurrent AML as defined by ≥5 %
myeloblasts in the bone marrow aspirate and or biopsy.

5. Must have received at least 1 cycle of induction therapy for front-line AML including
cytarabine continuous infusion + anthracycline +/- cladribine or etoposide for 1 or 2
cycles, high dose cytarabine with or without fludarabine, cladribine or clofarabine, >
4 cycles of azacitidine/decitabine or the equivalent experimental therapy (the latter
as confirmed by the PI)

6. Cytoreduction allowed with hydroxyurea and/or leukapheresis for up to 14 days prior to
D1 of treatment under LCCC1522. Patients must be off hydroxyurea for > 12 hours prior
to D1 of treatment under LCCC1522

7. Demonstrate adequate organ function as defined below. All screening labs should be
performed within 14 days of D1 of treatment under LCCC1522.

Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or calculated
creatinine clearance (GFR can also be used in place of creatinine or CrCl)-- ≥60
mL/min for subject with creatinine levels > 1.5 X institutional ULN Serum total
bilirubin ≤ 1.5 X ULN unless due to Gilbert's Disease, hemolysis or leukemic
infiltration OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5
ULN Aspartate Aminotransferase (AST)(SGOT) and Alanine Aminotransferase (ALT) (SGPT) ≤
5 X ULN International Normalized Ratio (INR) or Prothrombin Time (PT)- ≤1.5 X ULN
unless subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants or patient has disseminated
intravascular coagulation deemed by investigator to be due to leukemia Activated
Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants or patient has disseminated intravascular coagulation deemed by
investigator to be due to leukemia

8. Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of HiDAC treatment and
again prior to D1 of pembrolizumab treatment. If the urine test is positive or cannot
be confirmed as negative, a serum pregnancy test will be required.

9. Female subjects of childbearing potential should be willing to use adequate method of
contraception for the course of the study through 120 days after the last dose of
study medication. Subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year. The two birth
control methods can be two barrier methods or a barrier method plus a hormonal method
to prevent pregnancy. Subjects should start using birth control from the screening
visit throughout the study period up to 120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle preferred contraception
for the subject.

10. Male subjects must agree to use an adequate method of contraception starting with D1
of HiDAC through 120 days after the last dose of study therapy.

11. As determined by the enrolling physician or protocol designee, ability of the patient
to understand and comply with study procedures for the entire length of the study.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.

Exclusion Criteria:

1. Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 4 weeks of the first dose of
treatment.

2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of HiDAC
treatment. Note: use of steroid eye drops starting at the time of HiDAC administration
is allowed.

3. Has a known history of active Bacillus Tuberculosis (TB)

4. Hypersensitivity to pembrolizumab or any of its excipients

5. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
administered more than 4 weeks earlier.

6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent. Note: Subjects
with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the
study.

Note: If subject received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy.

7. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin that has undergone potentially curative therapy, or in situ cervical cancer that
has undergone potentially curative therapy.

8. Has known active central nervous system (CNS) leukemia; subjects with previously
treated CNS disease may participate provided they are stable (without evidence of
active disease by imaging for at least 4 weeks prior to the first dose of treatment,
and any neurologic symptoms have returned to baseline), have no evidence of new or
enlarging brain metastases, and are not using steroids for at least 7 days prior to D1
of treatment.

9. Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

10. Has evidence of interstitial lung disease or a history of ( non-infectious)
pneumonitis that required steroids or current pneumonitis.

11. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

12. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

13. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment

14. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways)

15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., hepatitis C
virus (HCV) RNA qualitative is detected).

17. Has received a live vaccine within 30 days prior to the first dose of trial treatment
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed

18. Has uncontrolled intercurrent illness including, but not limited to, active and
uncontrolled infection, symptomatic congestive heart failure, unstable angina
pectoris, and uncontrolled symptomatic cardiac arrhythmia. Patients with infection
under active treatment and controlled with antibiotics are eligible.

19. Diagnosed with acute promyelocytic leukemia (APL, M3)

20. Receipt of previous allogeneic stem cell transplant; receipt of previous autologous
transplant for AML or non-AML condition is allowed