High Dose Cytarabine Followed by Pembrolizumab in Relapsed/Refractory AML

Rationale:The purpose of this research study is to test the effectiveness of the standard high dose cytarabine (HiDAC) on days 1 through 5 followed by a single dose of pembrolizumab on day 14 as induction therapy in patients with relapsed and refractory acute myeloid leukemia (AML). Patients who achieve a response to treatment will continue on the study drug (pembrolizumab) every 3 weeks for up to 2 years maintenance therapy.

Purpose:This is a study about a new investigative drug, pembrolizumab (MK-3475) that is being studied in a clinical research trial together with standard chemotherapy (HiDAC) in relapsed and refractory AML. The study will also explore the association between potential immune biomarkers and clinical outcomes with pembrolizumab; therefore all patients will have blood and bone marrow samples collected before and after treatment to determine the dynamic nature of immune signatures pre and post-treatment.

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.

Eligibility Criteria:
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, or liposomal cytarabine and daunorubicin (CPX-351), or 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.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
11. As determined by the enrolling physician or protocol designee, ability of the patient to understand and comply with study procedures

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

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