Pembrolizumab and Decitabine for Refractory or Relapsed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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Background: Acute myeloid leukemia (AML) is a cancer of the white blood cells. It is fatal if not treated. Treatment for AML that has not responded to treatment (refractory) or has returned after treatment (relapsed) often do not work. Researchers want to see if an immunotherapy drug, combined with a less intense chemotherapy, may be able to help. Objective: To test if pembrolizumab, in combination with decitabine, is a possible treatment for people with relapsed or refractory AML. Eligibility: Adults 18 years of age and older with refractory AML or relapsed AML. Design: Participants will be first screened for eligibility. The study is counted in 21-day cycles. The initial phase of the study consists of 8 cycles. Participants may be in the study for up to 2 years if they are responding to the treatment. The first 3 weeks of treatment is usually done in the hospital. The rest may be done as an outpatient. Participants will get pembrolizumab at the beginning of each cycle through an IV. Participants will usually get decitabine by IV on days 8 12 and days 15 19 of every other cycle. Participants will give blood samples. Participants will have bone marrow exams. A needle will be inserted into the hip to extract cells from the bone marrow. Some participants may give a sample of saliva from the inside of their cheek. Some participants may give a small skin sample. The top layer of the skin is removed. Some patients may require leukapheresis before starting treatment. This is a procedure to remove leukemia cells in the blood stream.

Detailed Description
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This is a pilot study to determine the feasibility of a novel combination of Pembrolizumab and Decitabine in relapsed/refractory adult AML patients. While both Pembrolizumab and Decitabine are FDA approved agents, this study will explore giving these drugs in combination for this population of patients.

Official Title
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Pembrolizumab and Decitabine for Refractory or Relapsed Acute Myeloid Leukemia

Conditions
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Relapsed Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Decitabine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Unequivocal diagnosis of relapsed or refractory acute myeloid leukemia (AML) confirmed by an NIH attending pathologist within 30 days of study enrollment (includes residual AML as confirmed by institutional standards by NIH pathologists Received at least one prior AML therapy before study enrollment. Ability to comprehend the investigational nature of the study and provide informed consent. Be at least 18 years of age on day of signing informed consent. Availability of a physician willing to assume clinical care after completion of the study. Be willing to provide blood and bone marrow for research as described in the study. Have a performance status of less than or equal to 1 on the ECOG Performance Scale Demonstrate adequate organ function as defined below, all screening labs should be performed within 14 days of treatment initiation. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential must be willing to use an adequate method of contraception; Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy 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. Adequate Organ Function Laboratory Values: System Laboratory - Value Renal ---Serum Creatinine - Less than or equal to 1.5 X upper limit of normal (ULN) Hepatic Serum total bilirubin Less than or equal to 1.5 X ULN OR Direct bilirubin less than or equal to ULN for subjects with total bilirubin levels greater than 1.5 ULN AST (SGOT) and ALT(SGPT) Less than or equal to 3 X ULN EXCLUSION CRITERIA: The subject must be excluded from participating in the trial if the subject: Has a diagnosis of acute promyelocytic leukemia (APL) Has previously received an allogeneic hematopoietic stem cell transplant. Has received AML treatment with an investigational therapy or device within 4 weeks of the first dose of treatment. 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 trial treatment. Has a known history of active TB (Bacillus Tuberculosis) Has hypersensitivity to pembrolizumab or any of its excipients. Has hypersensitivity to decitabine or any of its excipients. Has received more than two prior cycles of decitabine. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1. --Note: Subjects who have received cytoreductive therapy with hydroxyurea at any time prior to study Day 1 are an exception to this criterion. Has not recovered (i.e., less than or equal to Grade 1 or at baseline) from adverse events due to previously administered AML therapy agents. Note: Subjects with less than or equal to Grade 2 neuropathy are an exception 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. Has a known additional malignancy that is progressing or requires active treatment. Patients with basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer would not be excluded. Has known malignant central nervous system (CNS) involvement. 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. Has history of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis. Has an active infection requiring intravenous systemic therapy. 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. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 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. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). Has received a live vaccine within 30 days of planned start of study therapy. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab and Decitabine for treatment of Acute Myeloid Leukemia<br>Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Up to eight cycles of pembrolizumab will be given during the initial induction phase. Each cycle is 21 days. Decitabine will be administered at a dose of 20 mg/m^2 by intravenous infusion over approximately 1 hour repeated daily ordinarily on days 8 through 12 and 15 through 19 of alternative cycles (ie: cycles 1, 3, 5, 7) for treatment relapsed/refractory AML. | Drug: Pembrolizumab<br>* 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Every effort should be made to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).<br>* Other names: MK-3475;Drug: Decitabine<br>* Will be administered at a dose of 20 mg/m^2 by continuous intravenous infusion over 1 hour repeated daily ordinarily on days 8 through 12 and 15 through 19 of alternative cycles (ie: cycles 1, 3, 5, 7). Decitabine should be repeated every 6 weeks.<br>* Other names: Dacogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of a Novel Combination of Pembrolizumab and Decitabine in Relapsed/Refractory Acute Myeloid Leukemia Participants | The number of patients who could be treated with a novel combination of Pembrolizumab and Decitabine in relapsed/refractory Acute Myeloid Leukemia participants without being removed from the protocol due to treatment related toxicities. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Days to First Response From Start of Study to Initial Achievement of First Response (mCR, mCRi, CR, CRi, PR, or SD) | Time to first response (days) is time from start of study to first response (mCR, mCRi, CR, CRi, PR, or SD) in relapsed/refractory acute myeloid leukemia (AML) participants. Measurable residual disease (MRD) negative complete remission is no evidence of residual disease, < 5% blasts, no Auer rods and may be with mCR or without count recovery (ANC ≥ 1,000/mcl and platelet count ≥ 100,000/mcl) as mCRi. Morphologic complete remission (CR) is ANC ≥ 1,000/mcl, platelet count ≥ 100,000/mcl, < 5% blasts, no Auer rods, no evidence of disease; Morphologic complete remission with incomplete blood count recovery (CRi) is same as CR but ANC may be < 1,000/mcl and/or platelet count < 100,000/mcl; Partial remission (PR) is ANC ≥ 1,000/mcl, platelet count > 100,000/mcl, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts < 5% with persistent Auer rods. Stable disease (SD) is absence of a complete or partial response, and no progressive disease. | At the end of each cycle 2 (week 6), 4 (week 12), 6 (week 18), 8 (up to week 24) | 
| Median Days to Best Response From Start of Study to Initial Achievement of Best Response (by the Order of mCR, mCRi, CR, CRi, PR, or SD) | Time to Best Response is defined as time (days) from start of study to initial achievement of best response. Best response is defined by the order of mCR, mCRi, CR, CRi, PR, or SD. Measurable residual disease (MRD) negative complete remission is no evidence of residual disease, < 5% blasts, no Auer rods and may be with mCR or without count recovery (ANC ≥ 1,000/mcl and platelet count ≥ 100,000/mcl) as mCRi. Morphologic complete remission (CR) is ANC ≥ 1,000/mcl, platelet count ≥ 100,000/mcl, < 5% blasts, no Auer rods, no evidence of disease; Morphologic complete remission with incomplete blood count recovery (CRi) is same as CR but ANC may be < 1,000/mcl and/or platelet count < 100,000/mcl; Partial remission (PR) is ANC ≥ 1,000/mcl, platelet count > 100,000/mcl, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts < 5% with persistent Auer rods. Stable disease (SD) is absence of a complete or partial response, and no progressive disease. | At the end of each cycle 2 (week 6), 4 (week 12), 6 (week 18), 8 (up to week 24) | 
| Median Duration (Days) of Response From Initial Achievement of Response to Loss of Response (mCR, mCRi, CR, CRi, PR, or SD) | To determine duration (days) of response as defined as time from initial achievement of response to loss of response (mCR, mCRi, CR, CRi, PR, or SD). Measurable residual disease (MRD) negative complete remission is no evidence of residual disease, < 5% blasts, no Auer rods and may be with mCR or without count recovery (ANC ≥ 1,000/mcl and platelet count ≥ 100,000/mcl) as mCRi. Morphologic complete remission (CR) is ANC ≥ 1,000/mcl, platelet count ≥ 100,000/mcl, < 5% blasts, no Auer rods, no evidence of disease; Morphologic complete remission with incomplete blood count recovery (CRi) is same as CR but ANC may be < 1,000/mcl and/or platelet count < 100,000/mcl; Partial remission (PR) is ANC ≥ 1,000/mcl, platelet count > 100,000/mcl, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts < 5% with persistent Auer rods. Stable disease (SD) is absence of a complete or partial response, and no progressive disease. | At the end of each cycle 2 (week 6), 4 (week 12), 6 (week 18), 8 (up to week 24) | 
| Median Duration (Days) of Best Response From Initial Achievement of Best Response to Loss of Best Response (by the Order of mCR, mCRi, CR, CRi, PR, or SD) | Duration of Best Response is time (days) from initial achievement of best response to loss of best response. Best response is defined by the order of mCR, mCRi, CR, CRi, PR, or SD. Measurable residual disease (MRD) negative complete remission is no evidence of residual disease, < 5% blasts, no Auer rods and may be with mCR or without count recovery (ANC ≥ 1,000/mcl and platelet count ≥ 100,000/mcl) as mCRi. Morphologic complete remission (CR) is ANC ≥ 1,000/mcl, platelet count ≥ 100,000/mcl, < 5% blasts, no Auer rods, no evidence of disease; Morphologic complete remission with incomplete blood count recovery (CRi) is same as CR but ANC may be < 1,000/mcl and/or platelet count < 100,000/mcl; Partial remission (PR) is ANC ≥ 1,000/mcl, platelet count > 100,000/mcl, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts < 5% with persistent Auer rods. Stable disease (SD) is absence of a complete or partial response, and no progressive disease. | At the end of each cycle 2 (week 6), 4 (week 12), 6 (week 18), 8 (up to week 24) | 
| Overall Survival | Number of participants overall survival is defined as death from any cause | from enrollment until date of death, assessed up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pembrolizumab, Decitabine, AML (Acute Myelogenous Leukemia)