BLAST MRD AML-1: BLockade of PD-1 Added to Standard Therapy to Target Measurable Residual Disease in Acute Myeloid Leukemia 1- A Randomized Phase 2 Study of Anti-PD-1 Pembrolizumab in Combination With Intensive Chemotherapy as Frontline Therapy in Patients With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This phase II trial studies how well cytarabine and idarubicin or daunorubicin with or without pembrolizumab work in treating patients with newly-diagnosed acute myeloid leukemia. Chemotherapy drugs, such as cytarabine, idarubicin, and daunorubicin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving induction chemotherapy with pembrolizumab may work better than induction chemotherapy alone in treating patients with acute myeloid leukemia.

Detailed Description
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PRIMARY OBJECTIVE: I. To assess the percentage of patients with minimal residual disease (MRD) negative complete remission (CR) (MRD-CR) as measured by flow cytometry at the end of first cycle of consolidation therapy with chemotherapy + MK-3475 (pembrolizumab) and compare between the two study arms. SECONDARY OBJECTIVES: I. Assess the rate of complete remission (CR)/complete remission with incomplete count recovery (CRi) as defined per European LeukemiaNet 2017 response criteria at time of count recovery after induction therapy with chemotherapy + MK-3475 (pembrolizumab) (Dohner et al., 2017). II. Rates of complete remission with partial recovery count (CRh) and hematologic improvement (HI) to red blood cells and platelets. III. Assess the rates of MRD negativity at day 14, MRD-negative CR at end of induction therapy and MRD negative CR after last consolidation cycle. IV. Assess event free survival (EFS), measured from randomization to failure to achieve CR/CRi, relapse or death from any cause, and relapse free survival (RFS), calculated as the time from first documentation of CR/CRi to either disease relapse or death from any cause. V. Assess the duration of response (DOR, defined as the time from first CR/CRi to the date of the first documented relapse or death, whichever occurs first) and overall survival (OS), defined as time from randomization to death from any cause. VI. Assess safety endpoints including proportion of patients who develop severe toxicity as defined in the protocol. EXPLORATORY OBJECTIVES: I. MRD assessment by duplex sequencing (DS) and comparing DS and multiparameter flow cytometry for MRD detection as an exploratory biomarker. II. Assessment of immune-checkpoint expression and dynamic change of immune cell subsets in response to the combination of checkpoint-inhibition and backbone combination in acute myeloid leukemia (AML). III. High-throughput sequencing of the T-cell receptor (TCR) Vb CDR3 regions on ﬂow cytometrically sorted t-cell subsets to assess the effect of immunotherapy on the diversity of the t-cell repertoire and assess for correlation to clinical outcomes. IV. Investigation of protein signatures and ribonucleic acid (RNA) signatures associated with response and efficacy using O-link cytokine panel and RNA-sequencing (seq), respectively. V. Determination of mutational load by whole exome sequencing to assess for correlation with clinical outcomes, immune infiltrating profile, and T cell repertoire diversity and clonality. VI. Correlate gut microbiome at baseline and changes in the microbiome with clinical response, both in standard chemotherapy and immunotherapy/chemotherapy therapy settings. VII. MRD assessment using duplex sequencing strategy for circulating cell-free tumor deoxyribonucleic acid (DNA) and correlation with long-term outcomes. OUTLINE: Patients are randomized to 1 of 2 arms. INDUCTION PHASE: ARM I: Patients receive cytarabine via continuous intravenous (IV) infusion on days 1-7 and idarubicin hydrochloride IV over 15-30 minutes or daunorubicin hydrochloride IV over 15-30 minutes on days 1-3 of a 28-35 day cycle. Patients who have evidence of residual leukemia receive cytarabine via continuous IV infusion over days 1-5 and idarubicin hydrochloride IV over 15-30 minutes or daunorubicin hydrochloride IV over 15-30 minutes on days 1-2 for an additional cycle in the absence of disease progression or unacceptable toxicity. Beginning day 8, patients receive pembrolizumab IV over 25-40 minutes. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients who achieve a CR or a CRi may undergo hematopoietic stem cell transplantation (HSCT) per physician discretion or continue to consolidation therapy. ARM II: Patients receive cytarabine via continuous IV infusion on days 1-7 and idarubicin hydrochloride IV over 15-30 minutes or daunorubicin hydrochloride IV over 15-30 minutes on days 1-3 of a 28-35 day cycle. Patients who have evidence of residual leukemia receive cytarabine via continuous IV infusion over days 1-5 and idarubicin hydrochloride IV over 15-30 minutes or daunorubicin hydrochloride IV over 15-30 minutes on days 1-2 for an additional cycle in the absence of disease progression or unacceptable toxicity. Patients who achieve a CR or a CRi may undergo HSCT per physician discretion or continue to consolidation therapy. CONSOLIDATION THERAPY: ARM I: Within 4 weeks of remission status documentation, patients receive high-dose cytarabine (HiDAC) IV over 1-3 hours every 10-12 hours on days 1, 3, and 5 for a total of 6 doses and pembrolizumab IV over 25-40 minutes. Cycles with HiDAC repeat every 28-42 days and cycles with pembrolizumab repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients who remain in CR or CRi receive up to 3 additional cycles of HiDAC and pembrolizumab in the absence of disease progression or unacceptable toxicity and continue to maintenance therapy. ARM II: Within 4 weeks of remission status documentation, patients receive HiDAC IV over 1-3 hours every 12 hours on days 1, 3, and 5 for a total of 6 doses in the absence of disease progression or unacceptable toxicity. Patients who remain in CR or CRi receive up to 3 additional cycles of HiDAC in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: ARM I: Patients receive pembrolizumab IV over 25-40 minutes. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. All patients also undergo a skin punch biopsy during screening, a bone marrow biopsy and collection of blood samples during screening and on study, an echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) during screening and on study, and an optional computed tomography (CT) scan during screening. After completion of study treatment, patients are followed up at 30 days and then every 6 months for up to 5 years. Patients who undergo HSCT are also followed up at 100 days post-transplant.

Official Title
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BLockade of PD-1 Added to Standard Therapy to Target Measurable Residual Disease in Acute Myeloid Leukemia 1 (BLAST MRD AML-1): A Randomized Phase 2 Study of the Anti-PD-1 Antibody Pembrolizumab in Combination With Conventional Intensive Chemotherapy as Frontline Therapy in Patients With Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Acute Myeloid Leukemia Post Cytotoxic Therapy, Secondary Acute Myeloid Leukemia

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Bone Marrow Biopsy
* Procedure: Computed Tomography
* Drug: Cytarabine
* Drug: Daunorubicin Hydrochloride
* Procedure: Echocardiography
* Procedure: Hematopoietic Cell Transplantation
* Drug: Idarubicin Hydrochloride
* Procedure: Multigated Acquisition Scan
* Biological: Pembrolizumab
* Procedure: Punch Biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed and pathologically-confirmed AML, confirmed by a bone marrow aspirate and/or biopsy and/or peripheral blood with >= 20% myeloid blasts. Bone marrow biopsy, or aspirate or peripheral blood that were obtained up to 3 weeks before signing consent are allowed for purposes of confirming AML diagnosis for eligibility purposes. Secondary AML (that is arising from prior myelodysplastic syndrome [MDS]/AML, therapy-related [t]-AML) are also allowed. AML arising from myeloproliferative neoplasms (MPN), MPN/MDS overlap (including chronic myelomonocytic leukemia [CMML]) or another malignancy are NOT allowed. Note 1: Patients must have evidence of bone marrow involvement on aspirate or biopsy. Patients with only extramedullary disease and no bone marrow involvement will be excluded. Note 2: Every effort should be made to get an aspirate for central flow assessment at screening and all subsequent required time points, but in cases where an aspirate cannot be collected-including dry taps-the patient will not be excluded and assessments will be performed on peripheral blood (PB) which should be collected at every time that bone marrow (BM) is collected. Note 3: Some patients with AML require initiation of therapy quickly after diagnosis, and full metaphase karyotype results in some centers can take 2-3 weeks to result. To avoid this issue being an impediment to accrual to study or to cause delays in initiation of therapy in patients who need fast initiation of therapy, we allow use of karyotype and/or fluorescence in situ hybridization (FISH) results (as well as FLT3 results) on samples from blood or marrow that were obtained up to 3 weeks before signing consent for purposes of eligibility and stratification. In any case, results from FISH or karyotype should show if CBF abnormalities are present by time of randomization as the presence of core-binding factor (CBF) abnormalities is a required stratification factor. Age > = 18 and =< 75 years Because no dosing or AE data are currently available on the use of pembrolizumab (MK-3475) in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials Eastern Cooperative Oncology Group (ECOG) performance status =< -2 The patient has to be eligible to receive intensive 7+3 induction chemotherapy as judged by the treating physician Prior use of hypomethylating agents (HMA), lenalidomide, erythropoiesis-stimulating agents (ESAs), and growth factors is allowed if used to treat prior MDS. AML must be previously untreated except as outlined below (hydroxyurea, or tretinoin [ATRA], or leukapheresis). Note: One dose of prophylactic intrathecal therapy is allowed during or before screening if a lumbar puncture is performed to rule out central nervous system (CNS) involvement. Hydroxyurea/leukapheresis allowed for control of hyperleukocytosis but hydroxyurea must be discontinued day prior to start of chemotherapy Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (CrCl) >= 60 mL/min for patient with creatinine levels > 1.5 x institutional ULN (within 3 days prior to the first day of 7+3) Creatinine clearance (CrCl) should be calculated per institutional standard Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl Total bilirubin =< 1.5 x ULN or direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 x ULN (within 3 days prior to the first day of 7+3) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN OR =< 5 x ULN for patients with liver metastases (within 3 days prior to the first day of 7+3) International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 3 days prior to the first day of 7+3) Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 3 days prior to the first day of 7+3) Patients with a known history of being human immunodeficiency virus (HIV) positive may participate IF they meet the following eligibility requirements: They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective Patients must have an undetectable HIV viral load Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Patients who have undergone major surgery must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this trial, patients should be class 2B or better Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of 7+3 treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). Female patients of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication. Male patients with female partners 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 patient Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible Exclusion Criteria: Patients with a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Prior treatment with the following are not allowed: Patients who have received anthracyclines for treatment of a prior, unrelated, curatively-treated malignancy which would limit their ability to receive 7 + 3 chemotherapy treatment on study Anti-PD-1, anti-PD-L1, or anti-PD-L2, for a prior, unrelated, curatively-treated malignancy, within last 3 months of enrollment in the study Anti-cancer monoclonal antibody (mAb) within 4 weeks, for a prior, unrelated, curatively-treated malignancy, prior to study registration or have not recovered (recovery defined as baseline or =< grade 1) from adverse events (AEs) due to agents administered more than 4 weeks earlier Experimental treatment within 4 weeks prior to study registration Patients who have had chemotherapy (except hydroxyurea and all trans retinoic acid [ATRA] which are allowed but have to be stopped the day before induction therapy starts), targeted small molecule therapy (aside from imatinib, dasatinib, or nilotinib), or curative-intent radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C), for a prior curatively treated malignancy, prior to entering the study Patients who have received prior anthracyclines not to exceed 150 mg/m^2 of daunorubicin or equivalent for treatment of a prior, unrelated, curatively-treated malignancy which would limit their ability to receive 7 + 3 chemotherapy treatment on study Patients with a cardiac ejection fraction less than 50% as determined by Echocardiogram or radionuclide ventriculogram scan (MUGA) scan. Other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy for their cancer) Patients who have FLT3-mutated AML FLT3-ITD or TKD mutations are defined as a mutation with a ratio of mutant to wild-type allele >= 0.05 or variant allele fraction of >= 5% by polymerase chain reaction (PCR) or next generation sequencing from either bone marrow or peripheral blood Note 1: FLT3, karyotype, or FISH results from bone marrow or peripheral blood that were performed up to 3 weeks before initiation of trial therapy are acceptable for eligibility determination or therapy stratification as long as they are performed in a Clinical Laboratory Improvement Act (CLIA) certified laboratory. Note 2: Patients are stratified based on age (younger than 65 verses (vs) 65 and older), presence of core-binding abnormalities by FISH or karyotype (yes/no), and by having t- AML or AML arising from prior/antecedent MDS (yes/no) Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., have not returned to baseline or have residual toxicities > grade 1) with the exception of =< grade 2 neuropathy and alopecia NOTE: Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease Patients currently participating and receiving study therapy or have participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment are ineligible History of hypersensitivity to MK-3475 (pembrolizumab) or any of its excipients, or other agents used in this study Current use of corticosteroids EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g., chronic adrenal insufficiency) is permitted Patients who underwent prior allogenic transplant Patients with a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) who are not on appropriate suppressive therapy Patient with 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 Patient with known active CNS disease and/or carcinomatous meningitis before study enrollment. Assessment of the cerebral spinal fluid (CSF) as per investigator judgement. Up to one dose of prophylactic intrathecal chemotherapy is allowed prior to study enrollment is not required to enroll in the study unless there is clinical suspicion for CNS involvement. However, if CSF assessment is performed for any reason, there should be no evidence of active leukemia in the CSF. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of protocol 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 protocol treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Patients with active autoimmune disease except for patients with hypothyroidism and vitiligo that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment Patients with a known history of non-infectious pneumonitis that required the use of steroids or current pneumonitis Patients with active infection requiring systemic therapy Patients with a known history of active TB (Bacillus tuberculosis) Patients with uncontrolled intercurrent illness Patients with psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study because MK-3475 (pembrolizumab) is humanized antibody with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MK-3475 (pembrolizumab), breastfeeding should be discontinued if the mother is treated with MK-3475 (pembrolizumab). These potential risks may also apply to other agents used in this study Patient who have 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 Active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation Patients with clinically significant disseminated intravascular coagulation (DIC), which cannot be managed with supportive care including transfusions, as assessed by treating physician, will be excluded from study Patients with no bone marrow involvement will be excluded (i.e., those with only extramedullary disease) Patients with acute promyelocytic leukemia will be excluded

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (cytarabine, idarubicin, daunorubicin, HSCT)<br>See Design details. | Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Drug: Cytarabine<br>* Given via continuous IV infusion<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Hematopoietic Cell Transplantation<br>* Undergo HSCT<br>* Other names: Stem Cell Transplantation, NOS;Drug: Idarubicin Hydrochloride<br>* Given IV<br>* Other names: Zavedos;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Procedure: Punch Biopsy<br>* Undergo a skin punch biopsy<br>* Other names: Punch Biopsy of Skin;|
| Active Comparator: Arm II (cytarabine, idarubicin, daunorubicin, HSCT)<br>See Design details. | Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Drug: Cytarabine<br>* Given via continuous IV infusion<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Hematopoietic Cell Transplantation<br>* Undergo HSCT<br>* Other names: Stem Cell Transplantation, NOS;Drug: Idarubicin Hydrochloride<br>* Given IV<br>* Other names: Zavedos;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Procedure: Punch Biopsy<br>* Undergo a skin punch biopsy<br>* Other names: Punch Biopsy of Skin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with minimal residual disease - complete response (MRD-CR) | MRD will be assessed by multicolor flow cytometry as an integral biomarker. | At time of count recovery after first cycle of consolidation therapy with chemotherapy and pembrolizumab | 
| Rate of MRD-negative CR |  | At end of induction therapy | 
| Rate of MRD-negative CR |  | At end of consolidation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the rate of CR/incomplete count recovery (CRi) | Will be defined per European LeukemiaNet 2017. | At time of count recovery after induction therapy with chemotherapy and pembrolizumab | 
| MRD negativity |  | At day 14 | 
| Event-free survival |  | From randomization to failure to achieve CR/CRi, relapse or death from any cause, assessed up to 5 years | 
| Relapse-free survival (RFS) | Median RFS will be estimated with Kaplan-Meier curves with 95% confidence interval calculated based on the Brookmeyer-Crowley method | From first documentation of CR/CRi to either disease relapse or death from any cause, assessed up to 5 years | 
| Duration of response (DOR) | Median DOR will be estimated with Kaplan-Meier curves with 95% confidence interval calculated based on the Brookmeyer-Crowley method. | From first CR to the date of the first documented relapse or death, whichever occurs first, assessed up to 5 years | 
| Incidence of adverse events | Will be assessed per Common Terminology Criteria for Adverse Events version 5.0. | Up to 35 days from start of treatment |