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
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ClinicalTrials.gov Identifier: NCT04214249
Recruitment Status :
(Other - pending protocol updates)
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. Drugs used in chemotherapy, 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.
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.
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.
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).
OUTLINE: Patients are randomized to 1 of 2 arms.
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.
ARM I: Within 4 weeks of remission status documentation, patients receive high-dose cytarabine (HiDAC) IV over 1-3 hours every 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.
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.
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.
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
Actual Study Start Date :
June 1, 2020
Estimated Primary Completion Date :
July 31, 2024
Estimated Study Completion Date :
July 31, 2024
Resource links provided by the National Library of Medicine
Percentage of patients with minimal residual disease - complete response (MRD-CR) [ Time Frame: At time of count recovery after first cycle of consolidation therapy with chemotherapy and pembrolizumab ]
MRD will be assessed by multicolor flow cytometry as an integral biomarker.
Rate of MRD-negative CR [ Time Frame: At end of induction therapy ]
Rate of MRD-negative CR [ Time Frame: At end of consolidation ]
Secondary Outcome Measures :
Assess the rate of CR/incomplete count recovery (CRi) [ Time Frame: At time of count recovery after induction therapy with chemotherapy and pembrolizumab ]
Will be defined per European LeukemiaNet 2017.
MRD negativity [ Time Frame: At day 14 ]
Event-free survival [ Time Frame: From randomization to failure to achieve CR/CRi, relapse or death from any cause, assessed up to 5 years ]
Relapse-free survival (RFS) [ Time Frame: From first documentation of CR/CRi to either disease relapse or death from any cause, assessed up to 5 years ]
Median RFS will be estimated with Kaplan-Meier curves with 95% confidence interval calculated based on the Brookmeyer-Crowley method
Duration of response (DOR) [ Time Frame: From first CR to the date of the first documented relapse or death, whichever occurs first, assessed up to 5 years ]
Median DOR will be estimated with Kaplan-Meier curves with 95% confidence interval calculated based on the Brookmeyer-Crowley method.
Incidence of adverse events [ Time Frame: Up to 35 days from start of treatment ]
Will be assessed per Common Terminology Criteria for Adverse Events version 5.0.
Other Outcome Measures:
MRD assessment [ Time Frame: Up to end of consolidation ]
Will be assessed by duplex sequencing. Library preparation, sequencing, and analysis will be performed with TwinStrand's optimized workflow, and TwinStrand's bioinformatics core will perform all analyses related to assay output.
MRD detection [ Time Frame: Up to end of consolidation ]
Will compare duplex sequencing and multiparameter flow cytometry for MRD detection. McNemar's Chi-squared test for paired samples (regular duplex sequencing versus multiparameter flow cytometry and ultra-deep duplex sequencing versus multiparameter flow cytometry) will be used to compare the MRD measures.
Immune cell subsets [ Time Frame: At time of relapse, assessed up to 3 years ]
Will assess immune cell subsets and correlate with response to combine chemotherapy and anti PD-1 directed therapy using mass cytometry. All data will be analyzed and graphs generated using the DVS Cytobank software (Cytobank). Will also measure CD47 levels on leukemic blasts prior to and after chemotherapy and pembrolizumab application to see whether CD47 expression levels correlate with responders versus non-responders and whether expression levels change at different times of therapy. Statistical analyses of the frequency of CD8 positive (+), CD4+, Foxp3 T regulatory cells (Tregs), CD8+/Foxp3+ Tregs, central memory effector (TCM)/ memory cells that re-express CD45RA (TEMRA), effector memory (TEM)/TEMRA, the percentage of Ki67 and GzmB in PD-1+, Eomes+ CD8 T-cells to compare changes over time from baseline to several time-points will be performed by using mixed effects modeling with a Benjamini-Hochberg correction to control for false discovery rates.
PD-1 and PD-L1 expression [ Time Frame: At time of relapse, assessed up to 3 years ]
An association of clinical response with the expression of PD-L1 acute myeloid leukemia bone marrow cells will be assessed by a Pearson Chi-square test on a 2 x 2 table of frequencies. The dependent variable will be defined as response (yes versus no), and quantitative immunofluorescence categories (negative versus positive) will be the independent variables. Will also monitor the dynamic change of PD-L1 expression over the course of treatment and its correlation with clinical response. Longitudinal measurements of PD-L1 will be examined using mixed-effects modeling.
Genomic deoxyribonucleic acid (DNA) of tumor cells [ Time Frame: Baseline ]
Will use massively parallel sequencing technology to sequence the genomic DNA of tumor cells (leukemic bone marrow) and normal cells (germline) obtained from patients with acute myeloid leukemia. Mutational load by whole-exome sequencing will be correlated with clinic-pathological parameters such as response to treatment, survival and immune infiltrating profile, and T cell repertoire diversity and clonality.
Protein signatures [ Time Frame: At time of relapse, assessed up to 3 years ]
Will investigate protein signatures associated with response and efficacy using the Olink inflammation biomarker panel.
Ribonucleic acid (RNA) integrity of formalin fixed paraffin-embedded RNA [ Time Frame: Up to time of relapse, assessed up to 3 years ]
Will be assessed using either the Agilent 4200 TapeStation and High Sensitivity RNA ScreenTape or the Agilent 2100 Bioanalyzer and RNA 6000 Pico Chip. Either method will employ the region analysis method to determine the percentage of RNA in the sample that is > 200 nt for each sample to be processed.
T cell receptor (TCR) sequencing [ Time Frame: Up to time of relapse, assessed up to 3 years ]
Will perform high-throughput sequencing of the TCR V beta 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. TCR diversity and clonality will be calculated using a software by Adaptive Technologies. T-cell repertoire diversity and clonality will be correlated with clinic-pathological parameters such as response to treatment, survival, and immune infiltrating profile, as well as genomic profiles (total mutation burden, non-synonymous mutation burden, predicted neoantigen burden, clonal mutation burden and clonal predicted neoantigen burden). TCR profile generated from treatment-refractory tumors at the time of disease progression will be compared to data from pre-treatment tumor samples to explore the TCR repertoire evolution of these tumors under therapeutic pressure.
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Layout table for eligibility information
Ages Eligible for Study:
18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:
Accepts Healthy Volunteers:
Newly diagnosed and pathologically-confirmed AML, confirmed by a bone marrow aspirate and/or biopsy with >= 20% myeloid blasts. Secondary AML (myelodysplastic syndrome [MDS]/AML, therapy-related [t]-AML) is also allowed. High risk MDS (EB2 with > 10% blasts) is excluded, but AML arising from prior MDS is allowed. AML arising from myeloproliferative neoplasms (MPN), MPN/MDS overlap (including chronic myelomonocytic leukemia [CMML]) or other hematologic malignancy are NOT allowed. Note: 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. Every effort should be made to get an aspirate for central flow assessment at screening and all subsequent required time points, but in cases were 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.
Eastern Cooperative Oncology Group (ECOG) performance status =< 1 and/or (Karnofsky >= 70%)
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
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 14 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 14 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 14 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 14 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 14 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 positive test for hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection might be enrolled if the viral load by polymerase chain reaction (PCR) is undetectable with/without active treatment
Patients who have received 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 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
Treatment with a BCR-ABL tyrosine kinase inhibitor (TKI) for another indication (e.g. a gastrointestinal stromal tumor [GIST]) is allowed in the study
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:
Patient 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%
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
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
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 received 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. Assessment of the cerebral spinal fluid (CSF) 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), 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