- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04284787
BLAST MRD AML-2: BLockade of PD-1 Added to Standard Therapy to Target Measurable Residual Disease in Acute Myeloid Leukemia 2- A Randomized Phase 2 Study of Anti-PD-1 Pembrolizumab in Combination With Azacitidine and Venetoclax as Frontline Therapy in Unfit Patients With Acute Myeloid Leukemia
BLockade of PD-1 Added to Standard Therapy to Target Measurable Residual Disease in Acute Myeloid Leukemia 2 (BLAST MRD AML-2): A Randomized Phase 2 Study of the Venetoclax, Azacitadine, and Pembrolizumab (VAP) Versus Venetoclax and Azacitadine as First Line Therapy in Older Patients With Acute Myeloid Leukemia (AML) Who Are Ineligible or Who Refuse Intensive Chemotherapy
Study Overview
Status
Conditions
Detailed Description
PRIMARY OBJECTIVE:
I. Assess the percentage of patients with minimal residual disease (MRD) negative complete remission (CR) (MRD-CR) or complete remission with incomplete count recovery (MRD-CRi) with azacitidine (AZA) + venetoclax (VEN) with pembrolizumab during the first 6 cycles and compare to control arm.
SECONDARY OBJECTIVES:
I. Assess the investigator-assessed rates of CR/CRi/partial remission (PR)/morphological leukemia free state (MLFS) as defined per the modified International Working Group (IWG) 2003 response criteria with AZA + VEN with pembrolizumab, as well as rates of MRD negative MLFS.
II. Rates of complete remission with partial count recovery (CRh) and hematologic improvement (HI) to red blood cells and platelets.
III. Assess time to MRD negativity and duration of MRD negative state, event free survival (EFS), relapse free survival (RFS), calculated as the time from initial treatment to either disease relapse or death, 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).
IV. Assess the proportion of patients who develop severe toxicity.
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. Profiling of deoxyribonucleic acid (DNA) methylation patterns before and after treatment to assess for correlation to response to treatment.
VII. Correlate gut microbiome at baseline and changes in the microbiome with clinical response, both in standard chemotherapy and immunotherapy/chemotherapy therapy settings.
VIII. MRD assessment using duplex sequencing strategy for circulating cell-free tumor DNA and correlation with long-term outcomes.
IX. Exploring different thresholds of MRD negativity using flow cytometry aside from the 0.1% level that will be used for the primary endpoint purposes (e.g. 0.01%).
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I (AZA + VEN):
INDUCTION THERAPY PHASE: Patients receive azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) on days 1-7 or days 1-5 in week 1 and 1-2 in week 2. Patients also receive venetoclax orally (PO) on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY PHASE: Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2. Patients also receive venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Cycles repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. After completion of 24 cycles, patients who respond to treatment or have stable disease (SD) may continue treatment per physician discretion.
Patients also undergo bone marrow biopsy and/or aspiration and collection of blood samples throughout the trial and undergo a skin biopsy at baseline.
ARM II (AZA + VEN + PEMBROLIZUMAB):
INDUCTION THERAPY PHASE: Patients receive pembrolizumab IV over 30 minutes on day 8 of cycle 1 and every 3 weeks in cycle 2-6, azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2, and venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY PHASE: Patients receive pembrolizumab IV over 30 minutes on day 8 of cycle 1 and every 3 weeks in cycle 2-6, azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2, and venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. After completion of 24 cycles, patients who respond to treatment or have SD may continue treatment with azacitidine and venetoclax per physician discretion.
Patients also undergo bone marrow biopsy and/or aspiration and collection of blood samples throughout the trial and undergo a skin biopsy at baseline.
Patients are followed p every 6 months for up to 3 years.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Amer Zeidan
- Phone Number: 203-737-7103
- Email: amer.zeidan@yale.edu
Study Locations
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Connecticut
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Greenwich, Connecticut, United States, 06830
- Smilow Cancer Hospital Care center at Greenwich
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Hartford, Connecticut, United States, 06105
- Smilow Cancer Hospital Care Center at Saint Francis
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New Haven, Connecticut, United States, 06520
- Yale University
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District of Columbia
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Washington, District of Columbia, United States, 20007
- MedStar Georgetown University Hospital
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Illinois
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Chicago, Illinois, United States, 60611
- Northwestern University
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Kansas
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Hays, Kansas, United States, 67601
- HaysMed University of Kansas Health System
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Kansas City, Kansas, United States, 66160
- University of Kansas Cancer Center
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Lawrence, Kansas, United States, 66044
- Lawrence Memorial Hospital
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Olathe, Kansas, United States, 66061
- Olathe Health Cancer Center
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Overland Park, Kansas, United States, 66210
- University of Kansas Cancer Center-Overland Park
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Pittsburg, Kansas, United States, 66762
- Ascension Via Christi - Pittsburg
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Salina, Kansas, United States, 67401
- Salina Regional Health Center
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Topeka, Kansas, United States, 66606
- University of Kansas Health System Saint Francis Campus
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Westwood, Kansas, United States, 66205
- University of Kansas Hospital-Westwood Cancer Center
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Maryland
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Baltimore, Maryland, United States, 21287
- Johns Hopkins University/Sidney Kimmel Cancer Center
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Missouri
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Creve Coeur, Missouri, United States, 63141
- Siteman Cancer Center at West County Hospital
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Kansas City, Missouri, United States, 64154
- University of Kansas Cancer Center - North
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Kansas City, Missouri, United States, 64108
- Truman Medical Centers
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Lee's Summit, Missouri, United States, 64064
- University of Kansas Cancer Center - Lee's Summit
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North Kansas City, Missouri, United States, 64116
- University of Kansas Cancer Center at North Kansas City Hospital
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Saint Louis, Missouri, United States, 63110
- Washington University School of Medicine
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Saint Louis, Missouri, United States, 63129
- Siteman Cancer Center-South County
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Saint Louis, Missouri, United States, 63136
- Siteman Cancer Center at Christian Hospital
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Saint Peters, Missouri, United States, 63376
- Siteman Cancer Center at Saint Peters Hospital
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New Hampshire
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Lebanon, New Hampshire, United States, 03756
- Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
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North Carolina
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Clemmons, North Carolina, United States, 27012
- Wake Forest University at Clemmons
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Wilkesboro, North Carolina, United States, 28659
- Wake Forest Baptist Health - Wilkes Medical Center
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Winston-Salem, North Carolina, United States, 27157
- Wake Forest University Health Sciences
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Oklahoma
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Oklahoma City, Oklahoma, United States, 73104
- University of Oklahoma Health Sciences Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Newly diagnosed and pathologically-confirmed, previously untreated AML as defined by World Health Organization (WHO) criteria. 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 arising from prior myelodysplastic syndrome (MDS), as long as they have not received more than full cycle of hypomethylating agent therapy for MDS, and therapy related (t)-AML are also allowed. AML arising from prior antecedent hematologic disorders defined as MDS, myeloproliferative neoplasm (MPN), or aplastic anemia are 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 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 exclude presence of core-binding factor (CBF) abnormalities by time of randomization
- Age >= 60 years
- Patients who are ineligible for intensive chemotherapy according to treating physician's assessment or who refuse intensive chemotherapy
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-3
- Prior use of lenalidomide, erythropoiesis-stimulating agents (ESAs), and growth factors is allowed if used to treat prior MDS. AML must be previously untreated except for hydroxyurea, or all-trans retinoic acid (ATRA) for suspicion of APL but both should be discontinued prior to initiation of study therapy. Hypomethylating agents are not allowed to have been used for AML therapy. If hypomethylating agent therapy was used for prior MDS or MPN therapy then it should not have exceeded one full cycle. 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 or leukopheresis are allowed for management of hyperleukocytosis, as well as ATRA, before initiation of study therapy. White blood cell (WBC) count must be < 25 x 10^9/L to start on study therapy per venetoclax label. Hydroxyurea and ATRA may be administered up to one day prior to start of study treatment
- Intermediate-risk or poor risk AML as well as favorable risk by National Comprehensive Cancer Network (NCCN)/European LeukemiaNet (ELN) with the exception of "good-risk" cytogenic profile (i.e., for eligibility patient should lack the presence of t(8;21), (inv[16] or t[16;16]), or t(15;17) by full cytogenetics or FISH). Clarification: We allow use of karyotype and/or 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. Adverse karyotype can be determined based on FISH results (e.g., loss of chromosome 7 or 5 or 3 or more abnormalities) based on the specific probes used in the FISH. If results of full metaphase karyotype are not available and the available FISH results do not suggest an adverse karyotype, and there is a need to initiate therapy before those full results are available, then the patient can be stratified into the unknown/intermediate NCCN cytogenetic group for randomization purposes. In any case, results from FISH or karyotype should show that core-binding factor (CBF) abnormalities are NOT present by at time of randomization as the presence of CBF abnormalities is an exclusion factor
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
- 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
- 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
Patients who are 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
- Female patients of childbearing potential must have a negative urine or serum pregnancy test 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. 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 24 consecutive months (i.e., has had menses at any time in the preceding 24 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 who have a female partner 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 CBF-AML and acute promyelocytic leukemia (APL)
- Received a prior anti-cancer monoclonal antibodies (mAb) within 4 weeks 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
- Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- Patients who have had chemotherapy, targeted small molecule therapy (aside from imatinib, dasatinib, or nilotinib, hydroxyurea, or ATRA), or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
- Left ventricular ejection fraction < 50% as determined by either echocardiogram or multi-gated acquisition (MUGA)
Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., 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-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 pembrolizumab (MK-3475) or any of its excipients, or other agents used in this study
Current use of systemic corticosteroids or immunosuppressive agents
- 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) inhaled corticosteroids, or topical steroids are permitted
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)
- Patient with known active CNS disease and/or carcinomatous meningitis before study enrollment. Assessment of the cerebrospinal 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 as per investigator judgement. Up to one dose of prophylactic intrathecal chemotherapy is allowed prior to study enrollment. 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 who received prior allogenic transplant
- 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 a diagnosis of immunodeficiency or receiving high dose systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment
- Patient 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
- Patient with a known history of non-infectious pneumonitis that required the use of steroids or current non-infectious pneumonitis
- Patient with active uncontrolled infection
- Patient 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 pembrolizumab (MK-3475) 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 pembrolizumab, breastfeeding should be discontinued if the mother is treated with pembrolizumab. These potential risks may also apply to other agents used in this study
- Patients with no bone marrow involvement (i.e., those with only extramedullary disease)
- Patients who received prior hypomethylating agent (HMA) therapy for more than one full cycle in treatment for prior MDS. Patient must not have received HMA therapy for treatment of AML
Patients that 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 [registered trademark]) are live attenuated vaccines, and are not allowed
- Patients with 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Arm II (AZA, VEN, pembrolizumab)
INDUCTION THERAPY PHASE: Patients receive pembrolizumab IV over 30 minutes on day 8 of cycle 1 and every 3 weeks in cycle 2-6, azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2, and venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE: Patients receive pembrolizumab IV over 30 minutes on day 8 of cycle 1 and every 3 weeks in cycle 2-6, azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2, and venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. After completion of 24 cycles, patients who respond to treatment or have SD may continue treatment with azacitidine and venetoclax per physician discretion. |
Given IV or SC
Other Names:
Given IV
Other Names:
Given PO
Other Names:
Undergo biopsy
Other Names:
Undergo blood specimen collection
Other Names:
|
Active Comparator: Arm I (AZA, VEN)
INDUCTION THERAPY PHASE: Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2. Patients also receive venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY PHASE: Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7 or days 1-5 in week 1 and 1-2 in week 2. Patients also receive venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Cycles repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. After completion of 24 cycles, patients who respond to treatment or have SD may continue treatment per physician discretion. Patients also undergo bone marrow biopsy and/or aspiration and collection of blood samples throughout the trial and undergo a skin biopsy at baseline. |
Given IV or SC
Other Names:
Given PO
Other Names:
Undergo biopsy
Other Names:
Undergo bone marrow aspiration
Undergo blood specimen collection
Other Names:
Undergo bone marrow biopsy
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Percentage of patients with minimal residual disease negative complete remission (MRD-CR) or MRD-complete remission with incomplete count recovery (Cri) with azacitidine (AZA) + venetoclax (VEN) with MK-3475 (pembrolizumab)
Time Frame: Up to 6 cycles (each cycle is 28 days)
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Up to 6 cycles (each cycle is 28 days)
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Proportion of patients who develop severe toxicity
Time Frame: Up to cycle 2 (each cycle is 28 days)
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Up to cycle 2 (each cycle is 28 days)
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Biomarkers or serial measurements of biomarkers associated with survival outcomes
Time Frame: Baseline up to 3 years
|
The Kaplan-Meier method and log-rank test will be used to estimate the distribution of survival between/among different marker strata.
Univariate or Multivariate cox proportional hazard models will be employed to explore the significance of biomarkers on survival outcomes, while adjusting for the potential prognostic factors.
The interaction effects between treatment and biomarkers also will be evaluated.
Serial measurements of biomarkers will be estimated at baseline, end of induction, post-cycle 1, 2, 4, and 6, every 3 months during maintenance, one year, and end of treatment when applicable.
Landmark analysis or joint modeling will be used to assess serial measurements of biomarkers dynamical impacts on survival outcomes, where appropriate.
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Baseline up to 3 years
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Correlations between biomarkers
Time Frame: Up to 3 years
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The correlations between biomarkers will be evaluated using Pearson/Spearman rank-order correlation coefficients, Chi-squared/Fisher's exact tests, and Wilcoxon rank sun / Kruskal-Wallis tests as appropriate.
A scatter plot, boxplot, and mosaic plot will also be generated for visualization.
The multiplicity of the endpoints will be adjusted using the correction of Benjamini and Hochberg.
|
Up to 3 years
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MRD assessment
Time Frame: Up to 3 years
|
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.
|
Up to 3 years
|
Cytokine panel analysis
Time Frame: At day 30 (after administration of pembrolizumab and count recovery) and after cycles 2, 4, and 6 (each cycle is 28 days)
|
IFN-gamma+/CD3+/ CD4+ or IFN-gamma+/CD3+/CD8+ events will be gated and percentages of the total CD4+ and CD8+ T cells will be determined.
Will compare levels of leukemia specific T-cell.
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At day 30 (after administration of pembrolizumab and count recovery) and after cycles 2, 4, and 6 (each cycle is 28 days)
|
Expression of PD-1, PD-L1 in acute myeloid leukemia (AML) bone marrow (BM)
Time Frame: At day 14 and at time of count recovery
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An association of clinical response with the expression of PD-L1 AML BM cells will be assessed by a Pearson chi-square test on a 2x2 table of frequencies.
|
At day 14 and at time of count recovery
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Biomarkers or serial measurements of biomarkers associated with response outcomes
Time Frame: Baseline up to 3 years
|
A univariate logistic regression will be selected to assess baseline biomarkers associated with response outcomes.
The dynamic changes of PD-L1/ PD-1 expressions, concentration of cytokine, and ribonucleic acid sequencing (seq)/T-cell receptor seq etc. will be monitored.
The measurements of biomarkers in changes over time from baseline to several time-points will be performed by using generalized linear mixed effects modeling with a Benjamini-Hochberg correction to control for false discovery rates.
|
Baseline up to 3 years
|
Biomarkers effects between treatment arms
Time Frame: Up to 3 years
|
The associations between treatment arms and baseline biomarkers will be evaluated using Chi-squared test/ Fisher's exact test, analysis of variance and the Mann-Whitney U tests as appropriate.
Trajectory trends of the changes in markers' values or status across the measurement time will be explored using generalized linear mixed models.
The bar plots and trajectory time plots will visually show the differences over time between treatment arms.
The associations between markers and the demographic/prognostic factors will also be assessed using the similar statistical methods.
|
Up to 3 years
|
Dynamic change of immune subsets
Time Frame: Baseline up to cycle 6 (each cycle is 28 days)
|
Statistical analyses of the frequency of CD8+, CD4+, Foxp3 regulatory T cells, CD8+/Foxp3+ Tregs, central memory T cell/effector memory T cell re-expressed CD45RA (TEMRA), effector memory T cell/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.
|
Baseline up to cycle 6 (each cycle is 28 days)
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Amer M Zeidan, Yale University Cancer Center LAO
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Histologic Type
- Neoplasms
- Bone Marrow Diseases
- Hematologic Diseases
- Neoplastic Processes
- Myelodysplastic Syndromes
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Neoplasm, Residual
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Antineoplastic Agents, Immunological
- Immune Checkpoint Inhibitors
- Venetoclax
- Pembrolizumab
- Azacitidine
Other Study ID Numbers
- NCI-2020-01016 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- UM1CA186689 (U.S. NIH Grant/Contract)
- 10334 (Other Identifier: CTEP)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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Jacqueline Garcia, MDEli Lilly and CompanyCompletedCombination Merestinib and LY2874455 for Patients With Relapsed or Refractory Acute Myeloid LeukemiaRelapsed Adult Acute Myeloid Leukemia | Refractory Adult Acute Myeloid LeukemiaUnited States
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Massachusetts General HospitalExelixisCompletedRefractory Acute Myeloid Leukemia | Relapsed Acute Myeloid LeukemiaUnited States
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University of NebraskaNational Cancer Institute (NCI)Active, not recruitingSecondary Acute Myeloid Leukemia | Therapy-Related Acute Myeloid Leukemia | Adult Acute Myeloid LeukemiaUnited States
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City of Hope Medical CenterNational Cancer Institute (NCI)RecruitingAcute Myeloid Leukemia | Recurrent Adult Acute Myeloid Leukemia | Secondary Acute Myeloid Leukemia | Refractory Acute Myeloid LeukemiaUnited States
Clinical Trials on Azacitidine
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Shandong Provincial HospitalUnknownMyelodysplastic Syndromes,Acute Myeloid LeukemiaChina
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TJ Biopharma Co., Ltd.Recruiting
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Peter MacCallum Cancer Centre, AustraliaGlaxoSmithKline; Celgene CorporationCompletedMyelodysplastic Syndromes (MDS) | Acute Myeloid Leukaemia (AML)Australia
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Eisai Inc.TerminatedMyelodysplastic SyndromesUnited States
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Navy General Hospital, BeijingRecruitingRefractory Classic Hodgkin Lymphoma | Relapsed Classic Hodgkin LymphomaChina
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University of BirminghamRecruitingAcute Myeloid Leukemia | MyelodysplasiaUnited Kingdom
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Nanexa ABUppsala UniversityCompletedMyelodysplastic Syndromes (MDS) | Acute Myeloid Leukemia (AML) | Chronic Myelomonocytic Leukemia (CMML)Sweden
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The First Affiliated Hospital of Soochow UniversityEnrolling by invitationMyelodysplastic/Myeloproliferative Neoplasms | AdultChina
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Bristol-Myers SquibbRecruitingMyelodysplastic SyndromesUnited States, Japan, Argentina, Hong Kong, Greece, Italy, China, Australia, Spain, Austria, Denmark, Germany, Sweden, Switzerland, Canada, Czechia, Korea, Republic of, Poland, Turkey, France
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CelgeneCompletedMyelodysplastic SyndromesUnited States