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Report for Clinical Trial NCT03092674

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Randomized Phase II/III Trial of "Novel Therapeutics" Versus Azacitidine in Newly Diagnosed Patients With Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS), Age 60 or Older LEAP: Less-Intense AML Platform Trial

This randomized phase II/III trial studies how well azacitidine with or without nivolumab or midostaurin, or decitabine and cytarabine alone work in treating older patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Drugs used in chemotherapy, such as azacitidine, decitabine, and cytarabine, 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 nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Midostaurin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine with or without nivolumab or midostaurin, or decitabine and cytarabine alone may kill more cancer cells.

NCT03092674 Acute Myeloid Leukemia Myelodysplastic Syndrome Myelodysplastic Synd Myelodysplastic Syndrome With Excess Blasts-2
MeSH: Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Preleukemia Myelodysplastic Syndromes Anemia, Refractory, with Excess of Blasts Syndrome
HPO: Acute megakaryocytic leukemia Acute myeloid leukemia Leukemia Myelodysplasia Myeloid leukemia

6 Interventions

Name: Azacitidine

Description: Given SC or IV

Type: Drug

Arm A Arm A (azacitidine) Arm B (azacitidine, nivolumab) Arm C (azacitidine, midostaurin)

Name: Cytarabine

Description: Given IV

Type: Drug

Arm D (decitabine, cytarabine)

Name: Decitabine

Description: Given IV

Type: Drug

Arm D (decitabine, cytarabine)

Name: Laboratory Biomarker Analysis

Description: Correlative studies

Type: Other

Arm A (azacitidine) Arm B (azacitidine, nivolumab) Arm C (azacitidine, midostaurin) Arm D (decitabine, cytarabine)

Name: Midostaurin

Description: Given PO

Type: Drug

Arm C (azacitidine, midostaurin)

Name: Nivolumab

Description: Given IV

Type: Biological

Arm B (azacitidine, nivolumab)


Primary Outcomes

Description: A stratified log-rank test of the null hypothesis (hazard ratio=1) with a one-sided alpha of 15% will be used to test an experimental arm versus azacitidine for further phase III testing.

Measure: Overall survival (OS) (Phase II)

Time: Day of registration on study until death from any cause, assessed for up to 5 years

Description: Will compare OS between the control arm and experimental arm(s) selected in the Phase II study. An efficacy test will be done using a stratified log-rank test with a one-sided alpha of 0.5%. A futility test will be done using a stratified log-rank test (modified to test the alternative HR) with a one-sided alpha of 1.0%. Each final test (stratified log-rank test of the null hypothesis) of an experimental arm versus azacitidine will be done with a two-sided alpha of 4.8%.

Measure: OS (Phase III)

Time: Day of registration on study until death from any cause, assessed for up to 5 years

Other Outcomes

Description: Will estimate toxicity rates to within +/- 6% (95% confidence interval).

Measure: Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

Time: Up to 5 years

Description: Will be tabulated.

Measure: Remission rates

Time: Up to 5 years

Description: Will be estimated using the Kaplan-Meier method or cumulative incident endpoints and associations. Will be assessed using Cox regression models (for cause-specific hazards as appropriate). Landmark analyses of different response categories will be evaluated based on dates at which 75% and 90% of patients have achieved a response (with other quantiles analyzed as needed).

Measure: OS

Time: Day of registration on study until death from any cause, assessed for up to 5 years

Description: Will be estimated using the Kaplan-Meier method or cumulative incident endpoints and associations. Will be assessed using Cox regression models (for cause-specific hazards as appropriate). Landmark analyses of different response categories will be evaluated based on dates at which 75% and 90% of patients have achieved a response (with other quantiles analyzed as needed).

Measure: Relapse-free survival (RFS) defined as patients achieving complete remission (CR), or CR with incomplete hematological recovery (CRi)

Time: Date of achievement of a remission until the date of relapse or death from any cause, assessed for up to 5 years

Description: Will be estimated using the Kaplan-Meier method or cumulative incident endpoints and associations. Will be assessed using Cox regression models (for cause-specific hazards as appropriate). Landmark analyses of different response categories will be evaluated based on dates at which 75% and 90% of patients have achieved a response (with other quantiles analyzed as needed).

Measure: Event-free survival (EFS)

Time: Date of randomization to the first of: date of primary refractory disease; date of progressive disease; date off protocol therapy without CR or CRi; date of relapse from CR or CRi, or death from any cause, assessed for up to 5 years

Description: Will be estimated using the Kaplan-Meier method or cumulative incident endpoints and associations. Will be assessed using Cox regression models (for cause-specific hazards as appropriate). Landmark analyses of different response categories will be evaluated based on dates at which 75% and 90% of patients have achieved a response (with other quantiles analyzed as needed).

Measure: Cumulative incidence of relapse defined as achieving CR or CRi

Time: Date of achievement of a remission until the date of relapse or death, assessed for up to 5 years

Description: The prognostic effect of FLT3-ITD (positive versus negative or non-evaluable) with respect to the outcome OS will be evaluated using Cox regression models. The predictive effect of FLT3-ITD (positive versus negative/non-evaluable) with respect to the outcome of OS and the treatments of azacitdine+midostaurin versus azacitidine will be evaluated using a Cox regression model with treatment arm and FLT3-ITD as covariates and including the interaction between the two covariates.

Measure: FLT3-ITD

Time: Up to 5 years

Description: Univariate and multivariable regression models will be used assess potential associations between outcomes (CR, OS, EFS, and RFS) and cytogenetic abnormalities and mutation status (including FLT3-ITD). Regression models including interaction terms with treatment arm will be fit. In addition to analyzing FLT3-ITD as categorical variable used in randomization stratification, we will analyze FLT3-TKD also and evaluate FLT3-ITD allelic ratio as a quantitative variable and as a binary variable using the threshold of 0.50.

Measure: Cytogenetic abnormalities, risk categories, and mutations in bone marrow

Time: Up to 5 years

Description: Only concurrently randomized patients will be evaluated in comparisons between arms.

Measure: Potential control arm drift

Time: Up to 5 years

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 S1612C

Only concurrently randomized patients will be evaluated in comparisons between arms.. Inclusion Criteria: - REGISTRATION STEP 1-SPECIMEN SUBMISSION - Patients must be suspected to have previously untreated acute myelogenous leukemia (AML) or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) - Patients must not be known to have AML in the central nervous system (CNS) - Patients must have specimens submitted for FLT3 testing for randomization stratification; collection of pretreatment specimens must be completed within 1 day of registration to Step 1; specimens must be submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System; FLT3 results will be used for stratification purposes at the time of randomization; E-mail notification of randomization assignment must be received prior to Step 2 registration - Patients must be offered participation in specimen banking; with patient consent, pretreatment specimens must be collected and submitted via the SWOG Specimen Tracking System - Patients who have received prior therapy with midostaurin, any anti-PD-1 or anti-PD-L1 therapy, any deoxyribonucleic acid (DNA)-methyltransferase inhibitor (including hypomethylating agents such as azacitidine, decitabine, or other investigational agent that acts by inhibiting DNA or ribonucleic acid [RNA] methylation) for any condition, or prior intensive cytotoxic therapy for myelodysplastic syndrome (MDS), are not eligible - Patients must be able to swallow oral medications without crushing or chewing - Prior malignancy is allowed providing it does not require concurrent therapy - Exception: active hormonal therapy is allowed - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception also includes (but is not limited to) heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or vasectomy; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Women must agree to avoid breast-feeding and women of child-bearing potential (WOCBP) must agree to use highly effective contraception while receiving study drug and for a period of 31 weeks after the last dose of study drug; sexually-active men must agree to use a condom while receiving study drug and for 31 weeks after the last dose of study drug; vasectomized men must also agree to use a condom to avoid delivering drug in the seminal fluid - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - REGISTRATION STEP 2-RANDOMIZATION: Patients must be registered to Step 2 no more than 42 days after registration to Step 1 and no more than 42 days after collection of specimens for FLT3 testing - REGISTRATION STEP 2-RANDOMIZATION: Patients must have morphologically confirmed, previously untreated acute myeloid leukemia (AML) or MDS with excess blasts-2 (MDS-EB-2) - Patients with acute promyelocytic leukemia (APL), biphenotypic leukemia, blastic transformation of chronic myelogenous leukemia (CML or BCR/ABL), are not eligible - Patients must have disease present in the blood or bone marrow; patients with only extramedullary disease in the absence of bone marrow or blood involvement are not eligible - All tests for establishing baseline disease status eligibility must be based on blood and/or bone marrow examination performed within 42 days prior to randomization (registration Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients must not be known to have AML in the CNS - REGISTRATION STEP 2-RANDOMIZATION: Patients must be deemed, in the judgment of the treating physician, to be ineligible for intensive induction therapy, or must have refused intensive induction therapy; rationale for clinical determination or notation of patient decision must be made - REGISTRATION STEP 2-RANDOMIZATION: Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 42 days prior to randomization (registration Step 2); reports of the results must be submitted - REGISTRATION STEP 2-RANDOMIZATION: FLT3 results will be used for stratification purposes at the time of randomization; E-mail notification that FLT3 specimens have been processed must be received prior to randomization (registration Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Prior treatment with hydroxyurea is permitted; prior all-trans retinoic acid (ATRA) for suspected APL and prior intrathecal therapy are permitted, but must plan to be discontinued prior to initiating protocol therapy; patients with signs/symptoms of hyperleukocytosis or white blood cells (WBC) >= 50,000/mcL can be treated with leukapheresis prior to randomization (registration to Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients may have received non-intensive therapy for antecedent hematologic disorders, including lenalidomide; patients may have received prior chemotherapy for prior cancers; these therapies must be discontinued at least 5 days prior to randomization (registration to Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients who are transfusion-dependent and patients receiving growth factor support are eligible; patients must discontinue growth factor support prior to initiation of protocol therapy - REGISTRATION STEP 2-RANDOMIZATION: The following tests must be performed within 14 days prior to randomization (registration to Step 2) to establish baseline values: - Performance status - Complete blood count (CBC)/differential/platelets - Creatinine clearance (Cockcroft-Gault) - Total bilirubin - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) - Lactate dehydrogenase (LDH) - Albumin - Glucose - Fibrinogen - Electrocardiogram (ECG) - REGISTRATION STEP 2-RANDOMIZATION: Patients must have complete history and physical examination within 28 days prior to randomization (registration to Step 2); history must include autoimmune disease status (to determine whether patient is eligible for Arm B) - REGISTRATION STEP 2-RANDOMIZATION: Patients must not have active infection (systemic bacterial, fungal, or viral infection) that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement despite appropriate antibiotics or other treatment) - REGISTRATION STEP 2-RANDOMIZATION: Patients must be eligible for at least one of the currently active investigational treatment arms (S1612B or S1612C); if the patient does not meet eligibility criteria for at least one active investigational arm, then the patient is not eligible for S1612 - REGISTRATION STEP 2-RANDOMIZATION: Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - ARM B (AZACITIDINE + NIVOLUMAB) - Patients must not have active autoimmune disease that has required systemic treatment in 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 must have AST and ALT =< 2.5 x institutional upper limit of normal (IULN) - Patients must have total bilirubin =< 1.5 x IULN - Patients must have baseline troponin test performed for eligibility; however, no associated values must be met in order for the patient to be eligible - ARM C (AZACITIDINE + MIDOSTAURIN) - Patients must have total bilirubin =< 2.5 x IULN - Patients must have creatinine clearance =< 2.5 x IULN - Patients must have corrected QT (QTc) interval < 500/msec (by Bazett's formula) on baseline ECG - Patients must not have any history of hypersensitivity to any drugs or metabolites of midostaurin - All tests for establishing baseline values must be completed within 14 days prior to registration to Step 2 (randomization) Inclusion Criteria: - REGISTRATION STEP 1-SPECIMEN SUBMISSION - Patients must be suspected to have previously untreated acute myelogenous leukemia (AML) or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) - Patients must not be known to have AML in the central nervous system (CNS) - Patients must have specimens submitted for FLT3 testing for randomization stratification; collection of pretreatment specimens must be completed within 1 day of registration to Step 1; specimens must be submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System; FLT3 results will be used for stratification purposes at the time of randomization; E-mail notification of randomization assignment must be received prior to Step 2 registration - Patients must be offered participation in specimen banking; with patient consent, pretreatment specimens must be collected and submitted via the SWOG Specimen Tracking System - Patients who have received prior therapy with midostaurin, any anti-PD-1 or anti-PD-L1 therapy, any deoxyribonucleic acid (DNA)-methyltransferase inhibitor (including hypomethylating agents such as azacitidine, decitabine, or other investigational agent that acts by inhibiting DNA or ribonucleic acid [RNA] methylation) for any condition, or prior intensive cytotoxic therapy for myelodysplastic syndrome (MDS), are not eligible - Patients must be able to swallow oral medications without crushing or chewing - Prior malignancy is allowed providing it does not require concurrent therapy - Exception: active hormonal therapy is allowed - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception also includes (but is not limited to) heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or vasectomy; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Women must agree to avoid breast-feeding and women of child-bearing potential (WOCBP) must agree to use highly effective contraception while receiving study drug and for a period of 31 weeks after the last dose of study drug; sexually-active men must agree to use a condom while receiving study drug and for 31 weeks after the last dose of study drug; vasectomized men must also agree to use a condom to avoid delivering drug in the seminal fluid - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - REGISTRATION STEP 2-RANDOMIZATION: Patients must be registered to Step 2 no more than 42 days after registration to Step 1 and no more than 42 days after collection of specimens for FLT3 testing - REGISTRATION STEP 2-RANDOMIZATION: Patients must have morphologically confirmed, previously untreated acute myeloid leukemia (AML) or MDS with excess blasts-2 (MDS-EB-2) - Patients with acute promyelocytic leukemia (APL), biphenotypic leukemia, blastic transformation of chronic myelogenous leukemia (CML or BCR/ABL), are not eligible - Patients must have disease present in the blood or bone marrow; patients with only extramedullary disease in the absence of bone marrow or blood involvement are not eligible - All tests for establishing baseline disease status eligibility must be based on blood and/or bone marrow examination performed within 42 days prior to randomization (registration Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients must not be known to have AML in the CNS - REGISTRATION STEP 2-RANDOMIZATION: Patients must be deemed, in the judgment of the treating physician, to be ineligible for intensive induction therapy, or must have refused intensive induction therapy; rationale for clinical determination or notation of patient decision must be made - REGISTRATION STEP 2-RANDOMIZATION: Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 42 days prior to randomization (registration Step 2); reports of the results must be submitted - REGISTRATION STEP 2-RANDOMIZATION: FLT3 results will be used for stratification purposes at the time of randomization; E-mail notification that FLT3 specimens have been processed must be received prior to randomization (registration Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Prior treatment with hydroxyurea is permitted; prior all-trans retinoic acid (ATRA) for suspected APL and prior intrathecal therapy are permitted, but must plan to be discontinued prior to initiating protocol therapy; patients with signs/symptoms of hyperleukocytosis or white blood cells (WBC) >= 50,000/mcL can be treated with leukapheresis prior to randomization (registration to Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients may have received non-intensive therapy for antecedent hematologic disorders, including lenalidomide; patients may have received prior chemotherapy for prior cancers; these therapies must be discontinued at least 5 days prior to randomization (registration to Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients who are transfusion-dependent and patients receiving growth factor support are eligible; patients must discontinue growth factor support prior to initiation of protocol therapy - REGISTRATION STEP 2-RANDOMIZATION: The following tests must be performed within 14 days prior to randomization (registration to Step 2) to establish baseline values: - Performance status - Complete blood count (CBC)/differential/platelets - Creatinine clearance (Cockcroft-Gault) - Total bilirubin - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) - Lactate dehydrogenase (LDH) - Albumin - Glucose - Fibrinogen - Electrocardiogram (ECG) - REGISTRATION STEP 2-RANDOMIZATION: Patients must have complete history and physical examination within 28 days prior to randomization (registration to Step 2); history must include autoimmune disease status (to determine whether patient is eligible for Arm B) - REGISTRATION STEP 2-RANDOMIZATION: Patients must not have active infection (systemic bacterial, fungal, or viral infection) that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement despite appropriate antibiotics or other treatment) - REGISTRATION STEP 2-RANDOMIZATION: Patients must be eligible for at least one of the currently active investigational treatment arms (S1612B or S1612C); if the patient does not meet eligibility criteria for at least one active investigational arm, then the patient is not eligible for S1612 - REGISTRATION STEP 2-RANDOMIZATION: Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - ARM B (AZACITIDINE + NIVOLUMAB) - Patients must not have active autoimmune disease that has required systemic treatment in 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 must have AST and ALT =< 2.5 x institutional upper limit of normal (IULN) - Patients must have total bilirubin =< 1.5 x IULN - Patients must have baseline troponin test performed for eligibility; however, no associated values must be met in order for the patient to be eligible - ARM C (AZACITIDINE + MIDOSTAURIN) - Patients must have total bilirubin =< 2.5 x IULN - Patients must have creatinine clearance =< 2.5 x IULN - Patients must have corrected QT (QTc) interval < 500/msec (by Bazett's formula) on baseline ECG - Patients must not have any history of hypersensitivity to any drugs or metabolites of midostaurin - All tests for establishing baseline values must be completed within 14 days prior to registration to Step 2 (randomization) Acute Myeloid Leukemia Myelodysplastic Syndrome Myelodysplastic Synd Myelodysplastic Syndrome With Excess Blasts-2 Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Preleukemia Myelodysplastic Syndromes Anemia, Refractory, with Excess of Blasts Syndrome PRIMARY OBJECTIVES: I. To select, based on overall survival, any or all of the "Novel Therapeutic" regimens for further testing against azacitidine in patients age 60 and older with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome with excessive blasts-2 (MDS-EB-2). --- S1612C ---

Only concurrently randomized patients will be evaluated in comparisons between arms.. Inclusion Criteria: - REGISTRATION STEP 1-SPECIMEN SUBMISSION - Patients must be suspected to have previously untreated acute myelogenous leukemia (AML) or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) - Patients must not be known to have AML in the central nervous system (CNS) - Patients must have specimens submitted for FLT3 testing for randomization stratification; collection of pretreatment specimens must be completed within 1 day of registration to Step 1; specimens must be submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System; FLT3 results will be used for stratification purposes at the time of randomization; E-mail notification of randomization assignment must be received prior to Step 2 registration - Patients must be offered participation in specimen banking; with patient consent, pretreatment specimens must be collected and submitted via the SWOG Specimen Tracking System - Patients who have received prior therapy with midostaurin, any anti-PD-1 or anti-PD-L1 therapy, any deoxyribonucleic acid (DNA)-methyltransferase inhibitor (including hypomethylating agents such as azacitidine, decitabine, or other investigational agent that acts by inhibiting DNA or ribonucleic acid [RNA] methylation) for any condition, or prior intensive cytotoxic therapy for myelodysplastic syndrome (MDS), are not eligible - Patients must be able to swallow oral medications without crushing or chewing - Prior malignancy is allowed providing it does not require concurrent therapy - Exception: active hormonal therapy is allowed - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception also includes (but is not limited to) heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or vasectomy; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Women must agree to avoid breast-feeding and women of child-bearing potential (WOCBP) must agree to use highly effective contraception while receiving study drug and for a period of 31 weeks after the last dose of study drug; sexually-active men must agree to use a condom while receiving study drug and for 31 weeks after the last dose of study drug; vasectomized men must also agree to use a condom to avoid delivering drug in the seminal fluid - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - REGISTRATION STEP 2-RANDOMIZATION: Patients must be registered to Step 2 no more than 42 days after registration to Step 1 and no more than 42 days after collection of specimens for FLT3 testing - REGISTRATION STEP 2-RANDOMIZATION: Patients must have morphologically confirmed, previously untreated acute myeloid leukemia (AML) or MDS with excess blasts-2 (MDS-EB-2) - Patients with acute promyelocytic leukemia (APL), biphenotypic leukemia, blastic transformation of chronic myelogenous leukemia (CML or BCR/ABL), are not eligible - Patients must have disease present in the blood or bone marrow; patients with only extramedullary disease in the absence of bone marrow or blood involvement are not eligible - All tests for establishing baseline disease status eligibility must be based on blood and/or bone marrow examination performed within 42 days prior to randomization (registration Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients must not be known to have AML in the CNS - REGISTRATION STEP 2-RANDOMIZATION: Patients must be deemed, in the judgment of the treating physician, to be ineligible for intensive induction therapy, or must have refused intensive induction therapy; rationale for clinical determination or notation of patient decision must be made - REGISTRATION STEP 2-RANDOMIZATION: Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 42 days prior to randomization (registration Step 2); reports of the results must be submitted - REGISTRATION STEP 2-RANDOMIZATION: FLT3 results will be used for stratification purposes at the time of randomization; E-mail notification that FLT3 specimens have been processed must be received prior to randomization (registration Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Prior treatment with hydroxyurea is permitted; prior all-trans retinoic acid (ATRA) for suspected APL and prior intrathecal therapy are permitted, but must plan to be discontinued prior to initiating protocol therapy; patients with signs/symptoms of hyperleukocytosis or white blood cells (WBC) >= 50,000/mcL can be treated with leukapheresis prior to randomization (registration to Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients may have received non-intensive therapy for antecedent hematologic disorders, including lenalidomide; patients may have received prior chemotherapy for prior cancers; these therapies must be discontinued at least 5 days prior to randomization (registration to Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients who are transfusion-dependent and patients receiving growth factor support are eligible; patients must discontinue growth factor support prior to initiation of protocol therapy - REGISTRATION STEP 2-RANDOMIZATION: The following tests must be performed within 14 days prior to randomization (registration to Step 2) to establish baseline values: - Performance status - Complete blood count (CBC)/differential/platelets - Creatinine clearance (Cockcroft-Gault) - Total bilirubin - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) - Lactate dehydrogenase (LDH) - Albumin - Glucose - Fibrinogen - Electrocardiogram (ECG) - REGISTRATION STEP 2-RANDOMIZATION: Patients must have complete history and physical examination within 28 days prior to randomization (registration to Step 2); history must include autoimmune disease status (to determine whether patient is eligible for Arm B) - REGISTRATION STEP 2-RANDOMIZATION: Patients must not have active infection (systemic bacterial, fungal, or viral infection) that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement despite appropriate antibiotics or other treatment) - REGISTRATION STEP 2-RANDOMIZATION: Patients must be eligible for at least one of the currently active investigational treatment arms (S1612B or S1612C); if the patient does not meet eligibility criteria for at least one active investigational arm, then the patient is not eligible for S1612 - REGISTRATION STEP 2-RANDOMIZATION: Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - ARM B (AZACITIDINE + NIVOLUMAB) - Patients must not have active autoimmune disease that has required systemic treatment in 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 must have AST and ALT =< 2.5 x institutional upper limit of normal (IULN) - Patients must have total bilirubin =< 1.5 x IULN - Patients must have baseline troponin test performed for eligibility; however, no associated values must be met in order for the patient to be eligible - ARM C (AZACITIDINE + MIDOSTAURIN) - Patients must have total bilirubin =< 2.5 x IULN - Patients must have creatinine clearance =< 2.5 x IULN - Patients must have corrected QT (QTc) interval < 500/msec (by Bazett's formula) on baseline ECG - Patients must not have any history of hypersensitivity to any drugs or metabolites of midostaurin - All tests for establishing baseline values must be completed within 14 days prior to registration to Step 2 (randomization) Inclusion Criteria: - REGISTRATION STEP 1-SPECIMEN SUBMISSION - Patients must be suspected to have previously untreated acute myelogenous leukemia (AML) or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) - Patients must not be known to have AML in the central nervous system (CNS) - Patients must have specimens submitted for FLT3 testing for randomization stratification; collection of pretreatment specimens must be completed within 1 day of registration to Step 1; specimens must be submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System; FLT3 results will be used for stratification purposes at the time of randomization; E-mail notification of randomization assignment must be received prior to Step 2 registration - Patients must be offered participation in specimen banking; with patient consent, pretreatment specimens must be collected and submitted via the SWOG Specimen Tracking System - Patients who have received prior therapy with midostaurin, any anti-PD-1 or anti-PD-L1 therapy, any deoxyribonucleic acid (DNA)-methyltransferase inhibitor (including hypomethylating agents such as azacitidine, decitabine, or other investigational agent that acts by inhibiting DNA or ribonucleic acid [RNA] methylation) for any condition, or prior intensive cytotoxic therapy for myelodysplastic syndrome (MDS), are not eligible - Patients must be able to swallow oral medications without crushing or chewing - Prior malignancy is allowed providing it does not require concurrent therapy - Exception: active hormonal therapy is allowed - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception also includes (but is not limited to) heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or vasectomy; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Women must agree to avoid breast-feeding and women of child-bearing potential (WOCBP) must agree to use highly effective contraception while receiving study drug and for a period of 31 weeks after the last dose of study drug; sexually-active men must agree to use a condom while receiving study drug and for 31 weeks after the last dose of study drug; vasectomized men must also agree to use a condom to avoid delivering drug in the seminal fluid - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - REGISTRATION STEP 2-RANDOMIZATION: Patients must be registered to Step 2 no more than 42 days after registration to Step 1 and no more than 42 days after collection of specimens for FLT3 testing - REGISTRATION STEP 2-RANDOMIZATION: Patients must have morphologically confirmed, previously untreated acute myeloid leukemia (AML) or MDS with excess blasts-2 (MDS-EB-2) - Patients with acute promyelocytic leukemia (APL), biphenotypic leukemia, blastic transformation of chronic myelogenous leukemia (CML or BCR/ABL), are not eligible - Patients must have disease present in the blood or bone marrow; patients with only extramedullary disease in the absence of bone marrow or blood involvement are not eligible - All tests for establishing baseline disease status eligibility must be based on blood and/or bone marrow examination performed within 42 days prior to randomization (registration Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients must not be known to have AML in the CNS - REGISTRATION STEP 2-RANDOMIZATION: Patients must be deemed, in the judgment of the treating physician, to be ineligible for intensive induction therapy, or must have refused intensive induction therapy; rationale for clinical determination or notation of patient decision must be made - REGISTRATION STEP 2-RANDOMIZATION: Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 42 days prior to randomization (registration Step 2); reports of the results must be submitted - REGISTRATION STEP 2-RANDOMIZATION: FLT3 results will be used for stratification purposes at the time of randomization; E-mail notification that FLT3 specimens have been processed must be received prior to randomization (registration Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Prior treatment with hydroxyurea is permitted; prior all-trans retinoic acid (ATRA) for suspected APL and prior intrathecal therapy are permitted, but must plan to be discontinued prior to initiating protocol therapy; patients with signs/symptoms of hyperleukocytosis or white blood cells (WBC) >= 50,000/mcL can be treated with leukapheresis prior to randomization (registration to Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients may have received non-intensive therapy for antecedent hematologic disorders, including lenalidomide; patients may have received prior chemotherapy for prior cancers; these therapies must be discontinued at least 5 days prior to randomization (registration to Step 2) - REGISTRATION STEP 2-RANDOMIZATION: Patients who are transfusion-dependent and patients receiving growth factor support are eligible; patients must discontinue growth factor support prior to initiation of protocol therapy - REGISTRATION STEP 2-RANDOMIZATION: The following tests must be performed within 14 days prior to randomization (registration to Step 2) to establish baseline values: - Performance status - Complete blood count (CBC)/differential/platelets - Creatinine clearance (Cockcroft-Gault) - Total bilirubin - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) - Lactate dehydrogenase (LDH) - Albumin - Glucose - Fibrinogen - Electrocardiogram (ECG) - REGISTRATION STEP 2-RANDOMIZATION: Patients must have complete history and physical examination within 28 days prior to randomization (registration to Step 2); history must include autoimmune disease status (to determine whether patient is eligible for Arm B) - REGISTRATION STEP 2-RANDOMIZATION: Patients must not have active infection (systemic bacterial, fungal, or viral infection) that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement despite appropriate antibiotics or other treatment) - REGISTRATION STEP 2-RANDOMIZATION: Patients must be eligible for at least one of the currently active investigational treatment arms (S1612B or S1612C); if the patient does not meet eligibility criteria for at least one active investigational arm, then the patient is not eligible for S1612 - REGISTRATION STEP 2-RANDOMIZATION: Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - ARM B (AZACITIDINE + NIVOLUMAB) - Patients must not have active autoimmune disease that has required systemic treatment in 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 must have AST and ALT =< 2.5 x institutional upper limit of normal (IULN) - Patients must have total bilirubin =< 1.5 x IULN - Patients must have baseline troponin test performed for eligibility; however, no associated values must be met in order for the patient to be eligible - ARM C (AZACITIDINE + MIDOSTAURIN) - Patients must have total bilirubin =< 2.5 x IULN - Patients must have creatinine clearance =< 2.5 x IULN - Patients must have corrected QT (QTc) interval < 500/msec (by Bazett's formula) on baseline ECG - Patients must not have any history of hypersensitivity to any drugs or metabolites of midostaurin - All tests for establishing baseline values must be completed within 14 days prior to registration to Step 2 (randomization) Acute Myeloid Leukemia Myelodysplastic Syndrome Myelodysplastic Synd Myelodysplastic Syndrome With Excess Blasts-2 Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Preleukemia Myelodysplastic Syndromes Anemia, Refractory, with Excess of Blasts Syndrome PRIMARY OBJECTIVES: I. To select, based on overall survival, any or all of the "Novel Therapeutic" regimens for further testing against azacitidine in patients age 60 and older with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome with excessive blasts-2 (MDS-EB-2). --- S1612C --- --- S1612C ---



HPO Nodes


HPO:
Acute megakaryocytic leukemia
Genes 1
GATA1
Acute myeloid leukemia
Genes 50
KIT DDX41 SBDS LPP ETV6 DNMT3A TERT JAK2 NUP214 CEBPA BRCA2 TCIRG1 DNAJC21 TET2 FLT3 TET2 JAK2 SRP54 SF3B1 SRP54 SH3GL1 KRAS EFL1 PIGA MLLT10 SRP54 DNAJC21 DKC1 RUNX1 RUNX1 MPL CBFB NSD1 THPO ELANE NPM1 ASXL1 CHIC2 MLF1 DNAJC21 ERBB3 GFI1 GFI1 SRSF2 KIT PICALM RPS14 GATA2 SBDS TET2
Leukemia
Genes 190
ATM KRAS KIT RPS15A NF1 MPL RPL35A RPL11 RPL18 DDX41 SBDS LPP ETV6 BUB1B F13A1 DNMT3A JAK2 NUP214 FANCD2 MSH6 FANCA PIGL NRAS TCIRG1 BUB1 TET2 FLT3 TAL1 ATRX TREX1 PDGFRA SRP54 RPS29 PTPN11 CALR FANCE WIPF1 SF3B1 GATA2 GLI1 STS SH3GL1 XRCC4 MPL SH2B3 EFL1 PIGA TREM2 CBL MPL RUNX1 MPL PIGL THPO FANCG NSD1 BRD4 NSUN2 SH2B3 RARA GATA2 NPM1 CBL CHIC2 ERBB3 GFI1 TERT KIT BCR ARHGAP26 DYNC2LI1 EVC SCN10A GATA1 ELANE RNASEH2B RPS14 SH2B3 JAK2 RPL15 SBDS NRAS RPL26 RPL27 ADA2 RPS7 TYROBP F13B MSH2 BCR WAS TERC TP53 TRIP13 MYD88 NUTM1 RPS24 GNB1 TP53 DNMT3A TERT NUMA1 NUP214 RPL5 SAMD9L TET2 CFTR POT1 FANCC RPS10 EP300 EVC2 BUB1B CEBPA BRCA2 DNAJC21 CALR SCN9A LIG4 ADAR BLM TET2 JAK2 SMPD1 RNASEH2C SCN11A GATA2 BUB3 PRSS1 KIF11 BCR RPL35 TAL2 SRP54 IFIH1 ABL1 PDGFRB KRAS RNASEH2A TET2 MLLT10 SRP54 DNAJC21 DKC1 RUNX1 APC LIG4 CBFB BLM THPO CALR NBN JAK2 MLH1 RPS19 ELANE SAMD9L RPL31 PMS2 ASXL1 TSR2 MLF1 PIK3CA DNAJC21 RUNX1 GFI1 SRSF2 SETBP1 HAX1 RPS26 RPS17 FLT3 RPS27 PIK3R1 KRAS CEP57 PICALM CREBBP GATA2 CTRC MYD88 TET2 RPS28 ABL1 RB1 SPINK1 GATA1 NBN JAK2 SAMHD1
Myelodysplasia
Genes 93
NAGS MPL SLX4 TET2 TERT TRIP13 DDX41 SBDS TP53 ATRX TET2 SF3B1 BUB1B TCIRG1 DNAJC21 RFWD3 BUB1 TET2 FANCL ATRX ASXL1 TET2 JAK2 SAMD9 SRP54 RPS14 PALB2 GINS1 SMARCD2 GATA2 SF3B1 BUB3 GATA2 SRP54 TET2 FANCB FANCE TET2 FANCM RFWD3 EFL1 RAD51 PIGA SRP54 DNAJC21 RAF1 DKC1 MPL RUNX1 MPL FANCD2 BRAF LIG4 FANCG RECQL4 THPO NBEAL2 CALR JAK2 TERC ERCC4 FANCI ELANE GATA2 SRP72 FANCG ASXL1 FANCC BRCA1 ERBB3 PTPN11 BRIP1 GFI1 SRSF2 HSPA9 KIT HAX1 GFI1B MAD2L2 CEP57 RPS14 FANCF SH2B3 XRCC2 RPS19 TINF2 SBDS TET2 BRCA2 RAD51C UBE2T JAK2 FANCA
Myeloid leukemia
Genes 20
KIT SETBP1 NF1 ARHGAP26 CBL TET2 KRAS PTPN11 F13A1 SAMD9L SAMD9L GATA2 CBL ASXL1 DNMT3A F13B NRAS SRSF2 TERC TERT