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Azacitidine With or Without Nivolumab or Midostaurin, or Decitabine and Cytarabine Alone in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

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ClinicalTrials.gov Identifier: NCT03092674
Recruitment Status : Suspended (Other - Safety data review, unscheduled)
First Posted : March 28, 2017
Last Update Posted : January 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplastic Syndrome Myelodysplastic Syndrome With Excess Blasts-2 Untreated Adult Acute Myeloid Leukemia Drug: Azacitidine Drug: Cytarabine Drug: Decitabine Other: Laboratory Biomarker Analysis Drug: Midostaurin Biological: Nivolumab Phase 2 Phase 3

Detailed Description:

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). (Phase II) II. To compare overall survival of the "Novel Therapeutic" regimens selected in the phase II portion of the trial to azacitidine in these patient populations. (Phase III)

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities of the regimens in these patient populations.

II. To estimate response rates, event-free survival, and relapse-free survival for these regimens in these patient populations.

TERTIARY OBJECTIVES:

I. To investigate associations between cytogenetic and molecular abnormalities (including FLT3) and outcomes for each of the regimens in these patient populations.

II. To bank specimens for future correlative studies.

OUTLINE: Patients are randomized to 1 of 4 arms.

ARM A: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) daily on days 1-7 or on an interrupted schedule which ensures that all 7 days of therapy are received within a 12 day period. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive azacitidine as in Arm A and nivolumab IV over 30-60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive azacitidine as in Arm A and midostaurin orally (PO) twice daily (BID) on days 8-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM D:

INDUCTION: Patients receive decitabine IV over 2 hours on days 1-5 and cytarabine IV continuously on days 6-11. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients deemed stable at the discretion of the treating physician receive decitabine as in Induction. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, then annually for 2 years.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1670 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 22, 2017
Estimated Primary Completion Date : August 1, 2023
Estimated Study Completion Date : August 1, 2023


Arm Intervention/treatment
Active Comparator: Arm A (azacitidine)
Patients receive azacitidine SC or IV daily on days 1-7 or on an interrupted schedule which ensures that all 7 days of therapy are received within a 12 day period. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Azacitidine
Given SC or IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Other: Laboratory Biomarker Analysis
Correlative studies

Experimental: Arm B (azacitidine, nivolumab)
Patients receive azacitidine as in Arm A and nivolumab IV over 30-60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Azacitidine
Given SC or IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Experimental: Arm C (azacitidine, midostaurin)
Patients receive azacitidine as in Arm A and midostaurin orally (PO) twice daily (BID) on days 8-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Azacitidine
Given SC or IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Midostaurin
Given PO
Other Names:
  • CGP 41251
  • CGP41251
  • N-Benzoyl-Staurosporine
  • N-Benzoylstaurosporine
  • PKC-412
  • PKC412
  • Rydapt

Experimental: Arm D (decitabine, cytarabine)

INDUCTION: Patients receive decitabine IV over 2 hours on days 1-5 and cytarabine IV continuously on days 6-11. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients deemed stable at the discretion of the treating physician receive decitabine as in Induction. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Cytarabine
Given IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Drug: Decitabine
Given IV
Other Names:
  • 5-Aza-2'-deoxycytidine
  • Aza-TdC
  • Dacogen
  • Decitabine for Injection
  • Deoxyazacytidine
  • Dezocitidine

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. Overall survival (OS) (Phase II) [ Time Frame: Day of registration on study until death from any cause, assessed for up to 5 years ]
    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.

  2. OS (Phase III) [ Time Frame: Day of registration on study until death from any cause, assessed for up to 5 years ]
    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%.


Other Outcome Measures:
  1. Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 [ Time Frame: Up to 5 years ]
    Will estimate toxicity rates to within +/- 6% (95% confidence interval).

  2. Remission rates [ Time Frame: Up to 5 years ]
    Will be tabulated.

  3. OS [ Time Frame: Day of registration on study until death from any cause, assessed for up to 5 years ]
    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).

  4. Relapse-free survival (RFS) defined as patients achieving complete remission (CR), or CR with incomplete hematological recovery (CRi) [ Time Frame: Date of achievement of a remission until the date of relapse or death from any cause, assessed for up to 5 years ]
    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).

  5. Event-free survival (EFS) [ Time Frame: 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 ]
    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).

  6. Cumulative incidence of relapse defined as achieving CR or CRi [ Time Frame: Date of achievement of a remission until the date of relapse or death, assessed for up to 5 years ]
    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).

  7. FLT3-ITD [ Time Frame: Up to 5 years ]
    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.

  8. Cytogenetic abnormalities, risk categories, and mutations in bone marrow [ Time Frame: Up to 5 years ]
    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.

  9. Potential control arm drift [ Time Frame: Up to 5 years ]
    Only concurrently randomized patients will be evaluated in comparisons between arms.



Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03092674


  Show 509 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Laura Michaelis Southwest Oncology Group

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03092674     History of Changes
Other Study ID Numbers: NCI-2017-00436
NCI-2017-00436 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1612 ( Other Identifier: SWOG )
S1612 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
First Posted: March 28, 2017    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Anemia, Refractory, with Excess of Blasts
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Anemia, Refractory
Anemia
Nivolumab
Decitabine
Midostaurin
Cytarabine
Azacitidine
Antibodies, Monoclonal
Staurosporine
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents