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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

NCT03092674

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Refractory Anemia with Excess Blasts
Recruiting Status:

Suspended

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00436
  • SECONDARY ID: NCI-2017-00436
  • SECONDARY ID: S1612
  • SECONDARY ID: S1612
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT03092674

Conditions

  • Acute Myeloid Leukemia
  • Adult Myelodysplastic Syndrome
  • Myelodysplastic Syndrome With Excess Blasts-2
  • Untreated Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaArm A (azacitidine)
Cytarabine.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-28453Arm D (decitabine, cytarabine)
Decitabine5-Aza-2'-deoxycytidine, Aza-TdC, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineArm D (decitabine, cytarabine)
MidostaurinCGP 41251, CGP41251, N-Benzoyl-Staurosporine, N-Benzoylstaurosporine, PKC-412, PKC412, RydaptArm C (azacitidine, midostaurin)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm B (azacitidine, nivolumab)

Purpose

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. Monoclonal antibodies, such as nivolumab, may interfere with the ability of cancer 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.

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 days 1-5 and 8-9. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (azacitidine)Active ComparatorPatients receive azacitidine SC or IV daily on days 1-7 or days 1-5 and 8-9. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
Arm B (azacitidine, nivolumab)ExperimentalPatients 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.
  • Azacitidine
Arm C (azacitidine, midostaurin)ExperimentalPatients 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.
  • Azacitidine
  • Midostaurin
Arm D (decitabine, cytarabine)ExperimentalINDUCTION: 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.
  • Cytarabine
  • Decitabine

Eligibility 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 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS) (Phase II)
Time Frame:Day of registration on study until death from any cause, assessed for up to 5 years
Safety Issue:
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.

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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