Patient case: 13-year-old male with acute myeloid leukemia; genetic feature: FLT3

Clinical trial: Azacitidine With or Without Nivolumab or Midostaurin, or Decitabine and Cytarabine Alone in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

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 previously untreated 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 this patient population. (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 and outcomes for each of the regimens in this patient population.
  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 60 minutes on days 1 and 14. 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 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.

Eligibility: Inclusion Criteria:
  -  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 registration
  -  Patient must not be known to have AML in the central nervous system (CNS)
  -  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 on the S1612 Onstudy Form
  -  Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 42 days prior to registration to S1612; reports of the results must be submitted
  -  Patients must have specimens submitted for FLT3 testing for randomization stratification; collection of pretreatment specimens must be completed within 42 days prior to registration to S1612; specimens must be submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System; e-mail notification of FLT3 testing must be received prior to registration
  -  Patients must be offered participation in specimen banking; with patient consent, collection of pretreatment specimens must be completed within 28 days prior to registration, and specimens must be submitted via the SWOG Specimen Tracking System
  -  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 registration
  -  Patients may have received non-intensive therapy for antecedent hematologic disorders, including lenalidomide and growth factors; patients may have received prior chemotherapy for prior cancers; these therapies must be discontinued at least 5 days prior to registration
  -  Patients who have received prior therapy with hypomethylating agents or a deoxyribonucleic acid (DNA)-methyltransferase inhibitory for any condition, or prior 7+3 therapy for MDS, are not eligible
  -  The following tests must be performed within 14 days prior to registration to establish baseline values:
  -  Performance status
  -  Complete blood count (CBC)/differential/platelets
  -  Serum creatinine
  -  Total bilirubin
  -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
  -  Lactate dehydrogenase (LDH)
  -  Albumin
  -  Glucose
  -  Fibrinogen
  -  Electrocardiogram (ECG)
  -  Patients must have complete history and physical examination within 28 days prior to registration; history must include autoimmune disease status
  -  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 heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; 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
  -  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
  -  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
  -  ARM B ELIGIBILITY
  -  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
  -  ARM C ELIGIBILITY
  -  Patients must have direct bilirubin =< 2.5 x institutional upper limit of normal (IULN)
  -  Patients must have serum creatinine =< 2.5 x IULN
  -  Patients must have corrected QT (QTc) interval < 500/msec on baseline ECG
  -  Patients must not have any history of hypersensitivity to any drugs or metabolites of midostaurin

Relevance to patient case: not relevant