Cytarabine and Daunorubicin Hydrochloride or Idarubicin and Cytarabine With or Without Vorinostat in Treating Younger Patients With Previously Untreated Acute Myeloid Leukemia
Condition: Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 3

Summary: 
      This randomized phase III trial studies cytarabine and daunorubicin hydrochloride or
      idarubicin and cytarabine with or without vorinostat to see how well they work in treating
      younger patients with previously untreated acute myeloid leukemia. Drugs used in
      chemotherapy, such as cytarabine, daunorubicin hydrochloride, idarubicin, and vorinostat,
      work in different ways to stop the growth of cancer cells, either by killing the cells,
      stopping them from dividing, or by stopping from spreading. Giving more than one drug
      (combination chemotherapy) and giving the drugs in different doses and in different
      combinations may kill more cancer cells. It is not yet known which combination chemotherapy
      is more effective in treating acute myeloid leukemia.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. To compare event-free survival (EFS) between patients with acute myeloid leukemia (AML)
      who receive standard 7+3 (cytarabine and daunorubicin hydrochloride) or idarubicin and
      high-dose cytarabine (IA) to patients who receive IA + vorinostat. (Chemotherapy) II. To
      determine whether it is possible to get 60% or more of adults with high-risk AML (by
      cytogenetics) in first complete remission (CR1) to allogeneic hematopoietic cell
      transplantation (HCT). (Transplant)

      SECONDARY OBJECTIVES:

      I. To estimate the frequency and severity of toxicities of the three regimens in this patient
      population. (Chemotherapy) II. To estimate disease-free survival (DFS) among patients who
      receive transplant. (Transplant) III. To compare event-free survival (EFS) between patients
      who receive standard 7 + 3 to patients who receive IA. (Chemotherapy) IV. To estimate the
      prevalence of the mutations nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPM1),
      isocitrate dehydrogenase 1 (NADP+), soluble (IDH1), isocitrate dehydrogenase 2 (NADP+),
      mitochondrial (IDH2), tet methylcytosine dioxygenase 2 (TET2) and deoxyribonucleic acid (DNA)
      (cytosine-5-)-methyltransferase 3 alpha (DNMT3A) and the cytogenetic risk distribution of
      patients on this study and to evaluate the association between these and overall survival
      (OS), event-free survival (EFS), disease-free survival (DFS), and complete remission rate.
      (Chemotherapy/Translational Medicine) V. To compare the complete response rate, disease-free
      survival (DFS), and overall survival (OS) between patients who receive standard 7+3 therapy
      or IA to patients who receive IA + vorinostat. (Chemotherapy)

      TERTIARY OBJECTIVES:

      I. Future planned studies will include testing of histone H3 acetylation, induction of gamma
      H2A histone family, member X (H2AX), analysis of reactive oxygen species (ROS) resistance and
      DNA methylation profiles. (Chemotherapy/Translational Medicine)

      OUTLINE: Patients are randomized to 1 of 3 treatment arms.

      INDUCTION/RE-INDUCTION:

      ARM I: Patients receive standard dose cytarabine intravenously (IV) continuously on days 1-7
      and daunorubicin hydrochloride IV on days 1-3. Patients with residual blasts may receive
      re-induction treatment beginning on day 15. Patients achieving complete remission (CR) or
      complete remission with incomplete platelet recover (CRi) may proceed to allogeneic
      hematopoietic stem cell transplant (HSCT) or to consolidation therapy.

      ARM II: Patients receive high dose cytarabine IV continuously on days 1-4 and idarubicin IV
      over 15 minutes on days 1-3. Patients with residual blasts may receive re-induction treatment
      beginning on day 28. Patients achieving CR or CRi may proceed to allogeneic HSCT or to
      consolidation therapy.

      ARM III: Patients receive vorinostat orally (PO) thrice daily (TID) on days 1-3, high-dose
      cytarabine IV continuously on days 4-7, and idarubicin IV over 15 minutes on days 4-6.
      Patients with residual blasts may receive re-induction treatment beginning on day 28.
      Patients achieving CR or CRi may proceed to allogeneic HSCT or to consolidation therapy.
      (Permanently closed to accrual, effective 6/2/2015) Patient previously randomized to Arm III
      may continue treatment without vorinostat.

      CONSOLIDATION:

      ARM I: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5.

      ARM II: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15
      minutes on days 1-2.

      ARM III: Patients receive vorinostat PO TID on days 1-3, cytarabine IV continuously on days
      4-6, and idarubicin IV over 15 minutes on days 4-5. (Permanently closed to accrual, effective
      6/2/2015) Patient previously randomized to Arm III may continue treatment with or without
      vorinostat.

      In all arms, treatment repeats every 28 days for 4 courses or until transplant in the absence
      of disease progression or unacceptable toxicity.

      TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or
      consolidation therapy.

      After completion of study treatment, patients are followed up every 3 months for 1 year,
      every 6 months for 2 years, and then annually for 2 years.
    

Intervention name(s): Allogeneic Hematopoietic Stem Cell Transplantation; Cytarabine; Daunorubicin Hydrochloride; Idarubicin; Laboratory Biomarker Analysis; Vorinostat
Intervention type(s): Procedure; Drug; Drug; Drug; Other; Drug
Intervention description(s): Undergo allogeneic transplant; Given IV; Given IV; Given IV; Correlative studies; Given PO
Other intervention name(s): Allogeneic Hematopoietic Cell Transplantation; allogeneic stem cell transplantation; HSC; HSCT; .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; Cytosar-U; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Cerubidin; Cerubidine; Cloridrato de Daunorubicina; Daunoblastin; Daunoblastina; Daunoblastine; Daunomycin hydrochloride; Daunomycin, hydrochloride; Daunorubicin.HCl; Daunorubicini Hydrochloridum; FI-6339; Ondena; RP-13057; Rubidomycin Hydrochloride; Rubilem; 4-Demethoxydaunomycin; 4-demethoxydaunorubicin; 4-DMDR; L-001079038; MSK-390; SAHA; Suberanilohydroxamic Acid; Suberoylanilide Hydroxamic Acid; Zolinza
Intervention MeSH terms: Cytarabine; Daunorubicin; Vorinostat; Idarubicin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment