Cytarabine and Daunorubicin Hydrochloride or Idarubicin and Cytarabine With or Without Vorinostat in Treating Younger Patients With Previously Untreated Acute Myeloid Leukemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01802333
First received: February 27, 2013
Last updated: July 22, 2014
Last verified: June 2014
  Purpose

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 or stopping them from dividing. 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.


Condition Intervention Phase
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Myelomonocytic Leukemia (M4)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Secondary Acute Myeloid Leukemia
Untreated Adult Acute Myeloid Leukemia
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: idarubicin hydrochloride
Drug: vorinostat
Procedure: allogeneic hematopoietic stem cell transplantation
Other: laboratory biomarker analysis
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Phase III Study of Standard Cytarabine Plus Daunorubicin (7+3) Therapy or Idarubicin With High Dose Cytarabine (IA) Versus IA With Vorinostat (NSC-701852) (IA+V) in Younger Patients With Previously Untreated Acute Myeloid Leukemia (AML)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • EFS [ Time Frame: From the date of initial registration on study until the first of the following: death from any cause, relapse from remission (CR or CRi) or completion of protocol Induction/Re-Induction therapy without documentation of CR or CRi, assessed up to 5 years ] [ Designated as safety issue: No ]
    A hazard ratio and two-sided tests will be used.

  • Rate of allogeneic HCT [ Time Frame: Up to 28 days after completion of treatment ] [ Designated as safety issue: No ]
    The goal of the transplant objective is to determine whether it is possible to conduct allogeneic HCT on 60% or more of adults with high-risk AML in first complete remission (alternative). If 40% or fewer of high-risk patients in CR can be transplanted, the proposed transplant support system will not be considered feasible. A one-sided binomial test compared to the null transplant rate will be conducted.


Secondary Outcome Measures:
  • EFS of 7 + 3 compared to IA [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    A two-sided test of the hazard ratio (HR) of 7:3: IA (versus the null hypothesis of HR =1) will be done using a proportional hazards regression model with the stratification factors included as covariates.

  • EFS rate [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    1-year, 2-year and 3-year EFS rates will be compared between patients who receive standard 7+3 or IA and patients who receive IA + V; between patients who receive standard 7+3 therapy versus IA; and between patients who receive standard 7+3 versus IA.

  • OS rate [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    1-year, 2-year and 3-year EFS rates will be compared between patients who receive standard 7+3 or IA and patients who receive IA + V; between patients who receive standard 7+3 therapy versus IA; and between patients who receive standard 7+3 versus IA.


Other Outcome Measures:
  • Prevalence of known AML-associated mutations [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Prognostic implication of known AML-associated mutations [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Prognostic significance of histone H3 acetylation [ Time Frame: Up to day 3 ] [ Designated as safety issue: No ]
  • Prognostic significance of gammaH2Ax [ Time Frame: Up to day 3 ] [ Designated as safety issue: No ]
  • Prognostic significance of Nrf2 and CYYB mRNA levels [ Time Frame: Up to day 3 ] [ Designated as safety issue: No ]
  • Potential predictive markers based on mRNA and miRNA expression [ Time Frame: Up to day 3 ] [ Designated as safety issue: No ]
  • Potential predictive markers based on DNA methylation [ Time Frame: Up to day 3 ] [ Designated as safety issue: No ]

Estimated Enrollment: 784
Study Start Date: February 2013
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (standard dose cytarabine, daunorubicin hydrochloride)

INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine 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 CR or CRi may proceed to allogeneic HSCT or to consolidation therapy.

CONSOLIDATION: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5.

TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy.

Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Cerubidin
  • Cerubidine
  • daunomycin hydrochloride
  • daunorubicin
  • RP-13057
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic transplant
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm II (high-dose cytarabine, idarubicin)

INDUCTION/RE-INDUCTION: 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.

CONSOLIDATION: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2.

TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy.

Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: idarubicin hydrochloride
Given IV
Other Names:
  • 4-demethoxydaunorubicin
  • 4-DMDR
  • DMDR
  • IDA
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic transplant
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm III (vorinostat, high-dose cytarabine, idarubicin)

INDUCTION/RE-INDUCTIONI: Patients receive vorinostat PO 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.

CONSOLIDATION: 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.

TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy.

Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: idarubicin hydrochloride
Given IV
Other Names:
  • 4-demethoxydaunorubicin
  • 4-DMDR
  • DMDR
  • IDA
Drug: vorinostat
Given PO
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic transplant
Other: laboratory biomarker analysis
Correlative studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • STEP 1 - INDUCTION/RE-INDUCTION
  • Patients must have morphologically confirmed newly diagnosed acute myelogenous leukemia (AML) with blood or bone marrow disease; patients with only extramedullary disease in the absence of bone marrow or blood involvement are not eligible; note: this protocol uses World Health Organization (WHO) diagnostic criteria for AML; patients with acute promyelocytic leukemia (APL, French-American-British [FAB], M3) or blastic transformation of chronic myelogenous leukemia (CML) are not eligible; patients with known core binding factor (CBF) or fms-like tyrosine kinase 3 (FLT3) related leukemias are eligible for this study, but should preferentially be placed on National Cancer Institute (NCI)-sponsored protocols specific for these subtypes, if available
  • Patients must have diagnostic/pre-treatment specimens obtained within 28 days prior to registration submitted for cytogenetic (and fluorescent in situ hybridization [FISH] if possible) analysis to determine risk status; high risk classification will be defined as del(5q)/-5, del(7q)/-7, abn3q26 [inv(3)/t(3;3)], 11q23 rearrangement [except t(9;11)], 17p-, t(6;9), t(9;22), complex (at least 3 unrelated abnormalities [abn]), and monosomal karyotype (either loss of two different chromosomes or loss of one chromosome along with a structural chromosome abnormality other than add, ring and mar); karyograms and cytogenetics/FISH analysis reports must be submitted for discipline review
  • Patients must be chemo-naïve, i.e., not have received any prior Induction chemotherapy for AML or myelodysplastic syndrome (MDS); temporary prior measures such as apheresis or hydroxyurea are allowed; prior anthracycline therapy is allowed, but must not exceed a dose of 200 mg/m^2 daunorubicin or equivalent; prior all-trans retinoic acid (ATRA) for suspected APL is allowed; prior methotrexate for central nervous system (CNS) involvement is allowed; patients with prior history of MDS must not have received azacitidine, decitabine, lenalidomide or vorinostat
  • Patients must have peripheral blood and bone marrow aspirate specimens obtained within 28 days prior to registration submitted for translational medicine; with patient consent, residuals will be banked for future research
  • Patients must have Zubrod performance status =< 3
  • Patients must have either echocardiogram (ECHO) or multi gated acquisition scan (MUGA) with ejection fraction >= 45% within 28 days prior to registration
  • Patients must not have prolonged corrected QT (QTc) interval (> 500 msec) determined by electrocardiogram (EKG) within 28 days prior to registration
  • Patients must not have cardiac disease defined as: New York Heart Association (NYHA) > class II; patients must not have unstable angina (angina symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months
  • Patients must not have any coexisting medical condition that is likely to interfere with study procedures or results, and must be reasonable candidates for intensive chemotherapy, in the opinion of their treating physicians
  • Patients who are known to be human immunodeficiency virus (HIV) positive (+) are eligible providing they meet all of the following additional criteria within 28 days prior to registration:

    • Cluster of differentiation (CD) 4 cells >= 500/mm^3
    • Viral load < 50 copies of HIV messenger ribonucleic acid (mRNA)/mm^3 if on combination antiretroviral therapy (cART) or < 25,000 copies of HIV mRNA if not on cART
    • No zidovudine or stavudine as part of cART; patients who are HIV+ and do not meet all of these criteria are not eligible for this study
  • Patients with known hepatitis B or hepatitis C infection may be eligible providing they have viral load < 800,000 IU/L within 28 days prior to registration
  • Patients must be able to take oral medications
  • Patients must have a history and physical examination obtained within 28 days prior to registration
  • 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
  • Prior malignancy is allowed providing it does not require concurrent therapy; exception: active hormonal therapy is allowed
  • Patients must not be receiving valproic acid
  • All patients must be informed of the investigational nature of this study; patients or a legally authorized representative must sign and give written informed consent in accordance with institutional and federal guidelines
  • As 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
  • STEP 2 - CONSOLIDATION
  • Patients may be registered for Consolidation provided that they were eligible for the initial Induction/Re-Induction registration and satisfy the following additional criteria:

    • Patients must have achieved morphologic remission (complete remission [CR] or complete remission with incomplete platelet recover [CRi]) after completion of Induction or Re-Induction therapy; patient must remain in remission until beginning Consolidation and this must be documented by bone marrow and peripheral blood examination within 28 days prior to registration to Step 2
    • All non-hematologic treatment related toxicities that are deemed clinically significant by the treating physician must have resolved to =< grade 2
    • Patients must not have received allogeneic stem cell transplant
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01802333

  Show 312 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Guillermo Garcia-Manero Southwest Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01802333     History of Changes
Other Study ID Numbers: NCI-2013-00490, NCI-2013-00490, SWOG-S1203, S1203, S1203, U10CA032102, U10CA180888
Study First Received: February 27, 2013
Last Updated: July 22, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Leukemia
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Cytarabine
Vorinostat
Daunorubicin
Idarubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 24, 2014