Clofarabine and Cytarabine or Standard Induction Therapy and Chemotherapy with or without Natural Killer Cell Transplant in Treating Younger Patients with Newly Diagnosed Acute Myeloid Leukemia

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase III, Phase IIBiomarker/Laboratory analysis, Treatment21 and underAML08
NCI-2011-03659, NCT00703820

Trial Description



The overall goal of this study is to see if the remission rate can be increased. This research study also plans to compare the response rate after one course of chemotherapy in participants treated with the standard 3-drug chemotherapy combination (cytarabine, daunorubicin [daunorubicin hydrochloride], etoposide) versus those treated with a new 2 drug combination (clofarabine and cytarabine); to find out if a new therapy called natural killer (NK) cell transplantation will be effective treatment for participants with standard risk acute myeloid leukemia (AML); to learn more about the biology and genetics of AML by performing research studies on blood and bone marrow samples; to learn more about how drugs used in the treatment of AML work in the body of participants with AML, how the drugs affect the body, and how participants’ genetics may predict who will have more side effects from treatment and who will or will not respond to the leukemia treatment; and to find out if major infections in participants treated on this study can be prevented by giving planned antibiotics and antifungal drugs after chemotherapy when the blood counts are very low.

Further Study Information


I. To compare the immunologic complete response rate after one course of therapy in patients who receive cytarabine + daunorubicin + etoposide (ADE) with that in patients who receive clofarabine + cytarabine (Clo/AraC).


I. To estimate the event-free survival (EFS) of standard risk (SR) patients who receive chemotherapy alone and the EFS of SR patients who receive chemotherapy followed by natural killer (NK) cell transplantation.


I. To genotype natural killer (NK) cell receptors and measure their expressions at diagnosis and after induction therapy, and to explore the associations of these features with treatment outcome.

II. To assess the prognostic value of levels of minimal residual disease in peripheral blood at day 8 of induction I.

III. To validate new markers and methods for minimal residual disease (MRD) detection.

IV. To identify new prognostic factors by applying new technologies to study patient material

V. To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors for treatment-related outcomes in the context of the systemic therapy used in the protocol.

VI. To describe the impact of antibiotic and antifungal prophylaxis on invasive bacterial and fungal infections, febrile neutropenia, hospitalization, and antibiotic resistance.

VII. To explore the feasibility and toxicity of administering vorinostat in combination with chemotherapy in selected high-risk patients.

OUTLINE: This is a randomized, phase III study of induction therapy and a phase II study of NK cell transplantation.

INDUCTION I: Patients are randomized to 1 of 2 treatment arms.

ARM I (high-dose [HD]-ADE): Patients receive cytarabine intravenously (IV) over 3 hours twice daily (BID) on days 1, 3, and 5; daunorubicin hydrochloride IV over 6 hours once daily (QD) on days 2, 4, and 6; and etoposide IV over 4 hours QD on days 2-6.

ARM II (CLO/ARAC): Patients receive clofarabine IV over 2 hours QD on days 1-5 followed by cytarabine IV over 2 hours QD on days 1-5.

In both arms, treatment repeats every 21 days for up to 2 courses.

INDUCTION II (low-dose [LD]-ADE): Patients receive cytarabine IV over 30 minutes BID on days 1-8; daunorubicin hydrochloride IV over 6 hours QD on days 2, 4, and 6; and etoposide IV over 4 hours QD on days 1-5. Patients with FMS-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) also receive sorafenib tosylate orally (PO) BID beginning one day after completion of Induction II and continuing for 21 days. Other high-risk (HR) patients also receive vorinostat PO QD, BID, or thrice daily (TID) on days -2 to 0 and days 1-6.

CONSOLIDATION I: Patients not undergoing stem cell transplant (SCT) receive mitoxantrone hydrochloride IV over 1 hour QD on days 3-5 and cytarabine IV over 2 hours BID on days 1-4. Patients with low levels of MRD may proceed directly to SCT; patients with a killer immunoglobulin-like receptor (KIR)-mismatched family member may proceed to NK cell transplantation; and patients with higher levels of MRD may receive additional consolidation chemotherapy before SCT.

CONSOLIDATION II: Patients receive cytarabine IV over 3 hours BID on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) or IV over 1 hour over 3 hours on days 2 and 9.

NK CELL TRANSPLANTATION: Patients receive cyclophosphamide IV over 1 hour on day -7; fludarabine phosphate IV over 30 minutes on days -6 to -2; aldesleukin subcutaneously (SC) on days -1, 1, 3, 5, 7, and 9. Patients undergo NK cell infusion on day 0. Patients then proceed to SCT.

CENTRAL NERVOUS SYSTEM (CNS) THERAPY: All patients undergo intrathecal (IT) chemotherapy comprising methotrexate, hydrocortisone, and cytarabine at the time of diagnosis.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 5 years.

Eligibility Criteria

Inclusion Criteria:

Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN

Alkaline phosphatase =< 2.5 x ULN


Participants must meet the following criteria to qualify for HD-ADE versus Clo/AraC randomization; participants who do not meet these criteria may still be enrolled, but will be treated on HD-ADE arm and will NOT be randomized

Male and female participants must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment

Female patients of childbearing potential must have a negative pregnancy test within 2 weeks prior to enrollment

Written informed consent according to institutional guidelines

No prior therapy for this malignancy except for one dose of intrathecal therapy and the use of hydroxyurea or low-dose cytarabine (100-200 mg/m^2 per day for one week or less) for hyperleukocytosis

Patients must have one of the following three characteristics:

Acute myeloid leukemia fulfilling the criteria of the World Health Organization (WHO) classification

< 20% marrow myeloblasts and evidence of a clonal de novo AML genetic abnormality [e.g., t(8;21), inv(16), t(9;11)]

Myeloid sarcoma (also referred to as extramedullary myeloid tumor, granulocytic sarcoma, or chloroma), with or without evidence of a leukemic process in the bone marrow or peripheral blood, with confirmation of myeloid differentiation

Patients with secondary AML following treatment of primary malignancy are eligible

Serum bilirubin =< 1.5 x upper limit of normal (ULN)

Normal creatinine for age



Exclusion Criteria:

Use of investigational agents within 30 days or any anticancer therapy for this malignancy within 2 weeks before study entry with the exception of IT therapy, hydroxyurea, or low-dose cytarabine as stated above; the patient must have recovered from all acute toxicities from any previous therapy

Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results

Pregnant or lactating patients

Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)

Use of concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol

Shwachman syndrome

Kostmann syndrome

Fanconi anemia (FA)

Juvenile myelomonocytic leukemia (JMML)

Acute promyelocytic leukemia (APL)

Down syndrome

Other bone marrow failure syndromes

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

St. Jude Children's Research Hospital

  • National Cancer Institute
Jeffrey E. Rubnitz, Principal Investigator

Trial Sites


Palo Alto

Lucile Packard Children's Hospital Stanford University

Gary Van Houten Dahl
Ph: 650-723-5535

Gary Van Houten Dahl
Principal Investigator

San Diego

Rady Children's Hospital - San Diego

Deborah E. Schiff
Ph: 858-966-5934

Deborah E. Schiff
Principal Investigator


University of Chicago Comprehensive Cancer Center

John Michael Cunningham
Ph: 773-834-7424

John Michael Cunningham
Principal Investigator


Dana-Farber Cancer Institute

Barbara Alsen Degar
Ph: 866-790-4500

Barbara Alsen Degar
Principal Investigator


Children's Hospital of Michigan

Jeffrey Warren Taub
Ph: 313-745-5515

Jeffrey Warren Taub
Principal Investigator


St. Jude Children's Research Hospital

Jeffrey E. Rubnitz
Ph: 901-595-2308

Jeffrey E. Rubnitz
Principal Investigator

Fort Worth

Cook Children's Medical Center

Kenneth Matthew Heym
Ph: 682-885-2103

Kenneth Matthew Heym
Principal Investigator

Republic of Singapore


National University Hospital Singapore

Allen Eng Juh Yeoh
Ph: 65 6772 4406

Allen Eng Juh Yeoh
Principal Investigator

Link to the current record.
NLM Identifer NCT00703820

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the record via the link above for more information about participating sites.