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Tretinoin, Cytarabine, and Daunorubicin Hydrochloride With or Without Arsenic Trioxide Followed by Tretinoin With or Without Mercaptopurine and Methotrexate in Treating Patients With Acute Promyelocytic Leukemia

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ClinicalTrials.gov Identifier: NCT00003934
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : June 5, 2013
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE November 1, 1999
First Posted Date  ICMJE January 27, 2003
Last Update Posted Date June 5, 2013
Study Start Date  ICMJE June 1999
Actual Primary Completion Date November 2006   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 19, 2012)
  • Response rates [ Time Frame: Up to 10 years ]
  • Distributions of event-free survival [ Time Frame: Up to 10 years ]
  • Disease-free survival [ Time Frame: Time from the date of the maintenance randomization to relapse or death, assessed up to 10 years ]
  • Survival [ Time Frame: Up to 10 years ]
  • Toxicities for the various therapies graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 [ Time Frame: Up to 30 days after last dose of study treatment ]
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tretinoin, Cytarabine, and Daunorubicin Hydrochloride With or Without Arsenic Trioxide Followed by Tretinoin With or Without Mercaptopurine and Methotrexate in Treating Patients With Acute Promyelocytic Leukemia
Official Title  ICMJE Phase III Randomized Study of Concurrent Tretinoin and Chemotherapy With or Without Arsenic Trioxide (AS2O3) (NSC # 706363) as Initial Consolidation Therapy Followed by Maintenance Therapy With Intermittent Tretinoin Versus Intermittent Tretinoin Plus Mercaptopurine and Methotrexate for Patients With Untreated Acute Promyelocytic Leukemia
Brief Summary This randomized phase III trial is studying tretinoin and combination chemotherapy to see how well they work compared to tretinoin, combination chemotherapy, and arsenic trioxide in treating patients with acute promyelocytic leukemia that has not been treated previously. Drugs used in chemotherapy, such as daunorubicin, cytarabine, mercaptopurine, methotrexate, and arsenic trioxide, work in different ways to stop cancer cells from dividing so they stop growing or die. Tretinoin may help leukemia cells develop into normal white blood cells. It is not yet known which regimen is more effective for acute promyelocytic leukemia.
Detailed Description

PRIMARY OBJECTIVES:

i. To compare the efficacy (event-free survival) and toxicities of two induction/consolidation therapies for patients with untreated APL: ATRA/ara-C/daunorubicin with or without arsenic trioxide (As2O3).

II. To evaluate the efficacy (disease-free survival) and toxicities of maintenance therapy with intermittent ATRA vs intermittent ATRA plus 6-MP/MTX for patients with APL who achieve a complete response.

III. To explore the relationship between CD56 expression at diagnosis and clinical outcomes.

IV. To evaluate the cardiac toxicity of intensive daunorubicin therapy, as given in this study, to pediatric patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (under 15 vs 15 to 60 vs over 60) for the induction phase. Patients are stratified according to age, as in the induction phase, and the consolidation arm (with vs without arsenic trioxide) for the consolidation phase. Patients under age 5 do not receive arsenic trioxide.

Induction: All patients receive oral tretinoin every 12 hours beginning on day 1 until complete response or for a maximum of 90 days. Patients also receive daunorubicin IV on days 3-6 and cytarabine IV continuously on days 3-9.

Consolidation: All patients achieving complete response (CR), or partial response (PR) after completion of tretinoin, proceed to consolidation within 2 weeks of achieving CR or PR, but not prior to 30 days from the start of induction. Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive oral tretinoin every 12 hours on days 1-7 and daunorubicin IV on days 1-2 or days 1-3, depending on age. Patients may receive an additional course. Treatment begins no earlier than 2 weeks and no later than 4 weeks after hematopoietic recovery.

Arm II: Patients receive arsenic trioxide IV over 2 hours daily 5 days a week for 5 weeks. After a 2-week rest, patients receive a second course of arsenic trioxide. Patients then receive tretinoin and daunorubicin as in arm I.

Maintenance: Patients maintaining CR or PR after consolidation therapy proceed to maintenance therapy, beginning no earlier than 2 weeks and no later than 4 weeks after hematopoietic recovery. Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive oral tretinoin every 12 hours for 7 days every other week for 1 year.

Arm II: Patients receive oral tretinoin as in arm I above. Patients also receive oral mercaptopurine once a day and oral methotrexate once weekly for up to 1 year.

Maintenance therapy continues for up to 1 year in the absence of unacceptable toxicity.

Patients are followed every 2 months for 2 years, every 3 months for 1 year, every 6 months for 2 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 522 patients (456 adults and 66 pediatric) will be accrued for this study within 4.75 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • Adult Acute Promyelocytic Leukemia (M3)
  • Childhood Acute Promyelocytic Leukemia (M3)
  • Untreated Adult Acute Myeloid Leukemia
  • Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies
Intervention  ICMJE
  • Drug: tretinoin
    Given orally
    Other Names:
    • ATRA
    • Retin-A
    • TRA
  • Drug: daunorubicin hydrochloride
    Given IV
    Other Names:
    • Cerubidin
    • Cerubidine
    • daunomycin hydrochloride
    • daunorubicin
    • RP-13057
  • Drug: cytarabine
    Given IV
    Other Names:
    • ARA-C
    • arabinofuranosylcytosine
    • arabinosylcytosine
    • Cytosar-U
    • cytosine arabinoside
  • Drug: mercaptopurine
    Given IV
    Other Names:
    • 6-mercaptopurine
    • 6-MP
    • Leukerin
    • MP
  • Drug: methotrexate
    Given IV
    Other Names:
    • amethopterin
    • Folex
    • methylaminopterin
    • Mexate
    • MTX
  • Drug: arsenic trioxide
    Given IV
    Other Names:
    • Arsenic (III) Oxide
    • Arsenic Sesquioxide
    • Arsenous Acid Anhydride
    • AS2O3
    • Trisenox
Study Arms  ICMJE
  • Experimental: Arm I

    Induction: All patients receive oral tretinoin every 12 hours beginning on day 1 until complete response or for a maximum of 90 days. Patients also receive daunorubicin IV on days 3-6 and cytarabine IV continuously on days 3-9.

    Consolidation: All patients achieving CR or PR after completion of tretinoin, proceed to consolidation within 2 weeks of achieving CR or PR, but not prior to 30 days from the start of induction. Patients are randomized to 1 of 2 treatment arms.

    Patients receive oral tretinoin every 12 hours on days 1-7 and daunorubicin IV on days 1-2 or days 1-3, depending on age. Patients may receive an additional course. Treatment begins no earlier than 2 weeks and no later than 4 weeks after hematopoietic recovery.

    Interventions:
    • Drug: tretinoin
    • Drug: daunorubicin hydrochloride
    • Drug: cytarabine
    • Drug: arsenic trioxide
  • Experimental: Arm II

    Induction: All patients receive oral tretinoin every 12 hours beginning on day 1 until complete response or for a maximum of 90 days. Patients also receive daunorubicin IV on days 3-6 and cytarabine IV continuously on days 3-9.

    Consolidation: All patients achieving CR or PR after completion of tretinoin, proceed to consolidation within 2 weeks of achieving CR or PR, but not prior to 30 days from the start of induction. Patients are randomized to 1 of 2 treatment arms.

    Patients receive oral tretinoin as in arm I above. Patients also receive oral mercaptopurine once a day and oral methotrexate once weekly for up to 1 year.

    Interventions:
    • Drug: tretinoin
    • Drug: daunorubicin hydrochloride
    • Drug: cytarabine
    • Drug: mercaptopurine
    • Drug: methotrexate
    • Drug: arsenic trioxide
Publications * Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. doi: 10.1182/blood-2010-02-269621. Epub 2010 Aug 12.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 19, 2012)
420
Original Enrollment  ICMJE Not Provided
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date November 2006   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have a clinical diagnosis of acute promyelocytic leukemia (APL) with proof of APL morphology (FAB-M3) confirmed by RT-PCR assay; a patient may be entered prior to completion of RT-PCR studies, but a patient who is subsequently found to be PML-RARα negative and RARα-PML negative will be removed from protocol treatment
  • FAB clasification: the aspirate smear must show M3 characteristics and at least 30% of cells must be abnormal promyelocytes with heavy granulation; the overall marrow cellularity must be normocellular or hypercellular; patients with the microgranular variant (M3V) are eligible, and the diagnosis will be based on characteristic morphologic findings (e.g., reniform or bilobed nuclei)
  • RT-PCR assay: submission of samples for RT-PCR assays for PML-RARα/RARα-PML transcripts is mandatory; the results do not have to be known prior to initiation of therapy; if the assay is subsequently found to be negative, the patient will be removed from protocol treatment and treated at the discretion of the responsible physician
  • Prior treatment: the patient must not have received any systemic definitive treatment for APL, including cytotoxic chemotherapy or retinoids; prior therapy with corticosteroids, hydroxyurea or leukapheresis will not exclude the patient
  • Non-pregnant, non-nursing: treatment under this protocol would expose an unborn child to significant risks; patients should not be pregnant or plan to become pregnant while on treatment; women and men of reproductive potential should agree to use an effective means of birth control; there is an extremely high risk of fetal malformation if pregnancy occurs while on ATRA in any amount even for short periods
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries Australia,   Canada,   Netherlands,   New Zealand,   Peru,   Puerto Rico,   Switzerland
 
Administrative Information
NCT Number  ICMJE NCT00003934
Other Study ID Numbers  ICMJE NCI-2012-02811
C9710
CDR0000067126
CALGB-C9710
U10CA031946 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Bayard Powell Cancer and Leukemia Group B
PRS Account National Cancer Institute (NCI)
Verification Date June 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP