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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Brief Title

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

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 Phase

Phase 3

Study Type

Interventional


Primary Outcome

Response rates


Condition

Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)

Intervention

tretinoin

Study Arms / Comparison Groups

 Arm I
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

420

Start Date

June 1999


Primary Completion Date

November 2006

Eligibility Criteria

        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
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Bayard Powell, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00003934

Organization ID

NCI-2012-02811

Secondary IDs

C9710

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Bayard Powell, Principal Investigator, Cancer and Leukemia Group B


Verification Date

June 2013