Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia

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Brief Title

Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia

Official Title

Risk Adapted Treatment of Newly Diagnosed Childhood Acute Promyelocytic Leukemia (APL) Using Arsenic Trioxide (Trisenox® IND# 103, 331) During Consolidation

Brief Summary

      This phase III trial is studying combination chemotherapy to see how well it works in
      treating young patients with newly diagnosed acute promyelocytic leukemia. Drugs used in
      chemotherapy work in different ways to stop the growth of cancer cells, either by killing the
      cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy)
      may kill more cancer cells.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To decrease the total anthracycline dose from the best current published results in
      standard risk childhood acute promyelocytic leukemia (APL) while still maintaining a
      comparable event-free survival (EFS).

      SECONDARY OBJECTIVES:

      I. To assign treatment based on risk stratification by white blood cell count (WBC) at
      diagnosis.

      II. To estimate the induction failure rate, toxic death rate, disease-free survival rate and
      overall survival rate in both standard and high risk APL patients.

      III. To monitor for cardiotoxicity in an idarubicin/mitoxantrone based regimen. IV. To
      document the toxicity of a traditional chemotherapy/all-trans retinoic acid (ATRA)
      (tretinoin) based regimen combined with arsenic trioxide therapy.

      V. To study the relationship of Fms-like tyrosine kinase 3 (FLT3) mutations to clinical
      features and outcome in APL.

      VI. To study risk factors for pseudotumor cerebri in APL. VII. To study the relationship of
      early progenitor cell involvement to treatment failure in FLT3 positive APL.

      VIII. To compare the EFS of children enrolled on AAML0631 with the EFS of children enrolled
      on C9710 who were between the ages of 2 and 21 and did not receive arsenic trioxide.

      IX. To estimate the proportion of patients who carry a cryptic t(15;17), i.e., those who are
      positive for a promyelocytes.(PML)-retinoic acid receptor alpha (RARA) fusion transcript by
      polymerase chain reaction (PCR) analysis but have normal chromosomes.

      X. To estimate the proportion of patients with variant RARA partners. XI. To compare the
      outcome of patients with only a t(15;17) with that of patients who carry a t(15;17) and other
      chromosomal abnormalities.

      OUTLINE: This is a multicenter study. Patients are treated based on risk factor
      (standard-risk [WBC less than 10,000/mm^3] or high-risk [WBC 10,000/mm^3 or higher]).

      INDUCTION THERAPY:

      STANDARD-RISK: Patients receive tretinoin orally (PO) twice daily (BID) on days 1-30 and
      idarubicin intravenously (IV) over 15 minutes once on days 3, 5, and 7.

      HIGH-RISK: Patients receive tretinoin PO BID on days 1-30 and idarubicin IV over 15 minutes
      once on days 1, 3, and 5. Patients proceed to consolidation therapy one week later or when
      blood counts recover.

      CONSOLIDATION THERAPY:

      CONSOLIDATION 1: Patients receive arsenic trioxide IV over 2 hours on days 1-5, 8-12, 15-19,
      22-26, and 29-33 and tretinoin PO BID on days 1-14. Treatment repeats every 5 weeks for 2
      courses, followed by a 2-week break, and then treatment repeats for 2 more courses. Beginning
      1 week later or when blood counts recover, patients proceed to consolidation 2.

      CONSOLIDATION 2: Patients receive cytarabine intrathecally (IT) on day 1, tretinoin PO BID on
      days 1-14, high-dose cytarabine IV over 3 hours every 12 hours on days 1-3, and mitoxantrone
      hydrochloride IV over 15-30 minutes once on days 3 and 4. Patients proceed to consolidation 3
      1 week later or when blood counts recover.

      CONSOLIDATION 3: Patients receive cytarabine IT on day 1, tretinoin PO BID on days 1-14, and
      idarubicin IV over 15 minutes once daily on days 1, 3, and 5. High-risk patients and those
      standard-risk patients who are positive for minimal residual disease by real-time
      quantitative (RQ)-PCR receive consolidation 4 one week later or when blood counts recover.
      All other standard-risk patients proceed to maintenance therapy.

      CONSOLIDATION 4 (patients with high-risk cytology): Patients receive cytarabine IT on day 1,
      tretinoin PO BID on days 1-14, high-dose cytarabine IV over 3 hours every 12 hours on days
      1-3, and idarubicin IV over 15 minutes once on day 4. Patients who demonstrate molecular
      complete remission (CR) and remain in hematological CR proceed to maintenance therapy 1 week
      later or when blood counts recover.

      MAINTENANCE THERAPY: Patients receive cytarabine IT on day 1 (course 1 only), tretinoin PO
      BID on days 1-14, mercaptopurine PO once daily (QD) on days 1-84, methotrexate PO once on
      days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 9
      courses.

      After completion of study treatment, patients are followed every month for 1 year, every 3
      months for 2 years, every 6 months for 2 years, and then annually for 5 years.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Event-free Survival (EFS)

Secondary Outcome

 Hematologic Remission Rate

Condition

Childhood Acute Promyelocytic Leukemia (M3)

Intervention

arsenic trioxide

Study Arms / Comparison Groups

 Standard Risk (WBC < 10000/uL)
Description:  See Detailed Description

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

108

Start Date

March 9, 2009


Primary Completion Date

June 30, 2015

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must be newly diagnosed with a clinical diagnosis of acute promyelocytic
             leukemia initially by morphology (bone marrow or peripheral blood); bone marrow is
             highly preferred but in cases where marrow cannot be obtained at diagnosis, peripheral
             blood will be accepted; APL is considered a hematological emergency and treatment
             should be initiated as quickly as possible without waiting for molecular or
             cytogenetic/fluorescence in situ hybridization (FISH) confirmation; for patients who
             are unable to begin receiving ATRA in a timely manner following a presumed diagnosis
             of APL, consideration should be given to initiating ATRA and proceeding with treatment
             outside of the AAML0631 protocol; if the RQ-PCR results are known at the time of study
             enrollment, the patient must demonstrate PML-RARA and/or RARA-PML transcripts by
             RQ-PCR to be eligible; patients without evidence of APL by bone marrow or peripheral
             blood morphology but with isolated myeloid sarcoma (myeloblastoma; chloroma, including
             leukemia cutis) are eligible provided that the t(15;17) translocation is documented on
             either marrow or tumor tissue by cytogenetics, FISH, or PCR prior to study enrollment;
             in this situation, touch preps from the tumor site can be evaluated by FISH with
             PML-RARA probes; NOTE: A lumbar puncture is not required to be enrolled on study; if
             the diagnosis of APL is known or suspected, extreme caution must be exercised in
             performing a lumbar puncture during active coagulopathy; in addition a computed
             tomography (CT) or magnetic resonance imaging (MRI) should be considered to rule out
             the possibility of an associated chloroma if central nervous system (CNS) disease is
             suspected or proven; if CNS disease is documented, patients are still eligible

          -  No minimal performance status criteria

          -  The patient must not have received systemic definitive treatment for APL or other
             suspected leukemia, including cytotoxic chemotherapy, retinoids, or arsenic; prior
             therapy with corticosteroids, hydroxyurea, or leukopheresis will not exclude the
             patient; if a patient received intrathecal cytarabine prior to the diagnosis of APL
             being known, the patient will still be eligible as long as they meet all other
             eligibility requirements

        Exclusion Criteria:

          -  Pregnant women or nursing mothers are excluded; 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

          -  Patients with a pre-existing prolonged QT Syndrome will not be eligible for this
             protocol due to the use of arsenic trioxide which can prolong the QT interval
      

Gender

All

Ages

2 Years - 21 Years

Accepts Healthy Volunteers

No

Contacts

John Gregory, MD, , 

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT00866918

Organization ID

AAML0631

Secondary IDs

NCI-2011-01904

Responsible Party

Sponsor

Study Sponsor

Children's Oncology Group

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

John Gregory, MD, Principal Investigator, Children's Oncology Group


Verification Date

February 2017