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

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ClinicalTrials.gov Identifier: NCT00866918
Recruitment Status : Completed
First Posted : March 23, 2009
Results First Posted : April 4, 2017
Last Update Posted : April 4, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

March 20, 2009
March 23, 2009
October 25, 2016
April 4, 2017
April 4, 2017
March 2009
June 2015   (Final data collection date for primary outcome measure)
Event-free Survival (EFS) [ Time Frame: At 3 years from study entry ]
EFS - time from study entry until failure to achieve complete remission during consolidation, relapse, or death. For further clarification see definitions provided in the protocol.
Event-free survival
Complete list of historical versions of study NCT00866918 on ClinicalTrials.gov Archive Site
  • Hematologic Remission Rate [ Time Frame: End of consolidation, course 1: up to 5 months ]
    Proportion of patients in hematologic remission at end of consolidation, course 1 are reported.
  • Hematologic, Molecular, and Cytogenetic Remission Rate [ Time Frame: End of consolidation, course 3; up to 7 months (for Standard Risk) or end of consolidation, course 4; up to 9 months (for High Risk) ]
    Proportion of patients in hematologic, molecular, and cytogenetic remission at end of consolidation, course 3 and 4 are reported. Patients were determined to be in remission by all three criteria.
  • Overall Survival (OS) [ Time Frame: At 3 years from study entry ]
    OS - time from study entry to death.
  • Hematologic, molecular, and cytogenetic remission rates after each phase of therapy
  • Overall survival
  • Percentage of patients experiencing grade 3 or 4 toxicity, or cardiac toxicity of any grade
  • Time to blood count recovery
  • Duration of hospitalization
Not Provided
Not Provided
 
Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia
Risk Adapted Treatment of Newly Diagnosed Childhood Acute Promyelocytic Leukemia (APL) Using Arsenic Trioxide (Trisenox® IND# 103, 331) During Consolidation
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.

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.

Interventional
Phase 3
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Childhood Acute Promyelocytic Leukemia (M3)
  • Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies
  • Drug: arsenic trioxide
    Given IV
    Other Names:
    • Arsenic (III) Oxide
    • Arsenic Sesquioxide
    • Arsenous Acid Anhydride
    • AS2O3
    • Trisenox
  • Drug: mitoxantrone hydrochloride
    Given IV
    Other Names:
    • CL 232315
    • DHAD
    • DHAQ
    • Novantrone
  • Other: diagnostic laboratory biomarker analysis
    Correlative studies
  • Drug: idarubicin
    Given IV
    Other Names:
    • 4-demethoxydaunorubicin
    • 4-DMDR
    • DMDR
    • IDA
  • Drug: tretinoin
    Given orally
    Other Names:
    • ATRA
    • Retin-A
    • TRA
  • Drug: cytarabine
    Given IT or IV
    Other Names:
    • ARA-C
    • arabinofuranosylcytosine
    • arabinosylcytosine
    • Cytosar-U
    • cytosine arabinoside
  • Drug: mercaptopurine tablet
    Given orally
    Other Names:
    • 6-mercaptopurine
    • 6-MP
    • Leukerin
    • MP
  • Drug: methotrexate
    Given orally
    Other Names:
    • amethopterin
    • Folex
    • methylaminopterin
    • Mexate
    • MTX
  • Experimental: Standard Risk (WBC < 10000/uL)
    See Detailed Description
    Interventions:
    • Drug: arsenic trioxide
    • Drug: mitoxantrone hydrochloride
    • Other: diagnostic laboratory biomarker analysis
    • Drug: idarubicin
    • Drug: tretinoin
    • Drug: cytarabine
    • Drug: mercaptopurine tablet
    • Drug: methotrexate
  • Active Comparator: High Risk (WBC > 10000/uL)
    See Detailed Description
    Interventions:
    • Drug: arsenic trioxide
    • Drug: mitoxantrone hydrochloride
    • Other: diagnostic laboratory biomarker analysis
    • Drug: idarubicin
    • Drug: tretinoin
    • Drug: cytarabine
    • Drug: mercaptopurine tablet
    • Drug: methotrexate
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
108
86
Not Provided
June 2015   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
2 Years to 21 Years   (Child, Adult)
No
Contact information is only displayed when the study is recruiting subjects
Canada,   Puerto Rico,   United States
 
 
NCT00866918
AAML0631
NCI-2011-01904 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000637184 ( Other Identifier: ClinicalTrials.gov )
AAML0631 ( Other Identifier: Children's Oncology Group )
AAML0631 ( Other Identifier: CTEP )
U10CA098543 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Not Provided
Children's Oncology Group
Children's Oncology Group
National Cancer Institute (NCI)
Principal Investigator: John Gregory, MD Children's Oncology Group
Children's Oncology Group
February 2017

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