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Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Patients With Acute Promyelocytic Leukemia

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ClinicalTrials.gov Identifier: NCT00002701
Recruitment Status : Unknown
Verified November 2006 by National Cancer Institute (NCI).
Recruitment status was:  Active, not recruiting
First Posted : April 11, 2003
Last Update Posted : September 20, 2013
Sponsor:
Collaborator:
Gruppo Italiano Malattie EMatologiche dell'Adulto
Information provided by:
National Cancer Institute (NCI)

Brief Summary:

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Bone marrow transplantation may be able to replace immune cells that were destroyed by chemotherapy to kill tumor cells. It is not yet known which regimen of combination chemotherapy with or without bone marrow transplantation is more effective in treating promyelocytic leukemia

PURPOSE: Randomized phase III trial to compare the effectiveness of different combination chemotherapy regimens with or without bone marrow transplantation in treating patients who have promyelocytic leukemia.


Condition or disease Intervention/treatment Phase
Leukemia Drug: busulfan Drug: cyclophosphamide Drug: cytarabine Drug: etoposide Drug: idarubicin Drug: mercaptopurine Drug: methotrexate Drug: mitoxantrone hydrochloride Drug: thioguanine Drug: tretinoin Procedure: allogeneic bone marrow transplantation Procedure: autologous bone marrow transplantation Radiation: radiation therapy Phase 3

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Detailed Description:

OBJECTIVES:

  • Determine the complete remission (CR) rate in patients with acute promyelocytic leukemia treated with induction comprising tretinoin (ATRA) and idarubicin (IDA).
  • Determine the presence of the promyelocyte-retinoic acid receptor alpha (PML-RARa) transcript using polymerase chain reaction (PCR) in patients with CR after 3 sequential consolidation regimens comprising cytarabine (ARA-C) plus IDA, followed by mitoxantrone plus etoposide, and then IDA, ARA-C, and thioguanine.
  • Determine the percentage of patients who complete the protocol, including PML-RARa-positive patients treated with post-consolidation bone marrow transplantation (BMT) and PML-RARa-negative patients treated with maintenance comprising mercaptopurine (MP) plus methotrexate (MTX) vs ATRA only vs MP plus MTX alternating with ATRA vs observation only.
  • Compare the disease-free survival (DFS) and overall survival of these patients treated with these regimens.
  • Determine the rate and type of grade 4 toxicity, treatment-related mortality, and time to granulocyte and platelet recovery associated with each phase of treatment in these patients.
  • Determine the DFS and overall survival of PML-RARa-positive patients who are ineligible for BMT and are treated with maintenance comprising MP plus MTX alternating with ATRA.
  • Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study.

  • Induction: Patients receive oral tretinoin (ATRA) twice daily beginning on day 1 and continuing for 30-90 days and idarubicin (IDA) IV over 15 minutes on days 2, 4, and 8. ATRA is discontinued before day 90 in the presence of complete remission (CR) at day 30 or 60, unacceptable toxicity, or disease progression or in the absence of at least a partial remission at day 60. Patients who achieve CR during induction proceed to consolidation.
  • Consolidation:

    • First consolidation: Within 2 weeks after achieving CR, patients receive cytarabine (ARA-C) IV over 6 hours followed 3 hours later by IDA IV over 15 minutes on days 1-4.
    • Second consolidation:Within 4-6 weeks after initiation of first consolidation, patients receive mitoxantrone IV over 30 minutes and etoposide IV over 1 hour (beginning 12 hours after initiation of mitoxantrone infusion) on days 1-5.
    • Third consolidation:Within 4-6 weeks after initiation of second consolidation, patients receive ARA-C subcutaneously every 8 hours and oral thioguanine every 8 hours on days 1-5 and IDA IV over 15 minutes on day 1.

Patients proceed to group A if they are promyelocyte-retinoic acid receptor alpha (PML-RARa)-negative after recovery from third consolidation. Patients proceed to allogeneic bone marrow transplantation (BMT) on group B if they are PML-RARa-positive, achieve CR, are under age 55, and have an HLA-A, -B, and -DR identical, chronic myelomonocytic leukemia nonreactive, family donor after recovery from third consolidation. Patients proceed to autologous BMT on group B if they are PML-RARa-positive, achieve CR, and have no identical family donor or are age 55 and over after recovery from third consolidation. Patients proceed to arm III of group A if they are PML-RARa-positive and ineligible for BMT after recovery from third consolidation.

  • Group A (maintenance): Patients are stratified according to participating center and initial white blood cell count. Patients are randomized to 1 of 4 treatment arms.

    • Arm I: Patients receive oral mercaptopurine (MP) daily and oral methotrexate (MTX) weekly.
    • Arm II: Beginning 3 months after recovery from third consolidation, patients receive oral ATRA on days 1-15.

Treatment on arms I and II continues every 3 months for 2 years in the absence of disease progression or unacceptable toxicity.

  • Arm III: Patients receive 1 course of arm I treatment, alternated by 1 course of arm II treatment. Alternating treatment continues every 3 months for 2 years in the absence of disease progression or unacceptable toxicity.
  • Arm IV: Patients undergo observation only.

    • Group B: Eligible patients receive conditioning comprising cyclophosphamide (CTX) IV for 2 days followed by total body irradiation or oral busulfan on days -9 to -6 and CTX on days -5 to -2. Autologous or allogeneic bone marrow is infused on day 0 (within 4 months after initiation of third consolidation).

Quality of life is assessed at baseline, after induction, after each consolidation regimen, and then every 3 months beginning after treatment on group A or B.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 750 patients will be accrued for this study within 7.5 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 750 participants
Allocation: Randomized
Primary Purpose: Treatment
Official Title: INDUCTION WITH ALL-TRANS RETINOIC ACID IN COMBINATION WITH IDARUBICIN AND INTENSIVE CONSOLIDATION FOLLOWED BY BONE MARROW TRANSPLANTATION OR A RANDOMIZED MAINTENANCE TREATMENT DEPENDING UPON THE AMOUNT OF MINIMAL RESIDUAL DISEASE IN ACUTE PROMYELOCYTIC LEUKEMIA
Study Start Date : October 1995






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Ages Eligible for Study:   16 Years to 74 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Newly diagnosed acute promyelocytic leukemia
  • Must have promyelocyte-retinoic acid receptor alpha transcript at disease presentation

PATIENT CHARACTERISTICS:

Age:

  • 16 to 74

Performance status:

  • Not specified

Life expectancy:

  • Not specified

Hematopoietic:

  • Not specified

Hepatic:

  • Bilirubin no greater than 3 times upper limit of normal (ULN)
  • AST no greater than 3 times ULN
  • Alkaline phosphatase no greater than 3 times ULN

Renal:

  • Creatinine no greater than 2.5 mg/dL

Cardiovascular:

  • No cardiac contraindication to anthracycline chemotherapy

Other:

  • No active serious infection not controlled by antibiotics
  • No severe concurrent psychiatric disease
  • No other malignancy except basal cell carcinoma
  • Not pregnant or nursing
  • Negative pregnancy test

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • Not specified

Chemotherapy:

  • No concurrent cytotoxic chemotherapy

Endocrine therapy:

  • Prior corticosteroids for leukemia allowed

Radiotherapy:

  • No concurrent radiotherapy

Surgery:

  • Not specified

Other:

  • No prior antileukemic therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00002701


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Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Gruppo Italiano Malattie EMatologiche dell'Adulto
Investigators
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Study Chair: Petra Muus, MD, PhD Universitair Medisch Centrum St. Radboud - Nijmegen
Study Chair: Franco Mandelli, MD Azienda Policlinico Umberto Primo

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ClinicalTrials.gov Identifier: NCT00002701     History of Changes
Other Study ID Numbers: CDR0000064499
EORTC-06952
ITA-GIMEMA-AIEOP-1
First Posted: April 11, 2003    Key Record Dates
Last Update Posted: September 20, 2013
Last Verified: November 2006
Keywords provided by National Cancer Institute (NCI):
untreated adult acute myeloid leukemia
adult acute promyelocytic leukemia (M3)
Additional relevant MeSH terms:
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Leukemia
Leukemia, Promyelocytic, Acute
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Cytarabine
Cyclophosphamide
Busulfan
Methotrexate
Etoposide
Mitoxantrone
Idarubicin
Mercaptopurine
Tretinoin
Thioguanine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites