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Treatment of Children and Adolescents With Refractory or Relapsed Acute Myeloid Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00186966
Recruitment Status : Completed
First Posted : September 16, 2005
Last Update Posted : April 6, 2011
Sponsor:
Collaborators:
International BFM Study Group
St. Jude Children's Research Hospital
Information provided by:
Dutch Childhood Oncology Group

Study Description
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Brief Summary:
This is an international multicenter open label randomized phase III trial in children with relapsed and refractory acute myeloid leukemia (AML) such a disease. The main purpose of this study is to determine the efficacy and toxicity of liposomal daunorubicin when added to fludarabine, ara-C and G-CSF(FLAG) in children with relapsed and refractory AML.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Fludarabine, Cytarabine, Liposomal daunorubicin (DaunoXome) Drug: Etoposide, Thioguanine, Cyclophosphamide, Busulfan, Melphalan Procedure: Hematopoietic stem cell transplant Radiation: Total body irradiation Phase 3

Detailed Description:

Secondary objectives of this trial are:

  • To determine the toxicity of liposomal daunorubicin when added to FLAG, in terms of mucosal toxicity, bone marrow aplasia, short- and long-term cardiotoxicity and other side effects as compared to patients treated with FLAG only.
  • To determine the long-term clinical outcome prospectively in a large group of children with refractory and relapsed acute myeloid leukemia.
  • To determine the changes in minimal residual disease over time, and the prognostic significance of minimal residual disease determined at various time-points.
  • To determine the relation between in vitro cellular drug resistance and clinical and cell biological features, minimal residual disease and clinical outcome in this patient group
  • To determine the pharmacokinetics of liposomal daunorubicin in relation to its toxicity and efficacy

Reinduction treatment will be done with 2 courses of combination chemotherapy, with FLAG (fludarabine, ara-C and G-CSF) in both courses as standard treatment. In the first course there will be a randomisation for liposomal daunorubicin (DaunoXome®) to be added or not. The second course should always concern FLAG. If patients have > 20% of blasts in the bone marrow after the 1st course, or if they are not in complete remission (CR) after the 2nd course, they will go off protocol. Patients in CR after reinduction treatment can immediately proceed to stem cell transplantation. Consolidation chemotherapy should be given if SCT is delayed. A 3rd course of intensive chemotherapy (VP16 and continuous infusion with cytarabine) is the general recommendation. In selected patients, a low intensity consolidation may be preferred, and such a schedule is described as well. The type of SCT is based on the risk-group. Preferably, a matched sibling donor (MSD) SCT is performed. If a MSD is not available all patients are candidates for a matched unrelated donor (MUD) SCT. If a MUD is also not available, patients with primary refractory disease, early relapse (within 1 year from diagnosis), or greater than or equal to 2nd relapse, are candidates for the more experimental haplo-identical donor (HID) SCT in view of the dismal prognosis. However, patients with a late relapse (>1 year from initial diagnosis) have a better prognosis and should be offered an autologous SCT if a MSD or MUD SCT is not possible. Only in case of autologous SCT, maintenance treatment and/or adjuvant immunotherapy could be considered.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 394 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase III Study of the Treatment of Children and Adolescents With Refractory or Relapsed Acute Myeloid Leukemia
Study Start Date : March 2002
Actual Primary Completion Date : April 2009
Actual Study Completion Date : September 2010

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
FLAG Drug: Fludarabine, Cytarabine, Liposomal daunorubicin (DaunoXome)
See Detailed Description section for details of treatment interventions.

Drug: Etoposide, Thioguanine, Cyclophosphamide, Busulfan, Melphalan
See Detailed Description section for details of treatment interventions.

Procedure: Hematopoietic stem cell transplant
See Detailed Description section for details of treatment interventions.

Radiation: Total body irradiation
See Detailed Description section for details of treatment interventions.
FLAG and LP Dox Drug: Fludarabine, Cytarabine, Liposomal daunorubicin (DaunoXome)
See Detailed Description section for details of treatment interventions.

Drug: Etoposide, Thioguanine, Cyclophosphamide, Busulfan, Melphalan
See Detailed Description section for details of treatment interventions.

Procedure: Hematopoietic stem cell transplant
See Detailed Description section for details of treatment interventions.

Radiation: Total body irradiation
See Detailed Description section for details of treatment interventions.


Outcome Measures
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Primary Outcome Measures :
  1. Response Rate [ Time Frame: 8-9 years ]

Secondary Outcome Measures :
  1. Toxicity between two arms [ Time Frame: 8-9 years ]

Eligibility Criteria
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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Children and adolescents less than eighteen years of age at start of chemotherapy.
  • Subject has one of the following: Primary refractory AML, first relapsed AML, second or subsequent relapsed AML and was not previously treated according to this particular protocol
  • Subjects with a combined relapse, or an isolated extramedullary relapse, or a bone marrow relapse are eligible, also for randomization.

Exclusion Criteria:

  • Symptomatic cardiac dysfunction.
  • Inadequate performance score.
  • Any other organ dysfunction that will interfere with the administration of the therapy.
  • FAB type M3
Contacts and Locations
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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): NCT00186966


Locations
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United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Sponsors and Collaborators
Dutch Childhood Oncology Group
International BFM Study Group
St. Jude Children's Research Hospital
Investigators
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Principal Investigator: Jeffrey Rubnitz, M.D. St. Jude Children's Research Hospital
More Information
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Additional Information:

Publications of Results:
Kaspers J, Zimmermann M, Fleischhack G, Tamminga R, Gibson B, Armendariz H, Dworzak M, Ha S, Hovi L, Maschan A, Philippe N, Razzouk B, Rizzari C, Smisek P, Smith O, Stark B, Will A, Creutzig U. Relapsed Acute Myeloid Leukemia in Children and Adolescents: Interim Report of the International Randomised Phase III Study Relapsed AML 2001/01. 2006 ASH Annual Meeting Abstracts 108: 2013.

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Responsible Party: Prof. G.J.L. Kaspers, MD PhD / Principal Investigator, Dutch Childhood Oncology Group, the Hague, the Netherlands
ClinicalTrials.gov Identifier: NCT00186966    
Other Study ID Numbers: TRIAL
TRIAL Relapsed AML 2001/01
First Posted: September 16, 2005    Key Record Dates
Last Update Posted: April 6, 2011
Last Verified: April 2011
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Cyclophosphamide
Melphalan
Busulfan
Fludarabine
Etoposide
Daunorubicin
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
Antimetabolites, Antineoplastic
Antimetabolites
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antiviral Agents
Anti-Infective Agents