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

This study has been completed.
Sponsor:
Collaborators:
International BFM Study Group
St. Jude Children's Research Hospital
Information provided by:
Dutch Childhood Oncology Group
ClinicalTrials.gov Identifier:
NCT00186966
First received: September 12, 2005
Last updated: April 5, 2011
Last verified: April 2011
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Dutch Childhood Oncology Group:

Primary Outcome Measures:
  • Response Rate [ Time Frame: 8-9 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Toxicity between two arms [ Time Frame: 8-9 years ] [ Designated as safety issue: Yes ]

Enrollment: 394
Study Start Date: March 2002
Study Completion Date: September 2010
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00186966

Locations
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
Principal Investigator: Jeffrey Rubnitz, M.D. St. Jude Children's Research Hospital
  More Information

Additional Information:
Publications:
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.

Responsible Party: Prof. G.J.L. Kaspers, MD PhD / Principal Investigator, Dutch Childhood Oncology Group, the Hague, the Netherlands
ClinicalTrials.gov Identifier: NCT00186966     History of Changes
Other Study ID Numbers: TRIAL, TRIAL Relapsed AML 2001/01
Study First Received: September 12, 2005
Last Updated: April 5, 2011
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Busulfan
Cyclophosphamide
Melphalan
Cytarabine
Fludarabine
Daunorubicin
Etoposide
Thioguanine
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Antirheumatic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors

ClinicalTrials.gov processed this record on September 14, 2014