Different Therapies in Treating Infants With Newly Diagnosed Acute Leukemia (Interfant06)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Dutch Childhood Oncology Group
Sponsor:
Collaborators:
BFM Germany
CORS Monza Italy
Associazione Italiana Ematologia Oncologia Pediatrica
ANZCHOG Austria New Zealand
BFM Austria
CLCG France Belgium Portugal
COALL Germany
CPH, Czech republic
DFCI consortium USA
FRALLE France
Hong Kong
MD Anderson USA
NOPHO Scandinavian countries
PINDA, Chile
PPLLSG Poland
Seattle USA
SJCRH USA
UKCCSG United Kingdom
Information provided by (Responsible Party):
Dutch Childhood Oncology Group
ClinicalTrials.gov Identifier:
NCT00550992
First received: October 22, 2007
Last updated: February 14, 2014
Last verified: February 2014
  Purpose

RATIONALE: Giving chemotherapy before a donor stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine, methotrexate, leucovorin, and antithymocyte globulin before and after transplant may stop this from happening. It is not yet known which treatment regimen is most effective in treating acute leukemia.

PURPOSE: This randomized clinical trial is studying how well different therapies work in treating infants with newly diagnosed acute leukemia.


Condition Intervention
Leukemia
Biological: anti-thymocyte globulin
Drug: asparaginase
Drug: busulfan
Drug: cyclophosphamide
Drug: cyclosporine
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: etoposide
Drug: leucovorin calcium
Drug: melphalan
Drug: mercaptopurine
Drug: methotrexate
Drug: mitoxantrone hydrochloride
Drug: pegaspargase
Drug: prednisolone
Drug: prednisone
Drug: therapeutic hydrocortisone
Drug: thioguanine
Drug: vincristine sulfate
Procedure: allogeneic bone marrow transplantation
Procedure: allogeneic hematopoietic stem cell transplantation
Procedure: umbilical cord blood transplantation

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: International Collaborative Treatment Protocol for Infants Under One Year With Acute Lymphoblastic or Biphenotypic Leukemia

Resource links provided by NLM:


Further study details as provided by Dutch Childhood Oncology Group:

Primary Outcome Measures:
  • Disease-free survival [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Survival [ Designated as safety issue: No ]
  • Event-free survival [ Designated as safety issue: No ]
  • Event-free survival within each risk group (i.e., low-risk, medium-risk, or high-risk) [ Designated as safety issue: No ]

Estimated Enrollment: 445
Study Start Date: June 2007
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
  Hide Detailed Description

Detailed Description:

OBJECTIVES:

Primary

  • To compare an early intensification regimen comprising two "acute myeloid leukemia" induction therapy blocks with a standard protocol IB regimen administered directly after induction therapy in medium-risk (MR) and high-risk (HR) patients with newly diagnosed acute lymphoblastic or biphenotypic leukemia.

Secondary

  • To compare through a randomized study the role of these regimens in treating these patients.
  • To compare the overall outcome of the Interfant-06 study with outcomes in the historical control series, especially in the Interfant-99 study.
  • To compare the outcomes of low-risk, MR, or HR patients in this study with those of patients in the historical control series Interfant-99 study.
  • To study which factors have independent prognostic value in patients treated with these regimens.
  • To assess the role of stem cell transplantation in HR patients.

OUTLINE: This is a multicenter study.

  • Induction therapy:

    • Prednisone phase: Patients receive prednisone orally or IV three times daily on days 1-7 and methotrexate (MTX) and prednisolone (PRDL) intrathecally (IT) on day 1. Patients then proceed to remission induction therapy.
    • Remission induction phase: Patients receive dexamethasone (DEXA) IV or orally three times daily on days 8-28 followed by a taper to 0 over 1 week; vincristine (VCR) IV on days 8, 15, 22, and 29; cytarabine (ARA-C) IV over 30 minutes on days 8-21; daunorubicin hydrochloride (DNR) IV over 1 hour on days 8 and 9; asparaginase (ASP) IV over 1 hour or intramuscularly (IM) on days 15, 18, 22, 25, 29, and 33; MTX IT on days 1 and 29*; and ARA-C IT on day 15. Patients also receive PRDL or therapeutic hydrocortisone (HC) IT on days 1, 15, and 29.

NOTE: *Patients with CNS involvement at initial diagnosis also receive MTX IT on days 8 and 22. If CNS leukemia is still present at day 29, then patients receive weekly MTX IT until the CNS is free of leukemia.

After completion of induction therapy, patients are stratified according to risk group (low-risk [LR] vs medium-risk [MR] vs high-risk [HR]). Patients with low-risk disease are assigned to treatment arm I. Patients with MR or HR disease that is in complete remission (CR) on day 33 are randomized to 1 of 2 treatment arms. These patients are stratified according to status (MR with rearranged MLL vs MR with unknown MLL vs HR).

  • Arm I (standard therapy):

    • Protocol IB therapy (beginning on day 36 of induction therapy): Patients receive cyclophosphamide (CPM) IV over 1 hour on days 1 and 29 and oral mercaptopurine (MP) on days 1-28; ARA-C IV on days 3-6, 10-13, 17-20, and 24-27; ARA-C IT on day 10; and MTX IT on day 24. Patients also receive PRDL or therapeutic HC IT on days 10 and 24.
    • MARMA therapy:

      • Part I: Patients receive oral MP once daily on days 1-14; high-dose (HD) MTX IV over 24 hours on days 1 and 8; leucovorin calcium orally or IV at 42, 48, and 54 hours after each dose of MTX until MTX plasma levels are safe; and MTX IT on days 2 and 9. Patients also receive PRDL or therapeutic HC IT on days 2 and 9.
      • Part II: Patients receive HD ARA-C IV over 3 hours twice daily with 12-hour intervals on days 15, 16, 22, and 23; and pegaspargase (PEG-ASP) IV over 1 hour or IM on day 23.
    • OCTADA(D) reinduction therapy:

      • Part I: At least 2 weeks after the completion of MARMA chemotherapy, patients receive oral dexamethasone (DEXA) three times daily on days 1-14, followed by a taper to 0 at day 21; oral thioguanine (TG) once daily on days 1-28; VCR IV on days 1, 8, 15, and 22; DNR IV over 1 hour on days 1, 8, 15, and 22; PEG-ASP IV over 1 hour or IM on day 1; ARA-C IV on days 2-5, 9-12, 16-19, and 23-26; and ARA-C IT on days 1 and 15. Patients also receive PRDL or therapeutic HC IT on days 1 and 15.
      • Part II: Patients receive oral TG once daily on days 36-49; ARA-C IV once daily on days 37-40 and 45-48; and CPM IV over 1 hour on days 36 and 49.
    • Maintenance therapy: At least 2 weeks after completion of the last course of OCTADA(D) chemotherapy, patients receive oral MP once daily; oral MTX once weekly; MTX IT in weeks 1 and 15; and ARA-C IT in week 8. Patients also receive PRDL or therapeutic HC IT in weeks 1, 8, and 15. Treatment continues for up to 104 weeks after initial diagnosis in the absence of disease progression or unacceptable toxicity.
  • Arm II (experimental therapy):

    • ADE therapy (beginning on day 36 of induction therapy: Patients receive ARA-C IV every 12 hours on days 1-10; DNR IV over 1 hour on days 1, 3, and 5; etoposide (VP-16) IV over 4 hours on days 1-5; and ARA-C IT on day 1. Patients also receive PRDL or therapeutic HC IT on day 1.
    • MAE therapy: Patients receive ARA-C IV every 12 hours on days 1-10; mitoxantrone hydrochloride IV over 1 hour on days 1, 3, and 5; VP-16 IV over 4 hours on days 1-5; and MTX IT on day 1. Patients also receive PRDL or therapeutic HC IT on day 1.
    • MARMA therapy:

      • Part I: Patients receive oral MP once daily on days 1-14; high-dose (HD) MTX IV over 24 hours on days 1 and 8; leucovorin calcium orally or IV at 42, 48, and 54 hours after each dose of MTX until MTX plasma levels are safe; and MTX IT on days 2 and 9. Patients also receive PRDL or therapeutic HC IT on days 2 and 9.
      • Part II: Patients receive HD ARA-C IV over 3 hours twice daily with 12-hour intervals on days 15, 16, 22, and 23; and pegaspargase (PEG-ASP) IV over 1 hour or IM on day 23.
    • OCTADA reinduction therapy:

      • Part I: At least 2 weeks after the completion of MARMA chemotherapy, patients receive oral DEXA three times daily on days 1-14, followed by a taper to 0 at day 21; oral TG once daily on days 1-28; VCR IV on days 1, 8, 15, and 22; PEG-ASP IV over 1 hour or IM on day 1; ARA-C IV on days 2-5, 9-12, 16-19, and 23-26; and ARA-C IT on days 1 and 15. Patients also receive PRDL or therapeutic HC IT on days 1 and 15.
      • Part II: Beginning 1 week after completion of part I, patients receive oral TG once daily on days 36-49; ARA-C IV once daily on days 37-40 and 45-48; and CPM IV over 1 hour on days 36 and 49.
    • Maintenance therapy: At least 2 weeks after completion of the last course of OCTADA chemotherapy, patients receive oral MP once daily; oral MTX once weekly; MTX IT in weeks 1 and 15; and ARA-C IT in week 8. Patients also receive PRDL or therapeutic HC IT in weeks 1, 8, and 15. Treatment continues for up to 104 weeks after initial diagnosis in the absence of disease progression or unacceptable toxicity.

All HR patients with a suitably matched donor are scheduled for allogeneic stem cell transplantation (SCT) after MARMA or before or during OCTADA(D) chemotherapy, provided they are in CR1 and no more than 8 months have elapsed since initial diagnosis.

  • Conditioning regimens for allogeneic SCT:

    • Matched sibling donor (MSD): Patients receive oral busulfan (BU) every 6 hours on days -7 to -4; CPM IV over 1 hour on days -3 to -2; and melphalan (MEL) IV over 1 hour on day -1.
    • Matched donors (MD): Patients receive oral BU every 6 hours on days -7 to -4; CPM IV over 1 hour on days -3 to -2; MEL IV over 1 hour on day -1; and anti-thymocyte globulin (ATG) IV over 4 hours on days -3 to -1.
  • Graft-Versus-Host Disease (GVHD) prophylaxis and therapy:

    • MSD: Patients receive cyclosporine (CsA) IV or orally twice daily beginning on day -1 and continuing to day 60 after SCT, followed by a taper in the absence of GVHD symptoms.
    • MD: Patients receive CsA as in group MSD; MTX IV on days 1, 3, and 6; leucovorin calcium IV on days 2, 4, and 7; and ATG IV on days -3 to -1.
  • Allogeneic SCT: Patients undergo infusion of bone marrow, peripheral blood, or cord blood hematopoietic stem cells on day 0.

After completion of study therapy, patients are followed periodically for up to 2 years.

  Eligibility

Ages Eligible for Study:   up to 1 Year
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

Inclusion criteria:

  • Diagnosis of acute lymphoblastic leukemia (ALL) or biphenotypic leukemia meeting the following criteria:

    • Based on European Group for the Classification of Acute Leukemia (EGIL) diagnostic criteria
    • Newly diagnosed disease
    • Verified by morphology and confirmed by cytochemistry and immunophenotyping

      • Trephine biopsy is recommended (unless diagnosis can be confirmed by peripheral blood examination) in the event that bone marrow aspiration results in a "dry tap"
  • Must have MLL gene rearrangements documented by split-signal fluorescence in situ hybridization and meets 1 of the following risk criteria:

    • Low-risk disease, defined as all MLL germline cases
    • Medium-risk disease, defined by 1 of the following criteria:

      • MLL status unknown
      • MLL rearranged AND age > 6 months
      • MLL rearranged AND age < 6 months AND WBC < 300 x 10^9/L AND prednisone good response
    • High-risk disease, defined by MLL rearrangement AND meets the following criteria:

      • Age at diagnosis < 6 months (i.e., < 183 days)
      • WBC ≥ 300 x 10^9/L AND/OR prednisone poor response
  • Minimum donor and stem cell requirements for high-risk patients undergoing stem cell transplantation:

    • Donor meeting 1 of the following criteria:

      • HLA-identical sibling
      • Very well-matched related or unrelated donor
      • Must be HLA compatible in 10/10 or 9/10 alleles by 4 digit/allele high-resolution molecular genotyping
    • Stem cell source

      • Bone marrow (preferred source) OR peripheral blood stem cells of filgrastim [G-CSF]-stimulated donors OR cord blood

        • Highly-matched unrelated umbilical cord blood (UCB) (> 7/8 matches identified by high-resolution typing) accepted if a sibling donor is not able to donate bone marrow AND UCB with a sufficient number of nucleated cells (NCs) (i.e., > 1.5 x 10^7/kg recipient body weight [BW]) is cryopreserved
    • Must have ≥ 3 x 10^8 NCs/kg BW OR 3 x 10^6/kg BW CD34-positive cells available for transplantation
  • CNS or testicular leukemia at diagnosis allowed

Exclusion criteria:

  • Mature B-ALL, defined by the immunophenotypical presence of surface immunoglobulins or t(8;14) and breakpoint as in B-ALL
  • Presence of the t(9;22) (q34;q11) or bcr-abl fusion in the leukemic cells (if data are not known, patient still may be eligible)
  • Relapsed ALL

PATIENT CHARACTERISTICS:

  • See Disease Characteristics

PRIOR CONCURRENT THERAPY:

  • More than 4 weeks since prior systemic corticosteroids

    • Corticosteroids by aerosol are allowed
  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: NCT00550992

Locations
United States, Massachusetts
Children's Hospital Boston Recruiting
Boston, Massachusetts, United States, 02215
Contact: Lewis B. Silverman, MD    617-632-5285      
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Clinical Trials Office - St. Jude Children's Research Hospital    901-595-4644      
United States, Texas
M. D. Anderson Cancer Center at University of Texas Recruiting
Houston, Texas, United States, 77030-4009
Contact: Clinical Trials Office - M. D. Anderson Cancer Center at the U    713-792-3245      
United States, Washington
Children's Hospital and Regional Medical Center - Seattle Recruiting
Seattle, Washington, United States, 98105
Contact: Blythe Thomson, MD    206-987-2106      
Austria
St. Anna Children's Hospital Recruiting
Vienna, Austria, A-1090
Contact: Georg Mann, MD    43-1-4017-1250      
Belgium
Hopital Universitaire Des Enfants Reine Fabiola Recruiting
Brussels, Belgium, 1020
Contact: Alice Ferster, MD    32-2-477-2678    aferster@ulb.ac.be   
Czech Republic
University Hospital Motol Recruiting
Prague, Czech Republic, 150 06
Contact: Jan Stary, MD    420-2-2443-6401    jan.stary@lfmotol.cuni.cz   
France
CHR Hotel Dieu Recruiting
Nantes, France, 44093
Contact: Francoise Mechinaud, MD    33-1-4249-9046      
Germany
University Medical Center Hamburg - Eppendorf Recruiting
Hamburg, Germany, D-20246
Contact: Gritta Janka-Schaub    49-404-2803-2580      
Medizinische Hochschule Hannover Recruiting
Hannover, Germany, D-30625
Contact: Martin Schrappe, MD, PhD    49-511-532-6713      
Italy
Nuovo Ospedale San Gerardo at University of Milano-Bicocca Recruiting
Monza, Italy, 20052
Contact: Andrea Biondi, MD    39-039-233-3661    biondi@galactica.it   
Netherlands
Erasmus MC - Sophia Children's Hospital Recruiting
Rotterdam, Netherlands, 3015 GJ
Contact: Rob Pieters, MD, MSC, PhD    31-10-463-6691    rob.pieters@erasmusmc.nl   
United Kingdom
Great Ormond Street Hospital for Children Recruiting
London, England, United Kingdom, WC1N 3JH
Contact: Phil Ancliff, MD    44-20-7829-8831      
Sponsors and Collaborators
Dutch Childhood Oncology Group
BFM Germany
CORS Monza Italy
Associazione Italiana Ematologia Oncologia Pediatrica
ANZCHOG Austria New Zealand
BFM Austria
CLCG France Belgium Portugal
COALL Germany
CPH, Czech republic
DFCI consortium USA
FRALLE France
Hong Kong
MD Anderson USA
NOPHO Scandinavian countries
PINDA, Chile
PPLLSG Poland
Seattle USA
SJCRH USA
UKCCSG United Kingdom
Investigators
Study Chair: Rob Pieters, MD, MSC, PhD Erasmus MC - Sophia Children's Hospital
Study Chair: Martin Schrappe, MD, PhD University of Schleswig-Holstein
  More Information

Additional Information:
No publications provided

Responsible Party: Dutch Childhood Oncology Group
ClinicalTrials.gov Identifier: NCT00550992     History of Changes
Other Study ID Numbers: CDR0000570260, DCOG-INTERFANT-06, EUDRACT-2005-004599-19, CCLG-LK-2006-10
Study First Received: October 22, 2007
Last Updated: February 14, 2014
Health Authority: Netherlands: Dutch Health Care Inspectorate
Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Dutch Childhood Oncology Group:
untreated childhood acute lymphoblastic leukemia
T-cell childhood acute lymphoblastic leukemia
acute undifferentiated leukemia

Additional relevant MeSH terms:
Leukemia
Neoplasms by Histologic Type
Neoplasms
6-Mercaptopurine
Cytarabine
Methotrexate
Thioguanine
Antilymphocyte Serum
Busulfan
Cyclophosphamide
Cyclosporins
Cyclosporine
Melphalan
Pegaspargase
Asparaginase
Daunorubicin
Etoposide
Prednisolone
Methylprednisolone Hemisuccinate
Mitoxantrone
Prednisone
Vincristine
Hydrocortisone-17-butyrate
Cortisol succinate
Hydrocortisone acetate
Hydrocortisone 17-butyrate 21-propionate
Methylprednisolone acetate
Prednisolone acetate
Hydrocortisone
Methylprednisolone

ClinicalTrials.gov processed this record on July 20, 2014