Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00003786

Trial Description

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Title

International Collaborative Treatment Protocol for Infants Under One Year With Acute Lymphoblastic or Biphenotypic Leukemia

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

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.

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Brief Summary in Scientific Language

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.

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Organizational Data

  •   DRKS00003786
  •   2012/05/04
  •   2007/10/22
  •   yes
  •   [---]*
  •   [---]*
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Secondary IDs

  •   2005-004599-19 
  •   NCT00550992  (ClinicalTrials.gov)
  •   CDR0000570260  (Dutch Childhood Oncology Group)
  •   DCOG-INTERFANT-06 
  •   CCLG-LK-2006-10 
  •   EUDRACT-2005-004599-19 
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Health Condition or Problem studied

  •   Leukemia
  •   C95.0 -  Acute leukaemia of unspecified cell type
  •   C91.0 -  Acute lymphoblastic leukaemia
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Interventions/Observational Groups

  •   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
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
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  •   Treatment
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  •   N/A
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Primary Outcome

- Disease-free survival

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Secondary Outcome

- Survival
- Event-free survival
- Event-free survival within each risk group (i.e., low-risk, medium-risk, or high-risk)

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Countries of Recruitment

  •   United States
  •   Austria
  •   Belgium
  •   Czech Republic
  •   France
  •   Germany
  •   Italy
  •   Netherlands
  •   United Kingdom
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Locations of Recruitment

  •  
  •  
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Recruitment

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  •   2007/06/30
  •   445
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   no minimum age
  •   1   Years
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Additional Inclusion 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

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Exclusion Criteria

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

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Addresses

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    • Dutch Childhood Oncology Group
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    • Erasmus MC - Sophia Children's Hospital
    • Rob Pieters, MD, MSC, PhD 
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  • start of 1:1-Block address public-contact
    • Erasmus MC - Sophia Children's Hospital
    • Rob Pieters, MD, MSC, PhD 
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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    •   [---]*
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   308
  •   2013/10/30
* This entry means the parameter is not applicable or has not been set.