Interfant06: Different Therapies in Treating Infants With Newly Diagnosed Acute Leukemia

Sponsor

Dutch Childhood Oncology Group (Other)

Overall Status

Unknown status

CT.gov ID

NCT00550992

Collaborator

BFM Germany (Other), CORS Monza Italy (Other), Associazione Italiana Ematologia Oncologia Pediatrica (Other), Australian and New Zealand Children's Oncology Group (Other), BFM Austria (Other), CLCG France Belgium Portugal (Other), COALL Germany (Other), CPH, Czech republic (Other), DFCI consortium USA (Other), FRALLE France (Other), Hong Kong (Other), MD Anderson USA (Other), NOPHO Scandinavian countries (Other), PINDA, Chile (Other), PPLLSG Poland (Other), Seattle USA (Other), SJCRH USA (Other), UKCCSG United Kingdom (Other)

445

Enrollment

Locations

34.2

Patients Per Site

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
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	N/A

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

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

445 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 1, 2006

Anticipated Primary Completion Date :

Dec 1, 2020

Outcome Measures

Primary Outcome Measures

Disease-free survival []

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 1 Year

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Boston	Boston	Massachusetts	United States	02215
2	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
3	M. D. Anderson Cancer Center at University of Texas	Houston	Texas	United States	77030-4009
4	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington	United States	98105
5	St. Anna Children's Hospital	Vienna		Austria	A-1090
6	Hopital Universitaire Des Enfants Reine Fabiola	Brussels		Belgium	1020
7	University Hospital Motol	Prague		Czechia	150 06
8	CHR Hotel Dieu	Nantes		France	44093
9	University Medical Center Hamburg - Eppendorf	Hamburg		Germany	D-20246
10	Medizinische Hochschule Hannover	Hannover		Germany	D-30625
11	Nuovo Ospedale San Gerardo at University of Milano-Bicocca	Monza		Italy	20052
12	Erasmus MC - Sophia Children's Hospital	Rotterdam		Netherlands	3015 GJ
13	Great Ormond Street Hospital for Children	London	England	United Kingdom	WC1N 3JH

Investigators

Study Chair: Rob Pieters, MD, MSC, PhD, Prinses Maxima Centrum voor kinderoncologie Utrecht
Study Chair: Martin Schrappe, MD, PhD, University Hospital Schleswig-Holstein