Comparison of Different Combination Chemotherapy Regimens in Treating Infants With Acute Lymphoblastic Leukemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Dutch Childhood Oncology Group
ClinicalTrials.gov Identifier:
NCT00015873
First received: May 6, 2001
Last updated: February 14, 2014
Last verified: February 2014
  Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known which combination chemotherapy regimen is most effective for treating infants with acute lymphoblastic leukemia.

PURPOSE: Randomized phase III trial to compare the effectiveness of different combination chemotherapy regimens in treating infants who have newly diagnosed acute lymphoblastic leukemia.


Condition Intervention Phase
Leukemia
Drug: asparaginase
Drug: cytarabine
Drug: mercaptopurine
Drug: methotrexate
Drug: prednisolone
Drug: vincristine sulfate
Phase 3

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 Leukemia

Resource links provided by NLM:


Further study details as provided by Dutch Childhood Oncology Group:

Primary Outcome Measures:
  • Event-free survival at 3-4 years after diagnosis [ Time Frame: 4 years after diagnosis ] [ Designated as safety issue: No ]
    Event-free survival


Estimated Enrollment: 350
Study Start Date: May 1999
Study Completion Date: December 2009
Primary Completion Date: February 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: A no VIMARAM
No VIMARAM preceding maintenance treatment
Experimental: B - VIMARAM
VCR i.v. 1.5 mg/m2/d - 4 days 6-MP p.o. 25 mg/m2/d - 15 days HD-MTX p.i.(24hr) 5 g/m2 - 2 days MTX + pred I.T. (age adapted) - 2 days HD-Ara-C p.i (3hr) 3 g/m2/12 hrs -8 days L-ASP p.i. (1hr) 5.000 U/m2 - 2 days
Drug: asparaginase Drug: cytarabine Drug: mercaptopurine Drug: methotrexate Drug: prednisolone Drug: vincristine sulfate

  Hide Detailed Description

Detailed Description:

OBJECTIVES:

  • Determine the outcome of induction chemotherapy followed by consolidation and reinduction chemotherapy with or without late intensification chemotherapy followed by a maintenance regimen or allogeneic bone marrow transplantation in infants with newly diagnosed acute lymphoblastic leukemia.
  • Determine the value of a late intensification course between reinduction and maintenance therapy in these patients.
  • Determine the prognostic value of age, immunophenotype, WBC, day 15 bone marrow status, and MLL gene rearrangement in patients treated with these regimens.

OUTLINE: This is a partially randomized, multicenter study. Patients are stratified according to risk (high vs standard).

Patients receive induction therapy comprising prednisone orally or IV three times a day on days 1-7; dexamethasone orally or IV three times a day on days 8-35; vincristine IV on days 8, 16, 22, and 30; cytarabine IV over 30 minutes on days 8-21; daunorubicin IV over 60 minutes on days 8 and 9; asparaginase IV over 1 hour or intramuscularly (IM) on days 15, 18, 22, 25, 29, and 33; methotrexate intrathecally (IT) on days 1 and 29; and cytarabine IT on day 15. Patients receive prednisolone IT in combination with any dose of intrathecal chemotherapy. Patients with CNS involvement receive additional doses of methotrexate IT on days 8 and 22 and then weekly after day 29 until there is no evidence of CNS leukemia.

After achieving complete remission, patients receive MARAM chemotherapy comprising oral mercaptopurine daily on days 1-14; methotrexate IV over 24 hours on days 1 and 8; leucovorin calcium orally or IV 36, 42, and 48 hours after beginning each dose of oral methotrexate; methotrexate IT on days 2 and 9; cytarabine IV over 3 hours twice daily on days 15, 16, 22, and 23; and asparaginase IV over 1 hour or IM on days 16 and 23. Patients receive prednisolone IT in combination with any dose of intrathecal methotrexate.

At least 2 weeks after the completion of MARAM chemotherapy, patients receive OCTADD chemotherapy comprising oral dexamethasone three times a day on days 1-21; oral thioguanine daily on days 1-28 and 36-49; vincristine IV on days 2, 8, 16, and 22; daunorubicin IV over 60 minutes on days 1, 8, 15, and 22; cytarabine IV on days 2-5, 9-12, 16-19, 23-26, 37-40, and 45-48; cytarabine IT on days 1 and 15; and cyclophosphamide IV over 1 hour on days 36 and 49. Patients receive prednisolone IT in combination with any dose of intrathecal methotrexate.

Patients are randomized to one of two treatment arms for late intensification therapy.

  • Arm I: Beginning at least 1 week after the completion of OCTADD chemotherapy, patients receive VIMARAM chemotherapy comprising vincristine IV on days 1, 8, 15, and 22; oral mercaptopurine daily on days 1-14; methotrexate IV over 24 hours on days 1 and 8; leucovorin calcium orally or IV 36, 42, and 48 hours after the beginning of each dose of oral methotrexate; methotrexate IT on days 2 and 9; cytarabine IV over 3 hours twice daily on days 15, 16, 22, and 23; and asparaginase IV over 1 hour or IM on days 16 and 23. Patients receive prednisolone IT in combination with any dose of intrathecal methotrexate. Patients then receive the appropriate maintenance therapy.
  • Arm II: Patients do not receive VIMARAM chemotherapy but receive appropriate maintenance therapy.

At least 2 weeks after the completion of the last course of chemotherapy, patients receive maintenance therapy. Patients with a good response to initial therapy with prednisone receive maintenance therapy comprising oral dexamethasone three times daily on weeks 1 and 2; vincristine IV on day 2 of weeks 1 and 2; oral mercaptopurine daily on weeks 1-14; and oral methotrexate once weekly on weeks 1-14.

Patients with a poor response to initial therapy with prednisone receive maintenance therapy comprising oral mercaptopurine daily for weeks 1-14; oral methotrexate once weekly for weeks 1-14; oral dexamethasone three times daily for weeks 1 and 2; vincristine IV on day 2 of weeks 1 and 2; etoposide IV over 2 hours once weekly on weeks 8 and 9; and cytarabine IV over 1 hour once weekly on weeks 8 and 9.

Treatment repeats in both maintenance therapy regimens every 14 weeks for a total of 3 courses. Patients also receive methotrexate IT on day 1 of the first and third course of therapy and cytarabine IT on day 1 of the second course of therapy. Patients receive prednisolone IT in combination with any dose of intrathecal chemotherapy.

Beginning after the completion of maintenance therapy, all patients receive continuing maintenance therapy comprising oral mercaptopurine daily and oral methotrexate once a week. Treatment continues until 104 weeks after initial diagnosis.

Patients with a poor response to initial therapy with prednisone may receive allogeneic bone marrow transplantation if a donor is available. The patient undergoes transplantation immediately after OCTADD chemotherapy rather than being randomized and receiving maintenance therapy. These patients receive conditioning regimen comprising oral busulfan four times a day on days -8 to -5, etoposide IV over 4 hours on day -4, methotrexate IT on day -3, and cyclophosphamide IV over 1 hour on days -3 and -2. Allogenic bone marrow is transplanted on day 0. Patients then receive cyclosporine orally or IV on days 1-180 as graft-versus-host disease prophylaxis.

Patients are followed annually.

PROJECTED ACCRUAL: A total of 350 patients will be accrued for this study within 5 years.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Diagnosis of acute lymphoblastic leukemia (ALL)

    • Newly diagnosed
    • Morphological verification by cytochemistry and immunophenotyping
  • CNS or testicular leukemia at diagnosis allowed
  • Trisomy 21 allowed

PATIENT CHARACTERISTICS:

Age:

  • 365 days or less

Performance status:

  • Not specified

Life expectancy:

  • Not specified

Hematopoietic:

  • Not specified

Hepatic:

  • Not specified

Renal:

  • Not specified

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • Not specified

Chemotherapy:

  • No prior chemotherapy for leukemia

Endocrine therapy:

  • At least 4 weeks since prior systemic corticosteroids
  • Prior inhaled steroids allowed

Radiotherapy:

  • No prior radiotherapy for leukemia

Surgery:

  • Not specified
  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: NCT00015873

  Show 33 Study Locations
Sponsors and Collaborators
Dutch Childhood Oncology Group
Investigators
Study Chair: Rob Pieters, MD, MSC, PhD Erasmus MC - Sophia Children's Hospital
  More Information

Additional Information:
Publications:
Pieters R, Schrappe M, de Lorenzo P, et al.: Outcome of infants less than one year of age with acute lymphoblastic leukemia treated with the Interfant-99 protocol. [Abstract] Blood 108 (11): A-145, 2006.

Responsible Party: Dutch Childhood Oncology Group
ClinicalTrials.gov Identifier: NCT00015873     History of Changes
Other Study ID Numbers: CDR0000068529, ICU-INTERFANT99, UKCCSG-LK-1999-05, EU-20063, EU-20588
Study First Received: May 6, 2001
Last Updated: February 14, 2014
Health Authority: United States: Federal Government
Netherlands: Dutch Health Care Inspectorate

Keywords provided by Dutch Childhood Oncology Group:
untreated childhood acute lymphoblastic leukemia

Additional relevant MeSH terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Methotrexate
Vincristine
Asparaginase
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on September 22, 2014