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

Information source: Dutch Childhood Oncology Group
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Leukemia

Intervention: asparaginase (Drug); cytarabine (Drug); mercaptopurine (Drug); methotrexate (Drug); prednisolone (Drug); vincristine sulfate (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Dutch Childhood Oncology Group

Official(s) and/or principal investigator(s):
Rob Pieters, MD, MSC, PhD, Study Chair, Affiliation: Erasmus MC - Sophia Children's Hospital

Summary

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.

Clinical Details

Official title: International Collaborative Treatment Protocol for Infants Under One Year With Acute Lymphoblastic Leukemia

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Event-free survival at 3-4 years after diagnosis

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

Minimum age: N/A. Maximum age: 1 Year. Gender(s): Both.

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

Locations and Contacts

St. Anna Children's Hospital, Vienna A-1090, Austria

Hopital Universitaire Des Enfants Reine Fabiola, Brussels 1020, Belgium

University Hospital Motol, Prague 150 06, Czech Republic

Hopital Saint-Louis, Paris 75475, France

University Medical Center Hamburg - Eppendorf, Hamburg D-20246, Germany

Medizinische Hochschule Hannover, Hannover D-30625, Germany

Our Lady's Hospital for Sick Children Crumlin, Dublin 12, Ireland

Nuovo Ospedale San Gerardo at University of Milano-Bicocca, Monza 20052, Italy

Ospedale San Gerardo, Monza 20052, Italy

Erasmus MC - Sophia Children's Hospital, Rotterdam 3015 GJ, Netherlands

Ostra Sjukhuset, Gothenburg 41685, Sweden

Birmingham Children's Hospital, Birmingham, England B4 6NH, United Kingdom

Institute of Child Health at University of Bristol, Bristol, England BS2 8AE, United Kingdom

Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust, Cambridge, England CB2 2QQ, United Kingdom

Leeds Cancer Centre at St. James's University Hospital, Leeds, England LS9 7TF, United Kingdom

Leicester Royal Infirmary, Leicester, England LE1 5WW, United Kingdom

Royal Liverpool Children's Hospital, Alder Hey, Liverpool, England L12 2AP, United Kingdom

Great Ormond Street Hospital for Children NHS Trust, London, England WC1N 3JH, United Kingdom

Royal London Hospital, London, England E1 1BB, United Kingdom

Central Manchester and Manchester Children's University Hospitals NHS Trust, Manchester, England M27 4HA, United Kingdom

Sir James Spence Institute of Child Health, Newcastle-Upon-Tyne, England NE1 4LP, United Kingdom

Queen's Medical Centre, Nottingham, England NG7 2UH, United Kingdom

Oxford Radcliffe Hospital, Oxford, England 0X3 9DU, United Kingdom

Children's Hospital - Sheffield, Sheffield, England S10 2TH, United Kingdom

Southampton University Hospital NHS Trust, Southampton, England SO16 6YD, United Kingdom

Royal Marsden NHS Foundation Trust - Surrey, Sutton, England SM2 5PT, United Kingdom

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston, Massachusetts 02115, United States

Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland BT12 6BE, United Kingdom

Royal Aberdeen Children's Hospital, Aberdeen, Scotland AB25 2ZG, United Kingdom

Royal Hospital for Sick Children, Edinburgh, Scotland EH9 1LF, United Kingdom

Royal Hospital for Sick Children, Glasgow, Scotland G3 8SJ, United Kingdom

St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States

Childrens Hospital for Wales, Cardiff, Wales CF14 4XW, United Kingdom

Additional Information

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: May 1999
Last updated: February 14, 2014

Page last updated: August 23, 2015

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