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

Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00015873
• Other study ID #: CDR0000068529
• Secondary ID: ICU-INTERFANT99U
• Status: Completed
• Phase: Phase 3
• First received: May 6, 2001
• Last updated: February 14, 2014
• Start date: May 1999
• Est. completion date: December 2009

Study information

• Verified date: February 2014
• Source: Dutch Childhood Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentNetherlands: Dutch Health Care Inspectorate
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 350
• Est. completion date: December 2009
• Est. primary completion date: February 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 1 Year

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• asparaginase

• cytarabine

• mercaptopurine

• methotrexate

• prednisolone

• vincristine sulfate

Locations

Country	Name	City	State
Austria	St. Anna Children's Hospital	Vienna
Belgium	Hopital Universitaire Des Enfants Reine Fabiola	Brussels
Czech Republic	University Hospital Motol	Prague
France	Hopital Saint-Louis	Paris
Germany	University Medical Center Hamburg - Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Ireland	Our Lady's Hospital for Sick Children Crumlin	Dublin
Italy	Nuovo Ospedale San Gerardo at University of Milano-Bicocca	Monza
Italy	Ospedale San Gerardo	Monza
Netherlands	Erasmus MC - Sophia Children's Hospital	Rotterdam
Sweden	Ostra Sjukhuset	Gothenburg
United Kingdom	Royal Aberdeen Children's Hospital	Aberdeen	Scotland
United Kingdom	Royal Belfast Hospital for Sick Children	Belfast	Northern Ireland
United Kingdom	Birmingham Children's Hospital	Birmingham	England
United Kingdom	Institute of Child Health at University of Bristol	Bristol	England
United Kingdom	Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust	Cambridge	England
United Kingdom	Childrens Hospital for Wales	Cardiff	Wales
United Kingdom	Royal Hospital for Sick Children	Edinburgh	Scotland
United Kingdom	Royal Hospital for Sick Children	Glasgow	Scotland
United Kingdom	Leeds Cancer Centre at St. James's University Hospital	Leeds	England
United Kingdom	Leicester Royal Infirmary	Leicester	England
United Kingdom	Royal Liverpool Children's Hospital, Alder Hey	Liverpool	England
United Kingdom	Great Ormond Street Hospital for Children NHS Trust	London	England
United Kingdom	Royal London Hospital	London	England
United Kingdom	Central Manchester and Manchester Children's University Hospitals NHS Trust	Manchester	England
United Kingdom	Sir James Spence Institute of Child Health	Newcastle-Upon-Tyne	England
United Kingdom	Queen's Medical Centre	Nottingham	England
United Kingdom	Oxford Radcliffe Hospital	Oxford	England
United Kingdom	Children's Hospital - Sheffield	Sheffield	England
United Kingdom	Southampton University Hospital NHS Trust	Southampton	England
United Kingdom	Royal Marsden NHS Foundation Trust - Surrey	Sutton	England
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	St. Jude Children's Research Hospital	Memphis	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Dutch Childhood Oncology Group

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Czech Republic,  France,  Germany,  Ireland,  Italy,  Netherlands,  Sweden,  United Kingdom, 

References & Publications (7)

Hempel G, Relling MV, de Rossi G, Stary J, De Lorenzo P, Valsecchi MG, Barisone E, Boos J, Pieters R. Pharmacokinetics of daunorubicin and daunorubicinol in infants with leukemia treated in the interfant 99 protocol. Pediatr Blood Cancer. 2010 Mar;54(3):3 — View Citation

Lönnerholm G, Valsecchi MG, De Lorenzo P, Schrappe M, Hovi L, Campbell M, Mann G, Janka-Schaub G, Li CK, Stary J, Hann I, Pieters R; Interfant-99 study group. Pharmacokinetics of high-dose methotrexate in infants treated for acute lymphoblastic leukemia. — View Citation

Mann G, Attarbaschi A, Schrappe M, De Lorenzo P, Peters C, Hann I, De Rossi G, Felice M, Lausen B, Leblanc T, Szczepanski T, Ferster A, Janka-Schaub G, Rubnitz J, Silverman LB, Stary J, Campbell M, Li CK, Suppiah R, Biondi A, Vora A, Valsecchi MG, Pieters — View Citation

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.

Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M, Hovi L, LeBlanc T, Szczepanski T, Ferster A, Janka G, Rubnitz J, Silverman L, Stary J, Campbell M, Li CK, Mann G, Suppiah R, Biondi A, Vora A, Valsecchi MG. A treatment protocol for infant — View Citation

van der Linden MH, Valsecchi MG, De Lorenzo P, Möricke A, Janka G, Leblanc TM, Felice M, Biondi A, Campbell M, Hann I, Rubnitz JE, Stary J, Szczepanski T, Vora A, Ferster A, Hovi L, Silverman LB, Pieters R. Outcome of congenital acute lymphoblastic leukem — View Citation

Van der Velden VH, Corral L, Valsecchi MG, Jansen MW, De Lorenzo P, Cazzaniga G, Panzer-Grümayer ER, Schrappe M, Schrauder A, Meyer C, Marschalek R, Nigro LL, Metzler M, Basso G, Mann G, Den Boer ML, Biondi A, Pieters R, Van Dongen JJ; Interfant-99 Study — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival at 3-4 years after diagnosis	Event-free survival	4 years after diagnosis	No