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

Sponsor

Dutch Childhood Oncology Group (Other)

Overall Status

Completed

CT.gov ID

NCT00015873

Collaborator

(none)

350

Enrollment

Locations

Arms

127

Duration (Months)

10.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: asparaginase Drug: cytarabine Drug: mercaptopurine Drug: methotrexate Drug: prednisolone Drug: vincristine sulfate	Phase 3

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

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

350 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 Leukemia

Study Start Date :

May 1, 1999

Actual Primary Completion Date :

Feb 1, 2006

Actual Study Completion Date :

Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
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

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

Event-free survival at 3-4 years after diagnosis [4 years after diagnosis]
Event-free survival

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 1 Year

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
2	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
3	St. Anna Children's Hospital	Vienna		Austria	A-1090
4	Hopital Universitaire Des Enfants Reine Fabiola	Brussels		Belgium	1020
5	University Hospital Motol	Prague		Czech Republic	150 06
6	Hopital Saint-Louis	Paris		France	75475
7	University Medical Center Hamburg - Eppendorf	Hamburg		Germany	D-20246
8	Medizinische Hochschule Hannover	Hannover		Germany	D-30625
9	Our Lady's Hospital for Sick Children Crumlin	Dublin		Ireland	12
10	Nuovo Ospedale San Gerardo at University of Milano-Bicocca	Monza		Italy	20052
11	Ospedale San Gerardo	Monza		Italy	20052
12	Erasmus MC - Sophia Children's Hospital	Rotterdam		Netherlands	3015 GJ
13	Ostra Sjukhuset	Gothenburg		Sweden	41685
14	Birmingham Children's Hospital	Birmingham	England	United Kingdom	B4 6NH
15	Institute of Child Health at University of Bristol	Bristol	England	United Kingdom	BS2 8AE
16	Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust	Cambridge	England	United Kingdom	CB2 2QQ
17	Leeds Cancer Centre at St. James's University Hospital	Leeds	England	United Kingdom	LS9 7TF
18	Leicester Royal Infirmary	Leicester	England	United Kingdom	LE1 5WW
19	Royal Liverpool Children's Hospital, Alder Hey	Liverpool	England	United Kingdom	L12 2AP
20	Royal London Hospital	London	England	United Kingdom	E1 1BB
21	Great Ormond Street Hospital for Children NHS Trust	London	England	United Kingdom	WC1N 3JH
22	Central Manchester and Manchester Children's University Hospitals NHS Trust	Manchester	England	United Kingdom	M27 4HA
23	Sir James Spence Institute of Child Health	Newcastle-Upon-Tyne	England	United Kingdom	NE1 4LP
24	Queen's Medical Centre	Nottingham	England	United Kingdom	NG7 2UH
25	Oxford Radcliffe Hospital	Oxford	England	United Kingdom	0X3 9DU
26	Children's Hospital - Sheffield	Sheffield	England	United Kingdom	S10 2TH
27	Southampton University Hospital NHS Trust	Southampton	England	United Kingdom	SO16 6YD
28	Royal Marsden NHS Foundation Trust - Surrey	Sutton	England	United Kingdom	SM2 5PT
29	Royal Belfast Hospital for Sick Children	Belfast	Northern Ireland	United Kingdom	BT12 6BE
30	Royal Aberdeen Children's Hospital	Aberdeen	Scotland	United Kingdom	AB25 2ZG
31	Royal Hospital for Sick Children	Edinburgh	Scotland	United Kingdom	EH9 1LF
32	Royal Hospital for Sick Children	Glasgow	Scotland	United Kingdom	G3 8SJ
33	Childrens Hospital for Wales	Cardiff	Wales	United Kingdom	CF14 4XW