Combination Chemotherapy in Treating Young Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia

Sponsor

Children's Cancer and Leukaemia Group (Other)

Overall Status

Completed

CT.gov ID

NCT00967057

Collaborator

(none)

470

Enrollment

Locations

Arms

110

Duration (Months)

78.3

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not yet known which combination chemotherapy regimen is more effective in treating young patients with acute lymphoblastic leukemia.

PURPOSE: This partially randomized phase III trial is studying how well combination chemotherapy works in treating young patients with relapsed or refractory acute lymphoblastic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: asparaginase Drug: dexamethasone Drug: idarubicin Drug: methotrexate Drug: mitoxantrone hydrochloride Drug: pegaspargase Drug: vincristine sulfate	Phase 3

Detailed Description

OBJECTIVES:

Primary

Evaluate the progression-free survival (defined as the time from study entry to the first occurrence of progression, relapse, death while in complete clinical remission, or second malignancy) of United Kingdom patients with relapsed or refractory acute lymphoblastic leukemia stratified by risk group.
Evaluate whether a minimal residual disease (MRD) level of 10^-4 is a suitable criterion at the end of induction therapy on which to decide whether chemotherapy or stem cell transplantation will be most beneficial to patients with intermediate-risk disease.

Secondary

Use MRD as a surrogate marker for response to therapy.

OUTLINE: This is a multicenter study. Patients are stratified by risk group (standard vs intermediate vs high) and participating country (UK and Ireland vs Australia and New Zealand vs The Netherlands).

Patients with standard-risk disease receive induction therapy, consolidation therapy, intensification therapy, interim maintenance therapy, and maintenance therapy. Patients with intermediate-risk disease receive induction therapy followed by assessment of minimal residual disease (MRD). Those whose MRD status is < 10^{-4 at week 5 (after induction therapy)
proceed to consolidation therapy followed by intensification therapy, interim maintenance
therapy, and maintenance therapy. Those whose MRD status is ≥ 10}-4 at week 5 (after induction therapy) proceed to consolidation therapy followed by intensification therapy and assessment of MRD at week 13 (after intensification therapy). Those whose MRD status is ≥ 10^{-3 at week 13 proceed to pre-stem cell transplantation cytoreduction (FLAD) followed by
allogeneic stem cell transplant (ASCT). Those whose MRD status is < 10}-3 at week 13 proceed directly to ASCT. Patients with high-risk disease receive induction therapy, consolidation therapy, and intensification therapy followed by assessment of MRD at week 13 (after intensification therapy). These patients then proceed to further treatment (FLAD and/or ASCT) based on the same MRD parameters at week 13 as for patients with intermediate-risk disease.

Induction therapy (weeks 1-4): Patients are randomized to 1 of 2 induction therapy arms.
Arm I: Patients receive idarubicin IV over 1 hour on days 1 and 2; oral dexamethasone twice daily on days 1-5 and 15-19; intrathecal (IT) methotrexate on days 1 and 8; vincristine sulfate IV on days 3, 10, 17, and 24; and pegaspargase intramuscularly (IM) on days 3 and 17 or asparaginase IM on days 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, and 25.
Arm II: Patients receive mitoxantrone IV over 1 hour on days 1 and 2. Patients also receive dexamethasone, methotrexate, vincristine sulfate, and pegaspargase or asparaginase as in arm I.
Consolidation therapy (weeks 5-8): Patients receive oral dexamethasone twice daily on days 1-5; vincristine sulfate IV on day 3; IT methotrexate on day 8; methotrexate IV continuously over 36 hours beginning on day 8; pegaspargase IM on day 9 or asparaginase IM on days 9, 11, 13, 15, 17, and 19; leucovorin calcium IV twice on day 10; and cyclophosphamide IV over 30 minutes and etoposide phosphate IV over 4 hours on days 15-19.
Intensification therapy (weeks 9-13): Patients receive oral dexamethasone twice daily on days 1-5; vincristine sulfate IV on 3; IT methotrexate on days 1 and 22; cytarabine IV over 3 hours twice on days 1, 2, 8, and 9; asparaginase IM on days 2, 4, 9, 11, and 23; methotrexate IV continuously over 36 hours beginning on day 22; and leucovorin calcium IV twice on day 24.
Interim maintenance therapy (weeks 14-29): Patients receive oral dexamethasone twice daily on days 1-5; IT methotrexate* on days 1 and 43; vincristine sulfate IV on day 3; high-dose oral methotrexate 4 times on day 22; oral leucovorin calcium twice on day 24; oral mercaptopurine once daily on days 1-42; oral methotrexate on days 8, 15, 29, and 36; oral thioguanine on days 43-49; etoposide phosphate IV over 4 hours and cyclophosphamide IV over 30 minutes on days 43 and 50; and cytarabine IV or subcutaneously (SC) on days 44-47 and 51-54. Treatment repeats every 56 days (8 weeks) for 2 courses.

Patients undergoing cranial irradiation do so before starting interim maintenance therapy. Patients undergoing testicular irradiation do so concurrently with interim maintenance therapy.

NOTE: *Patients who undergo cranial irradiation do not receive IT methotrexate.

Maintenance therapy (weeks 30-117): Patients receive IT methotrexate* on day 15; oral dexamethasone twice daily on days 1-5, 29-33, and 57-61; vincristine sulfate IV on days 1, 29, and 57; oral mercaptopurine once daily on days 1-84; and oral methotrexate on days 1, 8, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 84 days (12 weeks) for 7 courses. Patients then receive 4 additional weeks (course 8) of maintenance therapy without IT methotrexate.

NOTE: *Patients who undergo cranial irradiation do not receive IT methotrexate.

Pre-stem cell transplantation cytoreduction (FLAD): Patients receive fludarabine phosphate IV over 30 minutes and cytarabine over 4 hours on days 1-5 and liposomal daunorubicin citrate IV over 2 hours on day 1. Patients also receive filgrastim IV or SC beginning on day 7 and continuing until blood counts recover.
ASCT: Patients undergo ASCT (including conditioning and graft-vs-host disease [GVHD] prophylaxis) according to national transplant guidelines based on the type of donor.
Post-transplant immunotherapy: Patients who undergo ASCT may receive incremental doses of donor lymphocytes by infusion until a response and/or GVHD has occurred.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

470 participants

Allocation:

Randomized

Primary Purpose:

Treatment

Official Title:

ALLR3: An International Collaborative Trial for Relapsed and Refractory Acute Lymphoblastic Leukaemia (ALL)

Study Start Date :

Oct 1, 2002

Actual Primary Completion Date :

Jan 1, 2010

Actual Study Completion Date :

Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (induction therapy) Patients receive idarubicin IV over 1 hour on days 1 and 2; oral dexamethasone twice daily on days 1-5 and 15-19; intrathecal (IT) methotrexate on days 1 and 8; vincristine sulfate IV on days 3, 10, 17, and 24; and pegaspargase intramuscularly (IM) on days 3 and 17 or asparaginase IM on days 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, and 25.	Drug: asparaginase Given intramuscularly Drug: dexamethasone Given orally Drug: idarubicin Given IV Drug: methotrexate Given intrathecally Drug: pegaspargase Given intramuscularly Drug: vincristine sulfate Given IV
Experimental: Arm II (induction therapy) Patients receive mitoxantrone IV over 1 hour on days 1 and 2. Patients also receive dexamethasone, methotrexate, vincristine sulfate, and pegaspargase or asparaginase as in arm I.	Drug: asparaginase Given intramuscularly Drug: dexamethasone Given orally Drug: methotrexate Given intrathecally Drug: mitoxantrone hydrochloride Given IV Drug: pegaspargase Given intramuscularly Drug: vincristine sulfate Given IV

Arm

Intervention/Treatment

Experimental: Arm I (induction therapy)

Patients receive idarubicin IV over 1 hour on days 1 and 2; oral dexamethasone twice daily on days 1-5 and 15-19; intrathecal (IT) methotrexate on days 1 and 8; vincristine sulfate IV on days 3, 10, 17, and 24; and pegaspargase intramuscularly (IM) on days 3 and 17 or asparaginase IM on days 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, and 25.

Drug: asparaginase

Given intramuscularly

Drug: dexamethasone

Given orally

Drug: idarubicin

Given IV

Drug: methotrexate

Given intrathecally

Drug: pegaspargase

Given intramuscularly

Drug: vincristine sulfate

Given IV

Experimental: Arm II (induction therapy)

Patients receive mitoxantrone IV over 1 hour on days 1 and 2. Patients also receive dexamethasone, methotrexate, vincristine sulfate, and pegaspargase or asparaginase as in arm I.

Drug: asparaginase

Given intramuscularly

Drug: dexamethasone

Given orally

Drug: methotrexate

Given intrathecally

Drug: mitoxantrone hydrochloride

Given IV

Drug: pegaspargase

Given intramuscularly

Drug: vincristine sulfate

Given IV

Outcome Measures

Primary Outcome Measures

Progression-free survival (PFS) of United Kingdom (UK) patients stratified by risk groups []
Evaluation of whether a minimal residual disease (MRD) level of 10(-4) is a suitable criterion at the end of induction therapy on which to decide whether chemotherapy or stem cell transplantation will be most beneficial to patients with intermediate- ... []

Secondary Outcome Measures

MRD as a surrogate marker for treatment response and PFS []
Comparison of PFS, MRD level at day 35, and toxicity as response variables in patients randomized to receive induction therapy with mitoxantrone hydrochloride or idarubicin []
PFS of all patients (UK, Dutch, Australian, and New Zealand) stratified by risk groups []
Comparison of PFS and overall survival between patients enrolled in this study and patients enrolled in R2 or I-BFM []
Evaluation of whether pre-stem cell transplantation cytoreduction (FLAD) reduces tumor load and how it affects outcome following transplant []

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Diagnosis of acute lymphoblastic leukemia (ALL) meeting 1 of the following criteria:
In first relapse after treatment
Has not yet received chemotherapy or radiotherapy for the first relapse
Primary refractory disease
No mature B-cell ALL
Meets criteria for one of the following risk groups:
Standard-risk disease: non-T-cell or T-cell ALL with late isolated extramedullary relapse
Intermediate-risk disease: non-T-cell ALL with early isolated extramedullary relapse or combined marrow and extramedullary relapse; non-T-cell ALL with late combined marrow and extramedullary relapse or isolated marrow relapse; or T-cell ALL with early isolated extramedullary relapse
High-risk disease: non-T-cell ALL with very early isolated extramedullary relapse, combined marrow and extramedullary relapse, or isolated marrow relapse; non-T-cell ALL with early isolated marrow relapse; T-cell ALL with very early isolated extramedullary relapse, combined marrow and extramedullary relapse, or isolated marrow relapse; T-cell ALL with early combined marrow and extramedullary relapse or isolated marrow relapse; or T-cell ALL with late combined marrow and extramedullary relapse or isolated marrow relapse

PATIENT CHARACTERISTICS:

Not specified

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
No prior bone marrow transplant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Women's and Children's Hospital	North Adelaide	South Australia	Australia	5006
2	Birmingham Children's Hospital	Birmingham	England	United Kingdom	B4 6NH
3	Bristol Royal Hospital for Children	Bristol	England	United Kingdom	BS2 8BJ
4	Great Ormond Street Hospital for Children	London	England	United Kingdom	WC1N 3JH
5	Christie Hospital	Manchester	England	United Kingdom	M20 4BX
6	Southampton General Hospital	Southampton	England	United Kingdom	SO16 6YD