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


Phase 3
1 Year
18 Years
Open (Enrolling)
Both
Leukemia

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Trial Information

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


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.

Inclusion Criteria


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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival (PFS) of United Kingdom (UK) patients stratified by risk groups

Safety Issue:

No

Principal Investigator

Vaskar Saha, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Christie Hospital NHS Foundation Trust

Authority:

Unspecified

Study ID:

CDR0000642221

NCT ID:

NCT00967057

Start Date:

October 2002

Completion Date:

Related Keywords:

  • Leukemia
  • recurrent childhood acute lymphoblastic leukemia
  • T-cell childhood acute lymphoblastic leukemia
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma

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