CoALL-08-09

Acute lymphoblastic leukeamia

Sequential phase II/III study according to the German drug law (AMG), multi-center trial design including two randomizations

Primary objectives

• Assessment of the efficacy and safety of clofarabine combined with PEG-Asparaginase in high-risk ALL patients and MRD based comparison with the historical control group who received High dose Cytarabine /PEG-Asparginase in Phase II
• MRD based randomized assessment of the cytotoxic efficacy of clofarabine compared to high dose cytarabine each in combination with PEG-Asparaginase in Phase III
• Evaluation of the rate of severe infectious complications after Adriamycine versus Daunorubicine in re-induction in reinduction therapy

Secondary objectives

• Comparison of safety profiles of clofarabine/PEG-Asparaginase versus high-dose cytarabine/PEG-Asparaginase
• MRD-based comparison of the efficacy in the high-risk treatment arm between clofarabine/PEG-Asparaginase and high-dose cytarabine/PEG-Asparaginase respectively, and the historical control group Methotrexate/Cyclofosphamide/Asparaginase in protocol COALL 07-03
• Assessment of the impact of MRD-based stratification in COALL 09 on overall and event-free survival compared to historical COALL control groups

The CoALL-08-09 trial is a prospective, multicenter therapy-optmizing trial with the purpose to optimize the prognosis for children with acute lymphoblastic leukeamia. Depending of prognostic risk factors the patients will be stratified into the low-risk group or the high risk-group. A second stratification follows after the knowledge of the result of MRD on day 29 for patients with a B-progenitor ALL or day 43 for patients with a T-ALL.

A 3-drug-induction is followed by several sequentially administered cycles of combination chemotherapy . In phase II all high risk patients receive Clofarabin/PEG-Asparaginase without randomisation. In phase III the 1st randomization is: clofarabine (40 mg/m²) on day 29-33 + PEG-Asparaginase 2 500 IE/m² on day 33 versus High dose Cytarabin (HIDAC: 4x3g/m²) on day 29 - 31 + PEG-Asparaginase 2 500 IE/m² on day 31.
The 2nd randomization is: Daunorubicine 36 mg/m² versus Adriamycine 30 mg/m² on day 1 and 8 in the standard arm, on day 22 and 29 in the high-risk arm.

A quarter of all patients with B -precursor ALL don´t show any measurable MRD at the end of induction. These patients will not be part of the first randomization. Just as well will patients with a T-ALL and a MRD on day 29 < 10^-3be excluded from this randomization.

• Children and adolescents aged >1 and < 18 years with a confirmed diagnosis of acute B- progenitor or T-cell leukemia
• Parents or legal guardians written informed consent and child’s assent
• Phase II: high risk ALL defined by MRD load. B-progenitor ALL at day 29 >=10^-4, T-ALL at day 43 >=10^-3
• Phase III: MRD positive B-progenitor ALL und T-ALL with MRD >= 10^-3 at day 29
• Infants and patients with a philadelphia chromosome positive ALL will receive different therapy trials

Für die Therapie mit Clofarabin:

• Phase II: B-Vorläufer ALL mit d 29 MRD <10-4 und T-ALL mit d 43 MRD <10³
• Phase III: d 29 MRD negative B-Vorläufer ALL und T-ALL mit d 29 MRD < 10³