ALL is the most frequent malignancy in childhood and has favourable event-free and overall
      survival rates. About 15% of patients suffer relapse. At relapse prognosis is much inferior
      (about 50% survival) leukemic clones exhibit much more resistance to conventional
      chemotherapy. Patients with relapse require treatment intensification and different
      therapeutic strategies. At relapse, new targeted agents can provide the chance for better
      cure rates and need to be investigated in prospective controlled trials before they may be
      even eligible for frontline treatment strategies.

      The IntReALL SR 2010 trial is designed to achieve 2 major aims: Establishment of the best
      available standard chemotherapy treatment. This is addressed with the randomization of the 2
      best developed strategies for treatment of childhood relapsed ALL, the German ALL-REZ BFM
      2002 Protocol with the Protocol II IDA arm, and the British ALL-R3 protocol with the
      mitoxantrone arm. This randomization allows confirming the feasibility of both protocols in a
      large variety of different countries and study groups with different frontline therapy
      strategies. As result from this trial a common standard chemotherapy for childhood relapsed
      ALL will be developed which can serve as backbone for investigation of the most attractive
      targeted new agents.

      The 2nd aim is the investigation of the efficacy and tolerability of the humanized CD22
      directed monoclonal antibody Epratuzumab, manufactured and provided by the company
      Immunomedics, US. The drug will be randomly added to the respective consolidation
      chemotherapy, using EFS as primary endpoint. Epratuzumab has been developed in adult
      rheumatology indications and in B-cell malignancies. A phase I and early phase II combination
      trial in childhood relapse ALL has been conducted and published by the Children's Oncology
      Group (COG), and results of an extended phase II trial have been recently presented at the
      ASH meeting (12/2011). The drug showed a very favourable safety profile as single drug and in
      combination with multidrug chemotherapy. Activity was moderate, the recent trial showed a
      significantly better elimination of minimal residual disease (MRD) in patients achieving a
      2nd complete remission. This finding supports the strategy to use Epratuzumab in combination
      with consolidation chemotherapy after induction in patients having reduced the leukemia
      burden in the bone marrow to at least below 25%, most of them will be in 2nd complete
      remission. Epratuzumab will be given weekly at the established dose. Pharmacokinetics will be
      investigated in a reduced number of patients. The further treatment will be conventional
      intensive chemotherapy and maintenance therapy in patients with good MRD response after
      induction, or with allogeneic stem-cell transplantation (SCT) in those with insufficient MRD
      response. SCT will be considered as standard treatment element and will not lead to censoring
      of the patients of considered as endpoint. Epratuzumab is not licensed so far and the trial
      may add to the approval process in case.

      Scientific advice for the trial has been requested at the FDA and the EMA. Both institutions
      have responded supportively. Concerns and recommendations of FDA and EMA have been addressed
      in the protocol and the corresponding statistical analysis plan.

      The IntReALL SR 2010 trial will be financed within the FP7 project IntReALL 2010 supported by
      the European Commission. Within the project next to the SR trial a strategy for high Risk
      (HR) patients will be addressed, the establishment of harmonized diagnostic procedures, an
      international tumour bank and a comprehensive biologic/scientific programme will be set up, a
      web-based Good Clinical Practice (GCP) conform database will be established, a comprehensive
      statistical strategy for both trials are established, and drug development in this indication
      will be promoted and organized from side of the disease experts in cooperation with the
      established academic structures ITCC (Innovative Therapies for Children with Cancer), the
      ENCCA project (European Network for Cancer in Children and Adolescents) and SIOPe
      (International Society for Pediatric Oncology Europe), the central authorities (EMA, FDA) and
      Industry. Parent organisation and former patients are integrated into and accompany the
      process.

      Main aims of the IntReALL FP7 project are to establish a therapeutic platform for children
      with relapsed ALL in Europe and beyond and to give them access to the most promising new
      agents under academic control and free from commercial interests.

      Randomized evidence for efficacy and tolerability of new drugs are demanded by competent
      authorities. These trials are conducted beyond the mostly palliative patient group eligible
      for phase I/II trials in curative indications. Treatment protocols for with curative
      indications need to be conducted in the best interests of the patients, ideally with an
      academic sponsor. The design should be driven by medical and scientific evidence and not by
      commercial interests as is the case in industry sponsored trials. This concept was
      acknowledged by the European Commission selecting the project for funding from many other
      powerful applications.