International Study for Treatment of Standard Risk Childhood Relapsed ALL 2010 A Randomized Phase III Study Conducted by the Resistant Disease Committee of the International BFM Study Group

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.