The main goal of this study is to improve the outcome of children and adolescents with
standard risk (SR) first relapsed acute lymphoblastic leukemia. Furthermore, goal is to
set up a large international study group platform allowing for optimization of standard
treatment strategies and integration of new agents.

International Study for Treatment of Standard Risk Childhood Relapsed ALL 2010

Acute Lymphoblastic Leukemia (ALL)

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.

SR-A + Epratuzumab

SR-B + Epratuzumab

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

SR induction/consolidation ALL-REZ BFM 2002 versus UK-ALL-R3 (randomisation 1): 10% pEFS
superiority of arm B above a 65% pEFS at 4 years of arm A

SR consolidation +/- epratuzumab (randomisation 2): 10% pEFS superiority of the arm with
epratuzumab above an expected 74% pEFS at 4 years of the standard arm

PD Dr. med. Arend von Stackelberg

SR induction/consolidation: comparison of OS, toxicity, rate of CR2, and rate of MRD
between treatment groups

SR consolidation +/- epratuzumab: comparison of OS, toxicity, MRD levels, rate of MRD and
evaluation of pharmacokinetic parameters of Epratuzumab

Patients randomized to the SR-A Arm receive induction, consolidation and maintenance
therapy according to a modified protocol ALL-REZ BFM 2002 with Protocol II-IDA as 1st
consolidation element. In this arm patients are randomized not to receive
epratuzumab.This randomization has been stopped pre-term on 1.2.2019 since the
investigational product is not provided anymore by the manufacturer.

Patients randomized to the SR-A Arm receive induction, consolidation and maintenance
therapy according to a modified protocol ALL-REZ BFM 2002 with Protocol II-IDA as 1st
consolidation element. In this arm patients are randomized to receive epratuzumab. This
randomization has been stopped pre-term on 1.2.2019 since the investigational product is
not provided anymore by the manufacturer.

Patients randomized to the SR-B Arm receive induction, post-induction and maintenance
therapy according to the protocol ALL-R3. In this arm patients are randomized not to
receive epratuzumab. This randomization has been stopped pre-term on 1.2.2019 since the
investigational product is not provided anymore by the manufacturer.

Patients randomized to the SR-B Arm receive induction, post-induction and maintenance
therapy according to the protocol ALL-R3. In this arm patients are randomized to receive
epratuzumab. This randomization has been stopped pre-term on 1.2.2019 since the
investigational product is not provided anymore by the manufacturer.

International Study for Treatment of Standard Risk Childhood Relapsed ALL 2010

About this trial

Study ID

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Type

Phase

Placebo

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Trial Timing

What is this trial about?

What are the participation requirements?

Locations

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