Comparative efficacy and safety of two asparaginase preparations in children with previously untreated acute lymphoblastic leukemia (ALL), a phase III clinical trial

Acute lymphoblastic leukemia (ALL) is a clonal disease resulting from genetic
mutations and transformations of a single early progenitor lymphoid cell.
Uncontrolled expansion of leukemis blasts in the bone marrow leads to
suppression of normal haematopoiesis as well as disseminated infiltration of
organs and release of blasts into the perpheral blood.

ALL is the most common malignancy in children, accounting for 30% of all
cancers and 80% of all leukemias in this age group.

The treatment of ALL depends on the use of intensive multi-agent chemotherapy
given for 2 years. In selected patients irradiation and/or stem cell
transplantation are used. Patients with ALL are usually treated within a study
protocol. In the Netherlands, children with newly diagnosed ALL are currently
treated with the national protocol of the Dutch Childhood Oncology Group (DCOG)
ALL 10.

Asparaginase (ASNase) is an essential component of treatment of children with
newly diagnosed ALL. Several recently published trials have clearly
demonstrated that this drug contributes to the total treatment outcome of
children with ALL by at least 10 - 20%. Hence, allergy against asparaginase is
an important clinical problem, as this may lead to early interruption of
asparaginase therapy, resulting in a lower cumulative asparaginase dose which
worsens prognosis.

Recombinant ASNase (rASNase) has similar enzymatic, pharmacokinetic and
pharmacodynamic properties as E.coli-ASNase but is a much purer preparation.
This new ASNase may therefore cause less hypersensitivity reactions than the
currently approved drugs. In a recent pilot study at Erasmus MC it was shown
that this drug has a similar safety profile as regular E-Coli derived
asparaginase, and leads to similar asparagine depletion. The current study is
intended to compare the efficacy of the new rASNase preparation versus the
commercially available E-Coli derived Asparaginase from Medac in a larger
number of children with newly diagnosed ALL.

This multicentre phase III study is designed to assess the efficacy and safety
of recombinant versus E-Coli derived Aaparaginase from Medac, during treatment
of children with newly diagnosed ALL according to the DCOG ALL-10 protocol.

Futhermore: To determine the rate of patients with complete asparagine
depletion in serum during induction treatment, and to demonstrate
non-inferiority of rASNase compared to E-Coli derived Asparaginase Medac.

This is a multicentre, randomised, active-controlled, double-blind,
parallel-group phase III clinical trial to evaluate the efficacy and safety of
repeated ASNase infusions (recombinant versus E-Coli derived Asparaginase
Medac)

Treatment consists of either recombinant asparaginase - or E-Coli derived
Asparaginase Medac infusions (8 doses) in teh induction part of teh protocol.

For post-induction treatment, all patients are stratified into 3 risk groups
(standard risk, medium risk and high risk) based on stratification criteria
defined in the ALL 10 protocol. Patients will receive different treatment
according to their risk group assignment.

For patients in the SR and MR groups treatmnet will be continued using
PEG-asparaginase, and they will be followed for allergic reactions. In
addition, limited blood sampling will be performed to detect antibodies and
check asparaginase levels.

Patients in the HR-group will continue treatment with the standard E-Coli
derived asparaginase in their chemotherapy blocks 1,2 4 and 5, and the
so-called protocol II. Therefore they will continue with the study and recieve
either recombinant or E-Coli asparaginse. Each patient will receive the same
product as in induction.

The risks and burden of participation are similar to a standard treatment for
pediatric ALL. A potential benefit may arise if we can prove that patients with
recombinant asparaginse indeed have fewer allergic reactions to asparagine,
which may increase the cumulative asparaginase dose and lead to a better
prognosis for these children. Potential risks are associated with the blood and
CSF sampling - although this will be combined with regular blood and CSF
sampling time points according to the ALL-10 protocol. New side-effects may
occur in teh recombinant asparaginase group, as only limited experience exists
in humans with this compound, althuogh this is unlikely base don the chemical,
Pk and PD properties of the drug.