A pilot study to test the feasibility, safety and efficacy of the addition of the BiTE antibody Blinatumomab to the Interfant-06 backbone in infants with MLL-rearranged acute lymphoblastic leukemia. A collaborative study of the Interfant network.

Acute lymphoblastic leukemia (ALL) in infants is a rare disease and comprises
about 4% of childhood ALL. In contrast to greatly improved prognosis (> 85%
EFS) in older children with ALL, have newly diagnosed children (<1 year) with
ALL a significantly worse prognosis with an EFS of 47%. Especially the children
with a mixed lineage leukemia- rearrangement (MLL-R), which is found in 80% of
patients, have a worse prognosis than older children with ALL. Relapses occur
early and survival after relapse is only 20%. Therefore, the upfront treatment
must be improved and require these patients innovative strategies against novel
targets.

Blinatumomab is a bispecific single-chain antibody designed to link CD19
expressing B cells and CD3+ T cells resulting in T cell activation and a
cytotoxic T cell response against the CD19 expressing cells. In vitro data
indicate CD19+ lymphoma and leukemia cell lines to be extremely sensitive to
blinatumomab-mediated cytotoxicity. Blasts in infant ALL express CD19.

Blinatumomab belongs to a new class of bispecific antibody constructs called
bispecific T-cell engagers (BITE®). BITEs have been designed to direct
T-effector memory cells towards targets cells. It resembles standard cytotoxic
T-lymphocyte activation. Because blinatumomab targets cells that express CD19,
a marker solely expressed by B cells, including precursor B-ALL cells its
cytotoxicity is highly selective. Blinatumomab recruits and activates T-cells
via CD3. In vitro these activated T-cells induce target cell lysis ranging
between 10-100 pg/mL, showing that blinatumomab is an extremely potent
molecule.3
Blinatumomab needs both the presence of CD19 positive target cells and T-cells
for its cytotoxic activity.

Also, clinical studies show that blinatumomab is effective and well tolerated
in children and adults with ALL who are already pre-treated with intensive
chemotherapy. Our hypothesis is that one treatment blinatumomab can be safely
added to the Interfant-06 backbone and will reduce the MRD values.

The toxicity and efficacy data from this pilot study with blinatumomab will be
used to assess whether blinatumomab will be examined more extensive (eg, in a
randomized study) in the new joint protocol of the COG / JPLSG and Interfant
group.

The primary objective of the study is to assess the safety of 1 course of
blinatumomab added to the Interfant-06 backbone in infants with newly diagnosed
ALL.

The secondary objectives are:
• to assess the feasibility
• to define the preliminary response rate of these regimens
• to assess pharmacokinetics of blinatumomab in infants.

It is a prospective, open-label, non-randomized, international multicenter
pilot study conducted within the Interfant study group. This is a
collaborative network that consists of all major European study groups and
several large pediatric oncology study groups outside Europe. This pilot study
will be conducted in selected centers with experience with blinatumomab in
Europe and Australia and will be used to test the feasibility of adding one
course of blinatumomab to the standard arm (IB) of the Interfant-06 protocol.
Blinatumomab will be administered for 4 weeks immediately after induction
treatment (figure 2).
Infants with ALL are treated according to the current standard of therapy,
which is the Interfant-06 protocol. The only intervention will be the addition
of 1 course of blinatumomab.

This study will not include a randomized question because of the rarity of the
disease and the unsatisfactory outcome of a control arm without blinatumomab.
Moreover, the main objective is to assess the safety and feasibility of a
blinatumomab course in the Interfant-06 backbone. As to the secondary aim
concerning the evaluation of efficacy of this new schedule, a historical
comparison with the MRD and EFS data of the Interfant-06 protocol will be
performed.

The toxicity and safety data of this pilot study will directly influence the
drug choice and dose schedule given to infants in the worldwide future
collaborative COG/JPLSG/Interfant group trial, where a large number of
patients will allow to address randomized questions.

See also figure 2. Treatment schedule in protocol

The investigational product is blinatumomab. Blinatumomab will be manufactured,
packaged labelled and distributed by Amgen Inc.
The Summary of Product Characteristics contains detailed information regarding
the presentation, storage, preparation, and administration of blinatumomab. In
addition, preparation and administration guidelines for this specific study
population will be provided.
Blinatumomab is added to the Interfant-06 backbone, however the chemotherapy
prescribed according to the Interfant-06 protocol and the intrathecal therapy
at day 15 are standard of care and commercially available, and will not be
provided or reimbursed by the sponsor.

Possible risks and burden related to the study

In 2014, the US Food and Drug Administration (FDA) granted accelerated
approval for blinatumomab (BLINCYTO, Amgen Inc.) for the treatment of
Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL.
In 2015 it has been approved by the European Medicines Agency (EMA) for adults
and in August 2018 for children. In the EU and US, blinatumomab has been
approved for the treatment of adults with Philapdelphia negative B- ALL in
first or second CR with positive MRD.
Blinatumomab is added as an extra course in the Interfant-06 treatment
protocol. This increases the risk of blinatumomab related side effects. The
most important and majority of the side effects are observed in the first week
of treatment, during this time the most intensive monitoring is required.
Medically important toxicities are: 1) Neurological adverse events 2) Cytokine
release syndrome (CRS) 3) Immune suppression, caused by decreased
immunoglobulins and neutropenia.
Neurological events are mainly described in adult patients, no increased side
effects with the combinations of intrathecal therapy and blinatumomab have been
seen in the pediatric study, however neurological AEs will be closely monitored
and dose modifications and stopping rules are defined in the current study.
CRS was dose limiting in children with relapsed/refractory ALL when used as
induction treatment. Patients with less disease burden, as in patients after
induction treatment, are expected to experience less side effects.
The decreased immunoglobulins can be supplemented with intravenous
immunoglobulins. In general, these side effects can be managed by standard
supportive care. All R/R pediatric ALL patients in the phase II part of the
study experienced AEs, mostly flu-like symptoms. AEs regardless of causality
were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension
(26%), and cough (21%), increased alanine aminotransferase (18%), increased
aspartate aminotransferase (18%), and febrile neutropenia (15%). CRS occurred
in three (8%) patients.
Another possible risk is that blinatumomab is ineffective. Strict stopping
rules are defined to monitor the response during blinatumomab treatment section
5.5.3. In case of disease progression patients will continue with ADE/MAE
courses of the Interfant-06 protocol.
Patients need to be admitted for 4 days to 4 weeks, and 2 extra bone marrow
punctures and 2 lumbar punctures are performed. For the PK analysis 2 blood
samples (2 ml) are taken. Blood samples are taken from central venous line
and are often part of SOC in the treatment of infants with ALL, who need a very
intensive treatment, necessitating close monitoring of safety laboratory
parameters. Volumes of blood will be minimized as appropriate for this
pediatric population.

Possible benefits related to the study

Whereas the outcome of older children improved to >85% EFS, infants with ALL
have a less than 50% EFS. Especially those with MLL-R, which is found in 80% of
the infants, have a worse outcome than older children with ALL. Relapses occur
early and survival after relapse is only 20%. The current Interfant-06 protocol
did not significantly improve the outcome of infant ALL. These infants might
benefit from innovative strategies directed against novel targets. Blinatumomab
as monotherapy has shown complete remissions in CD19 positive
relapsed/refractory ALL and is also effective in MRD positive patients. In the
pediatric phase II studies in heavily pre-treated R/R ALL patients one third of
patients had CR, mostly after the first course.
In the current Interfant-06 protocol MR patients who have MRD levels =/ > 10-4
by PCR at the start of OCTADAD are eligible for allogenic SCT. When more
patients achieve a MRD level <10-4 before OCTADAD less patients need an
allogenic SCT, potentially reducing the toxicity and treatment related
mortality of an allogenic SCT.