A randomised phase IIb trial of bevacizumab added to temozolomide ± irinotecan for children with refractory/relapsed neuroblastoma - BEACON-Neuroblastoma Trial

Neuroblastoma is the most common extracranial solid tumour in childhood and the
principal cause of death due to cancer in infancy. It is also, after domestic
accident, the second most frequent cause of mortality in children. More than
1200 cases/year are diagnosed in USA and Europe. Half of those cases are
considered high-risk disease (metastatic/MYCN amplified). With the use of
intensive chemotherapy, surgery, myeloablative chemotherapy with haematopoeitic
stem cell rescue, radiotherapy and differentiating therapy with 13-cis-retinoic
acid, long-term survival for children with high-risk neuroblastoma has
moderately improved over the past 30 years, but in long-term reports, overall
survival is still below 50%. The recent introduction of immunotherapy into the
multimodal treatment of neuroblastoma has shown promising results with
improvements in 2-year event free survival (EFS) of up to 20% after the
addition of the anti-GD2 monoclonal antibody ch14.18 with interleukin-2 and
GM-CSF, although it remains to be established the long-term benefit of this
modality where late relapses have been described.
Up to 60% of children with high risk neuroblastoma will experience relapse with
current therapies. In metastatic neuroblastoma, 10-year OS was 2% after relapse
and 1.5% after progression according to Italian Registry data. In INRG, a
database with outcomes from 8800 children with neuroblastoma treated worldwide,
5-year overall survival (OS) after relapse was 8% for non-infants with relapsed
metastatic neuroblastoma and 4% for those with MYCN amplification. There is an
unmet need to develop new therapeutic strategies and test new agents in
children with neuroblastoma.
In addition to relapsed neuroblastoma, there are some patients that remain
refractory to current front-line conventional chemotherapy and also require
novel therapies.

Neuroblastoma is a highly vascular tumour. It has been shown that a high level
of expression of angiogenesis factors VEGF (Vascular Endothelial Growth Factor)
A and B is associated with poor prognosis. Bevacizumab is a recombinant
humanised monoclonal antibody against VEGF that blocks the binding of VEGF to
its receptors. It has been used in a large number of adult patients during
extensive phase III investigations and post-marketing authorisation (see
bevacizumab Summary of Product Characteristics [SPC] ) as single agent, or in
combination, with chemotherapy or radiotherapy. Studies in adults have
established the safety profile with manageable toxicity as a single agent and
in combination including experience with irinotecan in high grade glioma.
A phase I single agent evaluation of bevacizumab and a phase II study in
combination with irinotecan for high grade and diffuse pontine gliomas have
been completed in paediatrics while there are currently more than ten trials
using bevacizumab in combination in children with solid tumours. To date,
frequent toxicities reported in children have been infusion reactions,
proteinuria, rash, hypertension or haematological toxicity. Severe grade 3-4
toxicities have been rare, consisting of central nervous system (CNS) events
(ischaemia/haemorrhage), hypertension, proteinuria, haematological toxicity and
fatigue:
COG conducted a Phase I trial (Study AVF2771s) of bevacizumab in children with
refractory extracranial solid tumours. The primary aims included determining
the maximum-tolerated dose (MTD) or recommended Phase II (RP2D) dose through
use of a restricted dose escalation scheme based on clinically efficacious
doses in adults, defining dose limiting toxicities (DLTs) and other toxicities
and describing bevacizumab pharmacokinetics (PK) in children. Secondary aims
included assessment of bevacizumab anti-tumour activity and exploration of
potential biomarkers of anti-angiogenesis. Overall, bevacizumab therapy was
well tolerated in these paediatric patients and had an acceptable toxicity
profile when administered at doses of 5, 10, or 15 mg/kg every 2 weeks.

A randomised Phase II design is needed to ensure that patients allocated to the
experimental treatments are similar to those in the control group, thereby
avoiding problems of interpretation to which previous non-randomised studies in
this disease area have been subjected. Randomisation controls for selection
factors and will allow an unbiased estimate of the differences between arms at
the end of the trial.

Topotecan-temozolomide has been shown in a recent non-randomised studyies
(TOTEM) [24] to result in positive response rates of 24%, clinical benefit
ratio of 79% and 1-year progression free survival of 42% and a favourable
toxicity profile. Topotecan has been added to this randomised study to obtain
to provide supporting data for the use of topotecan in the treatment of
neuroblastoma in children.

Currently there is no standard chemotherapy for children with
relapsed/refractory neuroblastoma after first line treatment and both
irinotecan-temozolomide and temozolomide alone have been used.
Temozolomide and irinotecan-temozolomide are the combinations selected for
evaluation as they have shown the most promising results with tolerable side
effects and are widely used internationally. The irinotecan-temozolomide
combination is widely considered a *standard* treatment for relapsed or
refractory neuroblastoma, yet there is no good evidence that this regimen is
any better than single agent temozolomide: two studies of
irinotecan-temozolomide have reported response rates of 8% and 15%, while a
single study of temozolomide has reported a response rate of 20%. Hence, there
is no justification for the use of irinotecan-temozolomide as the standard
backbone in this trial and a randomisation between irinotecan-temozolomide and
temozolomide has been incorporated in order to obtain unbiased evidence on the
role of irinotecan.

The factorial design used in this trial will allow the benefit of a new agent
(bevacizumab) to be evaluated as well as evidence on the role of irinotecan and
less patients will be enrolled in one single trial than would be required for
two different trials. A Phase II trial is needed to obtain initial evidence of
activity before proceeding, if appropriate, to a Phase III trial that will
evaluate efficacy.
The best backbone chemotherapy regimen will be used to combine with new
molecularly targeted agents. Considering the large number of potential
molecularly targeted agents, novel clinical trial designs are required to test
agents efficiently.

Background for the dinutuximab beta amendment
GD2 is a ganglioside which is an excellent target in neuroblastoma. It is
almost universally expressed on neuroblastoma cells, but has a relatively
limited distribution (neurons, skin melanocytes and peripheral pain fibres) on
normal tissues. After the ANBL0032 study by the US Children*s Oncology Group
was reported, immunotherapy with the anti-GD2 monoclonal antibody dinutuximab
together with GM-CSF and interleukin-2 (IL-2) was introduced as consolidation
treatment after myeloablative chemotherapy in high risk neuroblastoma.
Dinutuximab (Unituxin, United Therapeutics) has FDA approval, but is not
available in Europe.

Dinutuximab beta (Quarziba, Eusa Pharma) is closely related to dinutuximab. The
two antibodies have identical amino acid sequences, but are produced in
different cell lines. This results in differing glycosylation patterns, which
confer some differences in biological properties. Therefore, although the
antibodies have similar specificity for GD2, they should be considered as
distinct agents. Dinutuximab beta received marketing authorisation from the EMA
in 2017. Dinutuximab beta has been most widely used in Europe, in the context
of the trials conducted by the European Neuroblastoma Research Network (SIOPEN)
where it has been given as consolidation therapy, with and without adjuvant
IL-2. In patients with relapsed or refract

This study has been transitioned to CTIS with ID 2024-518931-12-00 check the CTIS register for the current data.

Primary:
- To test whether bevacizumab added to a backbone chemotherapy regimen
(temozolomide or irinotecan-temozolomide or topotecan-temozolomide)
demonstrates activity in children with relapsed or refractory neuroblastoma
- To test whether the addition of irinotecan to temozolomide increases the
activity of chemotherapy in children with relapsed or refractory neuroblastoma
- To test whether the addition of topotecan to temozolomide increases the
activity of chemotherapy in children with relapsed or refractory neuroblastoma
- To test whether Dinutuximab Beta added to a backbone chemotherapy regimen
(temozolomide or topotecan-temozolomide) demonstrates activity in children with
relapsed or refractory neuroblastoma

Secondary:
- To evaluate the safety of the regimens

Tertiary:
- To undertake preliminary evaluation of the changes in magnetic resonance
imaging (MRI) derived functional imaging biomarkers of angiogenesis. This will
not take place in the Netherlanda due to lack of financing
- To undertake preliminary evaluation of the role of circulating mRNA levels
for tyrosine hydroxylase (TH), paired-like homeobox 2b (PHOX2B) and
doublecortin (DCX) as prognostic/predictive biomarkers in this
refractory/relapsed setting
- To study the pharmacokinetics of bevacizumab in children with neuroblastoma
- To undertake a preliminary evaluation of the role of tumour molecular
profiles including pharmacogenomic profiles as prognostic and predictive
biomarkers in children with neuroblastoma
- To perform a preliminary evaluation of the role of circulating angiogenic
cytokines as pharmacodynamic, prognostic and predictive biomarkers in children
with neuroblastoma
- To undertake a preliminary evaluation of biomarkers of response to
anti-GD2-therapy (Fc/KIR polymorphisms, ADCC and ADA(s) and of Dinutuximab Beta
pharmacokinetics (PK)
- Pilot descriptive study of neuroblastoma markers that may include:
O6-methylguanine-methyltransferase (MGMT) status, immunohistochemistry and
immunofluorescence markers on tumour samples (such as microvessel density
(MVD), CD31, Ki67, NRP1, VEGFR-1, VEGFR-2, C-KIT), DNA/RNA extraction from
tissue sections for tumour mutation screening and tumour expression profiling
- A preliminary correlation of the different biomarkers (Fc/KIR polymorphisms,
Antibody Dependent Cellular Toxicity (ADCC) and Anti-drug Antibodies (ADAs)
will be made with parameters of anti-tumour activity (response rate, PFS and
OS), PK parameters (Dinutuximab Beta trough levels) for this chemo
immunotherapy regimen will be described

This is an international open-label, randomised, multicentre phase II trial of
temozolomide ± irinotecan, with or without bevacizumab or Dinutumximab Beta,
for the treatment of patients with relapsed or refractory neuroblastoma. The
study will evaluate the safety and activity of these combinations.

Patients will receive treatment for 6 courses, lasting 18 or 24 weeks depending
on the arm of the trial that they are randomised to.
Patients with a response (CR, PR) or stable disease (SD) while on the
BEACON-Neuroblastoma trial will receive 6 cycles of trial treatment. If the
patient has achieved a satisfactory response (i.e. CR, PR or SD) with
acceptable toxicity, treatment may be extended beyond 6 cycles (up to 12
cycles) after discussion with the Sponsor and the CI.

Patients will be registered into the trial and randomised at the same time to
one of the following four arms (approximately 30 patients per arm):

Schedule 1: Temozolomide: 200 mg/m2/day , D1-5 po, q28d
Schedule 2: Temozolomide: 200 mg/m2/day , D1-5 po + Bevacizumab: 10 mg/kg,
D1+D15 iv, q28d
Schedule 3: Temozolomide: 100 mg/m2/day , D1-5 po + Irinotecan: 50 mg/m2/day,
D1-5 iv, q21d (closed in June 2018)
Schedule 4: Temozolomide: 100 mg/m2/day , D1-5 po + Irinotecan: 50 mg/m2/day,
D1-5 iv + Bevacizumab: 15 mg/kg, D1 iv, q21d (closed in June 2018)
Schedule 5: Temozolomide: 150 mg/m2/day , D1-5 po + Topotecan 0,75 mg/m2/day,
D1-5 iv, q28d
Schedule 6: Temozolomide: 150 mg/m2/day , D1-5 po + Topotecan 0,75 mg/m2/day,
D1-5 iv + Bevacizumab: 10 mg/kg, D1+D15 iv, q28d

Following completion of the bevacizumab randomization (160 patients) in March
2019 64 additional patients will be registered into the trial and randomized at
the same time to one of the following four arms (with a 2:1 ration in the
Dinutuximab Beta arms):
Schedule T: Temozolomide: 200 mg/m2/day, D1-5 po, q28d
Schedule dBT: Temozolomide: 200 mg/m2/day, D1-5 po+ Dinutuximab Beta 10
mg/kg/day 24h iv, D1-7, q28d
Schedule TTo: Temozolomide: 150 rng/m2/day, D1-5 po+ Topotecan 0,75 mg/m2/day,
D1-5 iv, q28d
Schedule dBTTo: Temozolomide: 150 mg/m2/day , D1-5 po+ Topotecan 0,75
mg/m2/day, D1-5 iv+ Dinutuximab Beta: 10 mg/kg/day 24h iv, D1-7, q28d

On January 28, 2020 the arms T and dBT are closed for inclusion following an
Urgent Safety Measure by the sponsor. Following review and discussion of the
results of the bevacizumab and irinotecan randomisations for event-free and
overall survival in the BEACON-Neuroblastoma trial at the Trial Management
Group (TMG), the results show that temozolomide alone is inferior.

Study medication as described above depending on the cohort the pt is
randomized in.

Bevacizumab
Bevacizumab has been used for many years in up to a million of adult patients
to treat a variety of adult cancers and has been shown to be safe. Side effects
in adults are well known however only a few hundred children have received
bevacizumab and so it is possible that some side effects could occur that we
have not expected. The main known side effects are:

• High blood pressure during treatment in about 25% of patients - your child*s
doctor will check their blood pressure regularly
• Feeling sick in about 60% of patients
• Constipation in about 40% of patients
• Diarrhoea - this can be severe in up to 1 in 3 people treated
• Fatigue (tiredness) during and after treatment
• Pain and weakness affecting the joints, muscles, chest and abdomen
• Numbness or tingling in fingers and toes
• Slow wound healing
• Protein in the urine in about 25% of patients - your child will have their
urine tested regularly
• Increased risk of bleeding - your child*s gums may bleed easily and they may
have nose bleeds, It is important to tell your child*s doctor if you notice any
bleeding
• Poor appetite

A small number of children have had bevacizumab to date and it is not known
whether it will have any effect in the growth of the bones. We will monitor
your child growth at every visit and we will perform an X-Ray of the left hand
and wrist to monitor their bone age. There are other rare side effects of
bevacizumab. If you would like a list of these, please ask your child*s doctor.

Irinotecan
The most common side effects of irinotecan are:

• Diarrhoea (see note below)
• Changes to blood liver enzyme levels and bilirubin levels
• Temporary hair loss
• A reduction in the number of blood cells that are produced by the bone marrow
which leads to:
o Fewer white blood cells (neutropenia), which can increase the risk of getting
an infection, some of which may be life threatening or possibly fatal
o Fewer red blood cells (anaemia) - this can result in shortness of breath,
weakness and fatigue. We will monitor your child closely and they may be given
a blood transfusion if their red cell levels become too low
o Fewer platelets (thrombocytopenia) - this may cause your child to bruise or
bleed more easily. We will monitor your child closely and they may be given a
platelet transfusion if their platelet levels become too low

Other possible less common side effects include nausea and vomiting,
constipation, feeling weak, increased creatinine levels in the blood (an
indication of abnormal kidney function), dehydration, fever and the development
of an *Acute Cholinergic Syndrome* (diarrhoea, flushing, watery eyes, nose and
mouth, constricted pupils, visual disturbance and dizziness within 24 hours of
last receiving irinotecan).

Special note about diarrhoea:

If your child*s develops diarrhoea that starts more than 24 hours after they
last received irinotecan (*delayed diarrhoea*) it may become serious. The
diarrhoea should be treated and kept under close supervision. After the first
diarrhoea appears it is important to do the following:

1. Give your child any anti-diarrhoeal treatment that their doctor has
prescribed
2. Ensure that your child drinks lots of fluids
3. Inform your child*s doctor about their diarrhoea

There are other rare side effects of irinotecan. If you would like a list of
these, please ask your child*s doctor.


Temozolomide
Temozolomide is usually very well tolerated, but possible side effects include:

1. Nausea and/or vomiting
2. A reduction in red blood cells, white blood cells and platelets as mentioned
above for irinotecan
3. Inflammation of the gums and other membranes and linings
4. Weight loss
5. Hair loss in rare cases

There are other rare side effects of Temozolomide. If you would like a list of
these, please ask your child*s doctor.

Topotecan

Topotecan has been used in adults over a number of years and the side effects
are well known. Possible side effects include:

• A reduction in red blood cells, white blood cells and platelets as mentioned
above for temozolomide, irinotecan and bevacizumab
• Fever
• Loss of appetite
• Vomiting and diarrhoea
• Constipation
• Abdominal pain
• Hair loss
• Itchy skin
• Tiredness

Other important side effects:
There have been some cases of the following side effects in patients receiving
topotecan, including some with fatal outcomes:
• bowel inflammation (neutropenic colitis)
• excessive immune reaction (sepsis)
• lung disease

Dinutuximab Beta
The most important side effect of this anti-GD2 drug is severe pain, which can
occur temporarily. The pain is controlled with strong pain medication,
including morphine per infusion. Other side effects that may occur during the
administration of the medicine are fever, cough and severe allergic reactions.
Eye problems can also occur, these are usually temporary. Some patients retain
fluid; in severe cases this can cause low blood pressure and breathing
difficulties.

Other possible side effects are:
* Pain in the head, back, abdomen, intestines, arms, legs, joints or other
parts of the body that require pain medication during the infusion
* Accelerated heartbeat
* Lowering of blood pressure
* Nausea and vomiting
* Diarrhea
* Constipation
* Fever
* Retain swelling and moisture
* Skin rash
* Cough
* Infections
* Decrease in the number of white blood cells, red blood cells and platelets. A
decrease in the number of white blood cells increases the chance of an
infection, possibly with a fever. Treatment with antibiotics is then often
necessary. If the number of red blood cells (this is called anemia or anemia)
decreases, a feeling of tiredness may arise. Fewer platelets can increase the
risk of bleeding and bleeding after an injury, but spontaneous bleeding can
also occur. If necessary, platelets or red blood cells should be treated with a
transfusion.
* Neurological problems, including loss of function of nerves, which can
sometimes be serious or permanent

There are even more rare side effects with Dinutuximab Beta, which can
sometimes be serious or life-threatening.


Group allocation

As this is a randomised trial, there is a possibility that your child may not
be assigned to the treatment group that you (or they) would prefer. The
treatment that your child receives cannot be selected by choice. If you do not
wish for your child to have their treatment allocated by chance i.e. by
randomisation, then they cannot be part of this study and will receive
treatment as recommended by their doctor.

Blood Sampling Risk

If your child takes part in this clinical trial, additional blood samples will
be taken. The risks of having blood taken from the vein include pain, bruising
or infection at the site where the blood is taken, and fainting. If your child
has a Hickman line or Port-a-cath, blood will be taken from there instead of
directly from a peripheral vein. In this case there is a slight risk of
infection when the device is used, but this is no more than for any other
occasion when it is used.

Bone Marrow Sampling Risks

During this study, samples of your child*s bone marrow will be taken so that we
can see if neuroblastoma has spread to this area. Additional bone marrow
sampling will also be performed at the same time for research purposes as
detailed in the Biomarker section of question 6 earlier. Risks of bone marrow
sampling include pain, bleeding and infection at the sampling site. If your
child is allocated to receive bevacizumab there is an additional risk of poor
wound healing after having this test. For this reason, children who are
receiving bevacizumab and have no neuroblastoma in their bone marrow at the
beginning of the study will not have bone marrow samples taken after receiv