A phase II open-label, randomized, multi-centre comparative study of bevacizumab-based therapy in paediatric patients with newly diagnosed supratentorial, infratentorial cerebellar, or peduncular high-grade glioma.

The biological rationale for the addition of the anti-angiogenic agent
bevacizumab is strong for HGG in both children and adults in these highly
vascularised and VEGFRexpressing tumours. Results in adult recurrent
glioblastoma have been encouraging and have led to ongoing large randomised
Phase III trials in newly diagnosed patients, where it is hoped that, in
addition to direct anti-angiogenic effects, there will also be a potential
synergistic/additive effect with chemotherapy and radiation. In the post*human-
genome era, it may be hoped that the understanding of the inherent biology of
paediatric CNS tumours will lead, not only to improved therapies, but also to
safer treatments and improved quality of life. This may occur through better
classification, stratification/prognostication, and prediction through use of
molecular markers in association with conventional therapies, as well as by
defining molecular targets for new anti-cancer treatments.

To evaluate the efficacy, safety, tolerability, and pharmacokinetics of
bevacizumab when added to postoperative radiotherapy with concomitant and
adjuvant temozolomide (TMZ) and to determine whether the addition of
anti-angiogenic therapy with bevacizumab to the initial management of
paediatric patients with newly diagnosed supratentorial, infratenrorial
cerebellar, or penducular high-grade glioma (HGG) confers a clinical benefit.

The additional cohort for young patients has been added to the current study
with the aim of exploring pharmacokinetics, safety, and response to bevacizumab
when added to temozolomide in younger children aged 6 months to 3 years with
HGG relapsing or progressing after their first-line chemo-surgical treatment

Newly diagnosed patients:
Children between the age of 3 and 18 years with a newly diagnosed
histologically documented localised supratentorial, infratenrorial cerebellar,
or penducular non-brainstem WHO Grade III or IV HGG are potentially eligible to
participate in this study. Eligibility will, however, require the confirmation
of the institution*s histopathologic diagnosis by an independent designated
reference neuro-pathologist. Since the primary interest in this trial is to
identify patients who have developed a tumour progression or recurrence, both
patients with measurable and assessable HGG will be potentially eligible to
participate in this study.

Patients with a histological confirmed WHO grade III or IV HGG diagnosis,
fulfilling all the other inclusion and exclusion criteria, will be randomly
assigned, using minimisation methods, to one of the following 2 treatment arms:

Arm A: Chemoradiation with TMZ followed, after a TMZ treatment break of
approximately 4 weeks, by up to 12 cycles of TMZ

Arm B: Bevacizumab delivered concomitantly with Chemoradiation with TMZ, during
the TMZ treatment break of approximately 4 weeks and thereafter concomitantly
with 12 cycles of adjuvant TMZ

Follow-up:
On completion of study treatment, patients in whom efficacy endpoint events
have not been observed must be followed for efficacy and safety.

The end of the study will be the date of the final scheduled clinic visit for
the last patient to complete the study or the date on which the last data point
from the last patient, which is required for the overall survival analysis has
been received, whichever is the later date.
For an individual patient the end of the study (i.e. the last visit) will occur
when the patient withdraws consent, has been lost to follow-up, dies or when
the IDMC recommends to stopping the trial earlier than initially assumed for
futility or safety issues.

Patients with progressive or relapsed disease:
Young patients aged >= 6 months to < 3 years with localised or metastatic,
supratentorial, infratentoriaal cerebellair of pedunculair non-brainstem WHO
Grade III or IV HGG recurring or progressing after first-line therapy with
surgery and chemotherapy will receive up to twelve 28-day cycles of TMZ and
bevacizumab.
This is an open-label, single-arm study of the addition of bevacizumab to TMZ
given in twelve 28-day cycles:
• Bevacizumab: 10 mg/kg/every 2 weeks at Days 1 and 15
• TMZ: 150-200 mg/m2/day from Days 1-5

During the follow-up period, patients must at a minimum be monitored for the
development of tumour recurrence and progression (please refer to table of
follow-up assessments on page 191 of the protocol).
Once a patient has been diagnosed with either a new progressive or recurrent
disease, that
patient must continue to be followed for safety only.

The approximate length of the study will be 6 years from first patient in to
end of study.

Newly diagnosed patients:
Arm A: Chemoradiation with TMZ followed, after a TMZ treatment break of
approximately 4 weeks, by up to 12 cycles of TMZ
Arm B: Bevacizumab delivered concomitantly with Chemoradiation with TMZ, during
the TMZ treatment break of approximately 4 weeks and thereafter concomitantly
with 12 cycles of adjuvant TMZ

Patients with progressive or relapsed disease:
Twelve 28-day cycles (without radiation therapy):
• Bevacizumab: 10 mg/kg/every 2 weeks at Days 1 and 15
• TMZ: 150-200 mg/m2/day from Days 1-5

All patients experience risks from the standard treatment of Chemoradiation
therapy and TMZ. This includes the known risks that come with Imaging and
Laboratory Assessments.

The patients who are randomized to receive treatment with bevacizumab have an
increased risk of experiencing side-effects. As bevacizumab has not been given
to many children as yet there may be unknown side-effects that appear during
this study.

The most important symptoms are:
- allergy and possible infusion reactions (symptoms that start within a few
minutes or hours of the infusion, e.g., wheezing, tightness in the throat or
chest, rash, and facial swelling)
- bleeding and high fever (this last symptom may be a sign of a serious
infection associated with an impaired immune system)
- impaired brain function (e.g., dizziness, blurred vision, confusion)

(please see Investigator Brochure for all risks related with the
Investigational Product)