A Phase II Study of Concurrent Radiation and Temozolomide Followed by Temozolomide and Lomustine (CCNU) in the Treatment of Children with High Grade Glioma

Children with high grade glioma continue to have a poor prognosis, despite the
use of multimodality therapy including surgery, radiation therapy and
chemotherapy. Complete resection is of prognostic significance, but rarely
possible and surgery alone is rarely curative. Radiation prolongs survival time
but has a limited impact on long-term overall survival. The role of
chemotherapy is not yet clear.
The SKION committee for high grade glioma studied the open research protocols
and choose to participipate in the COG ACNS 0423 protocol. Except for
scientific reasons we also wanted to avoid that patients with a poor prognosis
are exposed to a protocol with too much burden or risks. According to the
committees judgement the ACNS 0423 has a optimal balance between expected
burden and toxicity on one hand and efficacy on the other hand.
The ratio behind this protocol is the expected synergistic effect from the
combination of Temozolomide and CCNU. Temozolomide, an oral alkylating agent,
has shown significant pre-clinical and clinical activity against high grade
gliomas and is well tolerated by children. Nitrosurea are considered amongst
the most active agents against high grade gliomas. The activity of Temozolomide
is influenced by the amount of MGMT: an enzyme that repairs Temozolomide
induced DNA damage, and therefore induces resistance. High grade gliomas in
children seem to respond less to Temozolomide than high grade gliomas in
adults. A possible explanation for this could be a difference in the amount of
MGMT. Nitrosurea deplete the cel of MGMT. The synergistic effect of
Temozolomide and BCNU has been shown in mice with human tumor xenografts and
has been studied in adults with high grade gliomas. In a recent phase I study
in children with newly diagnosed high grade glioma the MTD for the combination
of Temozolomide and CCNU has been determinded. (The advantage of CCNU compared
to BCNU is its excellent oral bioavailalibility and less pulmonary toxicity)
(see also attached safety report).

Determine whether temozolomide given during radiation therapy followed by the
combination of temozolomide and CCNU as adjuvant therapy results in an
improvement in event-free survival compared to historical control cohorts.
To further assess the toxicity of adjuvant treatment with CCNU and temozolomide
following XRT and concurrent temozolomide in a larger group of patients.
Biological studies amongst others to explore mechanisms of resistance.

A single arm phase II study in which children with high grade gliomas receive
after surgery simultaneous radiation therapy and temozolomide during for 42
days (90mg/m2/d). Four weeks following the completion of radiotherapy the
patient will receive a maintenance therapy with the combination of temozolomide
(160 mg/m2/d x 5 days) and CCNU (90 mg/m2/d on day 1 of the temozolomide) each
42 days for a total of 6 cycles

See study design

The additional burden and risks for the participants are the result of the
addition of the chemotherapy given in this protocol compared to the standard
treatment with surgery and radiation therapy. The chemotherapy can be taken at
home, orally, which means a minimal extra burden. The side effects of
chemotherapy may differ per patient. In general and as far as known the side
effects of temozolomide and CCNU separately, in combination and on short term
are looked upon as relatively mild. The long term side effects are not yet
fully known.