A comprehensive and targeted therapy approach in pediatric malignant pontine gliomas

Children with malignant pediatric pontine gliomas have a dismal prognosis. The
median overall survival is approximately nine months, the two-year survival
less than 10%. In the past twenty years prognosis has remained unchanged,
despite several treatment strategies that have been applied. In this study, the
feasibility and efficacy of the radiosensitizer gemcitabine and a new
combination of targeted agents will be investigated. The combination is based
on targeting angiogenesis, epithelial growth factor receptor (overexpressed in
DIPG) and a downstream pathway; mammalian target of rapamycin (mTOR)
concomitantly. This study consists of two phases. Depending on the maturation
of the present study, and on preceeding therapy, an individual patient may
enroll in phase a or phase a and b. Patients are separately asked informed
consent for performing a biopsy: apart from histological confirmation, the
tissue will also be used for retrospective correlation of DNA/RNA amplification
or mutation and protein expression and clinical response. With regard to
performing biopsies on DIPG-patients; the past five years biopsies have been
taken regularly from DIPG-patients in France (Roujeau 2007) without mortality
and 8% transient morbidity.

Phase A:
Primary objective: Determining the feasibility of gemcitabine as a
radiosensitizer in DIPG
Secondary objective: Evaluation of efficacy in terms of clinical and
radiological response rate and progression free survival
Tertiary objectives: Evaluation of quality of life (QOL)

Phase B:
Primary objective: Determining the feasibility of adding erlotinib and
everolimus to bevacizumab and irinotecan, based on two dose levels
Secondary objective: Evaluation of efficacy in terms of median duration of
survival from time of progression
Tertiary objectives:
- Response on MRI
- Evaluation of quality of life (QOL)
- Pharmacokinetics of erlotinib and everolimus


General exploratory objectives:
- Evaluate the contribution of MRS to MRI
- Translational research on tumor tissue (if informed consent is given)
- Proteomics in blood (if informed consent is given)

Phase A: non-randomised open-label single-arm phase I-II trial. Cohorts of 3
patients will receive local radiotherapy (54Gy) with escalating dose levels of
gemcitabine, or until an MTD has been established, according to the following
dose escalation table. The starting dose is 80% of the MTD in adults with GBM.

Phase B: Non-randomised open-label single-arm phase I-II trial. Drugs are given
in 2-week lasting courses. Backbone therapy consists of irinotecan 125mg/m2 IV
2-weekly and bevacizumab 10mg/kg IV 2-weekly. Cohorts of 3 patients will
receive escalating dose levels of erlotinib, or until MTD has been established.
The starting dose is 80% of the MTD established in children.
After the MTD of erlotinib is established (or erlotinib is safe at both doses)
everolimus is added. Cohorts of 3 patients will receive escalating dose levels
of everolimus, or until MTD has been established. The starting dose is 80% of
the MTD in children. If no DLT occurs during the first two courses of both
drugs, patients will be treated in an expanded cohort on the same dose level,
until progressive disease or death occurs

At diagnosis (MRI): patients with a focal pontine tumor (and DIPG if separate
informed consent has been obtained) are biopsied before starting treatment.

Chemoradiotherapy: Radiotherapy starts within two weeks after diagnosis, five
times a week with a total dose of 54 Gy. Gemcitabine (radiosensitizer), dosed
140-200mg/m2 IV, is given once a week, for 6 weeks in total. Each gift will be
given 24 hours before radiotherapy.

Combination treatment: Irinotecan 125mg/m2 IV and bevacizumab 10mg/kg IV are
given 2-weekly on the same day. Everolimus (2-3mg/m2 PO) and erlotinib
(60-85mg/m2 PO) should be taken daily.

This study has treatment related risks as common in pediatric oncology, but in
our opinion, with regard to the current infaust prognosis, the chance of
prolongation of survival or even curation outweighs the risks. Of importance is
that all agents have been used in children before, and are administered at
tolerable dosages as reported in several phase I/II studies. If toxicities
occur, dosages are modified or drugs are discontinued as described in the
protocol.

Burden: Standard treatment is six weeks of radiotherapy. In this study,
patients need an extra day in the hospital during irradiation to receive
therapy. During combination therapy, they visit the hospital 2-weekly for IV
administration and blood collection. In addition, they have to take 2 drugs a a
day orally. A medical history physical and neurological examination is
performed weekly dring chemoradiotherapy and biweekly during combination
therapy. Imaging is performed 3-monthly for response evaluation and and QOL
assessments take place 4-monthly. Separate informed consent is asked for a
biopsy (in case of DIPG) and for collecting an extra tube for proteomics during
a venapuncture.