Trial Information

Cilengitide and Metronomic Temozolomide for Relapsed or Refractory High Grade Gliomas or Diffuse Intrinsic Pontine Gliomas in Children and Adolescents - A Phase II Study HIT-HGG-CilMetro - A Clinical Phase II Trial of the HIT-HGG Study Group -

Indication:

Treatment of relapsed or refractory high grade gliomas and diffuse intrinsic pontine gliomas
in paediatric patients ≥ 3 years and < 18 years of age.

Background and rationale:

Relapsed or refractory high-grade gliomas or diffuse intrinsic pontine gliomas (in the
following both addressed as high grade gliomas = HGG) in children and adolescents represent
a very bad prognosis group for which a recommended standard salvage therapy is currently not
available.

The combination of cilengitide and metronomic temozolomide will be investigated in the
present trial as new treatment strategy for these patients.

Metronomic temozolomide was shown to act via inhibition of tumour angiogenesis and as a
cytotoxic agent. Cilengitide might act via tumour angiogenesis and also inhibits tumour cell
migration.

For both drugs, safe doses with only low toxicity had been defined in phase I trials for
paediatric patients with recurrent or refractory brain tumours (Cilengitide: 1800 mg/m²
twice weekly; metronomic Temozolomide: 75-80 mg/m²/d in a 6 week schedule followed by one
week rest) In a phase II trial for adult patients with relapsed glioblastoma cilengitide as
single agent showed a trend towards higher efficacy with 2000 mg twice weekly as compared to
500 mg twice weekly. Furthermore, in a phase II trial of newly diagnosed adult glioblastoma
patients, signs of clinical activity of cilengitide in combination with radiotherapy and
conventional temozolomide was seen in the methylated MGMT gene promoter subgroup. Based on
these findings, a large randomized phase III trial investigating cilengitide in combination
with standard therapy (temozolomide and radiation) in this subgroup was started recently.

Metronomic temozolomide was also shown to be still effective in glioma patients suffering
from relapse after temozolomide standard therapy. Interestingly, the mode of action appears
to be widely independent of the MGMT status, probably due to MGMT depletion by continuous
treatment.

In conclusion, for both drugs signs of clinical activity have been shown in relapsed
glioblastoma patients, even after failure of temozolomide standard therapy.

Study design:

Prospective, non-randomized phase II trial.

Study population:

Patients 3 years and < 18 years of age with high grade glioma or diffuse intrinsic pontine
glioma relapsed after or refractory to standard therapy recruited by approved trial sites

Sample size:

It is planned to include 33 patients.

Therapy:

Patients included in the study receive

- Cilengitide 1800 mg/m² i.v. twice weekly

- Temozolomide 75 mg/m²/d p.o. for 6 weeks, followed by 1 week rest with a mandatory
platelet-count dependent dose adaptation rule: mandatory blood counts twice weekely:
Platelets ≥ 100 000/µl (≥ 100 Gpt/l): 75 mg/m², platelets ≥ 50 000 - < 100 000/µl (≥ 50
- <100 Gpt/l): 50 mg/m², platelets < 50 000/µl (<50 Gpt/l): stop temozolomide until
platelet recovery ≥ 100 000/µl (≥100 Gpt/l)

- Study treatment in the individual patient is scheduled for 1 year unless tumor
progression or excessive toxicity occurs. However, study treatment may be extended
beyond 1 year upon individual decision.

Biometry:

Statistical analysis and sample size calculation:

The feasibility and efficacy of the HIT-HGG-CilMetro therapy will be assessed by a single
stage analysis. Sample size calculation is based on the 6 month overall survival rate. This
survival rate was found to be 44% in a historical study population from the HIT-GBM data
base. An overall survival rate of 59% in the present study is considered to be of clinical
relevance. Based on a one sided one sample χ2-test and a significance level α=5% a sample
size of 33 patients is planned. This sample size implies a power of 50%.

Schedule:

The study is scheduled to start on January 1, 2012. The recruitment period for the trial
will last 24 months until December 31, 2013. Individual follow-up for at least 1 year after
study entry is required for this protocol. The study will be finished 30 days after
completion of study treatment of the last patient enrolled, i.e. the expected end of the
trial will be January 31, 2015.

Long-term follow-up is strongly recommended and will be organised via the HIT-HGG Study
Office.

If the start of the study is delayed, given dates will change accordingly.

Financial support:

Merck KGaA, Darmstadt, Germany, provides a grant for the conduct of the trial, supplies
Cilengitide free of charge and agrees to perform the laboratory assessments for
pharmacokinetics.