HIT-HGG CilMetro

Primary objectives

To evaluate the efficacy of a combined treatment with cilengitide and metronomic oral temozolomide as measured by 6 months overall survival (OS) after diagnosis of relapse or tumour progression in children and adolescents with relapsed or refractory high-grade malignant glioma and diffuse intrinsic pontine glioma.

Secondary objectives

1. To evaluate the safety and toxicity of the study treatment by common toxicity criteria (CTC; version 4.0).
2. To assess - the response rates at 6 months (continuous complete response = CCR, complete response = CR, partial response = PR, stable disease = SD, progressive disease = PD) and - progression-free survival (PFS) at 6 months, and - response rates, OS, and PFS at 12 months after relapse diagnosis or diagnosis of tumor progression. Response will be presented including histopathological variants.
3. To assess the pharmacokinetics of cilengitide administered as part of the study treatment.

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 dose adaptation rule depending of haematatological and non-haematological toxicities.

• Diagnosis of high-grade malignant glioma confirmed by central neuropathological review (last MRI diagnosis not older than 4 weeks) - including glioblastoma multiforme (WHO IV), anaplastic astrocytoma (WHO III), anaplastic oligodendroglioma (WHO III),
• anaplastic oligoastrocytoma (WHO III), anaplastic pilocytic astrocytoma (WHO III), anaplastic ganglioglioma (WHO III), anaplastic pleomorphic xanthoastrocytoma (analogous to WHO III), giant cell glioblastoma (WHO IV), and gliosarcoma (WHO IV) - or
• diagnosis of diffuse intrinsic pontine glioma confirmed by central neuroradiological review - refractory to standard treatment, or relapsed or progressive after first-line therapy.
• 2. Patient aged 3 years and older but under 18 years at time of relapse diagnosis
• 3. Written informed consent of the patient (mandatory from 15 years of age) or the parents (mandatory till 18 years of age).

• Known hypersensitivity or contraindication to any study drugs
• Other (simultaneous) malignancies
• Pregnancy and / or lactation
• Patients who are sexually active refusing to use effective contraception (oral contraception, intrauterine devices, barrier method of contraception in conjunction with spermicidal jelly or surgical sterile)
• Current or recent (within 30 days prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial
• Severe concomitant diseases (e.g. immune deficiency syndrome) 7. Severe psychological disease or neurological damage without possibility to communicate
• Clinical signs of intracranial pressure
• Intracerebral hemorrhage or history of intracerebral hemorrhage
• Following laboratory test results (not older than 2 weeks before patient´s inclusion):

Platelets < 100 000/μl (< 100 Gpt/l) PT, INR and PTT above normal range, absolute neutrophil count < 1 500/μl (< 1,5 Gpt/l),
Hemoglobin < 10g/dl (< 6,4 mmol/L),
Serum creatinine ≥ 1,5 x upper limit of normal range or creatinine clearance rate < 60 ml/min/m2 corrected for body surface area),
Total bilirubin ≥ 1,5 x upper limit of normal range SGOT (ASAT) and SGPT (ALAT) ≥ 2,5 x upper limit of normal range,
Alkaline phosphatase ≥ 2,5 x upper limit of normal range

• Hereditary Intrinsic Platelet Disorders
• Ongoing irradiation or chemotherapy (within the last 4 weeks)
• Estimated life expectancy of less than 2 months

HIT-HGG-CilMetro International Study Office
University Children’s Hospital
Martin-Luther-University Halle-Wittenberg
Ernst-Grube-Str. 40 06120 Halle (Saale) Germany
Tel+49 (345) 557-2503 or -2388
Fax +49 (345) 557-2480 or -2389
hit-hgg-studie@uke-halle.de