| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| First or second tumour recrurrence/progression of a histological confirmed supratentorial malignant glioma WHO Grade III-IV |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065443 |
| E.1.2 | Term | Malignant glioma |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine
- the objective radiological response (RR), objective radiological response rate (ORR) and objective response duration (ORD) using MRI and PET neuroimaging
- the predictive / prognostic value of the MRI / PET neuroimaging data for Avastin / Irinotecan chemotherapy due to comparing with the clinical trial parameters (time to tumor progression TTP, progression free survival rate at 6 months PFS6, overall survival OS and overall survival rate at 12 months OS12)
- the safety and tolerability of Avastin / Irinotecan chemotherapy in malignant glioma patients
|
|
| E.2.2 | Secondary objectives of the trial |
To compare MRI / PET neuroimaging parameters
- with each other using image fusion methods
- with Quality of Life (QOL)
- with Molecular Tissue and Serum / Plasma Biomarkers |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Investigation of predictive and prognostic impact of several molecular markers in glimoma tissue and serum/plasma of patients weith recurrent or progressive malignant glioma during Avastin/Irinotecan chemotherapy |
|
| E.3 | Principal inclusion criteria |
[1] Patients present with a first or second tumor recurrence / progression of a histological confirmed supratentorial malignant glioma WHO Grade III-IV (Classification following WHO criteria).
Note: Patients may be entered based on neuropathology from the original diagnostic tumor specimen. For Translational Research Studies the original paraffin block - including sufficient tissue of the primary tumor - is required. Stereotactic biopsies or open biopsies of the primary malignant glioma without sufficient tumor tissue are not feasible and the patients must not be enrolled in this study.
[2] Patients with surgical resection of tumor recurrence / progression: Following standard therapy (first recurrent / progressed tumor) or standard therapy / second line chemotherapy excepting anti-angiogenic approaches (second recurrent /progressed tumor), patients must have evidence of further tumor progression measured by standard MRI sequences (MacDonald criteria). If possible, patients may have prior surgical resection of the tumor progression and will be eligible if the following conditions apply:
Patients must have recovered from the effects of surgery
To adequately asses the malignant glioma before surgery and the extent of residual disease postoperatively, two MRIs scans have to be performed:
A first standard MRI scan has to be done within 1 week before surgery to document a progressed or recurrent malignant glioma.
A second standard / functional MRI scan has to be done between 24 and 48 hours after surgery to document the postoperative malignant glioma (Baseline MRI scan).
Note: Patients must be on a steroid dosage that has been stable for at least 5 days before MRI. If the 48-hour scan is performed more than 14 days prior to study enrollment, the scan needs to be repeated (third MRI scan), however, the 24-48 hour MRI is the baseline scan.
FET- / FLT-PET scans have to be done within 2 weeks after surgery to document the postoperative malignant glioma (Baseline PET scans).
Patients without surgical resection of the tumor recurrence / progression: Patients must have evidence of tumor progression measured by standard MRI sequences (MacDonald criteria).
Additional functional MRI sequences have to be done within 1 week prior to study enrollment.
Note: Patients must be on a steroid dosage that has been stable for at least 5 days before MRI. If the 48-hour scan is performed more than 14 days prior to study enrollment, the scan needs to be repeated (third MRI scan), however, the 24-48 hour MRI is the baseline scan.
FET- / FLT-PET scans have to be done within 2 weeks after surgery to document the postoperative malignant glioma (Baseline PET scans).
[3] Resolution of all acute toxic effects of prior therapy to grade ≤ 1 (except alopecia, see Protocol Attachment A.5)
[4] Patients must have an ECOG performance status of 0-2 (refer to Protocol Attachment A.4)
[5] Patients must be ≥ 18 years and ≤ 80 years of age, with a life expectancy of greater than 8 weeks
[6] Patients must have adequate organ function as defined by the following criteria:
Bone Marrow Reserve - Platelets ≥ 75.000/μL
- Absolute Neutrophil Count ≥ 1500/μL
- Hemoglobin ≥ 10.0 g/dL
Blood Coagulation - aPTT ≤ 1.5 times upper limit of normal (ULN)
Hepatic Function - ASAT and ALAT ≤ 2.5 times ULN
- ALP ≤ 2.5 times ULN
- Total SERUM Bilirubin < 1.5 times ULN
Renal Function - SERUM Creatinine ≤ 1.5 times ULN
Metabolism - SERUM Albumin ≥ 3.0 g/dL
All tests must be performed ≤ 3 days prior to study enrollment. Eligibility for hemoglobin count may be reached by transfusion
[7] Signed and dated informed consent document by the patient, indicating that the patient has been informed of all the pertinent aspects of the trial prior to study enrollment
[8] Willingness and ability of the patient to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures |
|
| E.4 | Principal exclusion criteria |
[9] The patient is active participant in another clinical trial, which investigates substances with anti-angiogenic effectiveness
[10] Exclusion of patients in the event of
surgery of a recurrent / progressed malignant glioma within 2 weeks prior to study enrollment
chemotherapy (Standardtherapy o Second Line Chemotherapy) within 2 weeks prior to study enrollment
radiation therapy (Standardtherapy) within4 weeks to study enrollment
evidence in baseline MRI of intratumoral or peritumoral hemorrhage deemed clinically significant by the treating physician (area of hemorrhage > 25% of tumor area)
[11] Significant Co-Morbidities within 12 months prior to study enrollment
myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure
cerebrovascular accident including transient ischemic attack
[12] Significant Co-Morbidities at Baseline Evaluation
Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy)
pulmonary embolus within4 weeks to study enrollment
A known HIV (human immunodeficiency virus) or Hepatitis B/C infection or severe acute infection
[13] Anticoagulation: Current treatment with therapeutic doses of Marcoumar / Sintrom excluding thrombosis prophylaxis with low dose Heparin.
[14] Pregnancy, Breastfeeding and Non-Contraception
Female patients who are pregnant or nursing
Patients who are sexually active and unwilling or unable to use a medically acceptable method of contraception during the trial.
Note: Female and male patients with reproductive potential have to use an approved contraceptive method (e.g., hormonal contraception, intrauterine device, condom with spermicide, etc.) during and for 3 months after discontinuation of study treatment. Female Patients with child-bearing age must have a negative serum pregnancy test ≤ 3 days prior to study enrollment. During study treatment pregnancy has to be excluded (serum pregnancy tests every 2 weeks until tumor progression).
[15] Evidence of increased intracranial pressure
midline shift > 5 mm
headache, distinct nausea and vomiting
[16] Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would impart excess risk associated with study participation or study drug administration, or which would make the patient inappropriate for entry into this study. The decision to enroll the patient in this study is in the judgment of the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - Objective response criteria (RR, ORR, ORD) asses by Standard MRI and FET-/FLT-PET during Avastin/Irinotecan chemotherapy |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The active part of the trial is finished when subject suffers again from tumor recurrence/progresseion
The follow-up part of the trial ends with the subject's death |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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