E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
2nd line therapy of recurrent GBM (Glioblastoma multiforme), scheduled for repeat XRT. |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of Brain Cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the safety and tolerability of intravenous 131I-IPA administered concomitantly to 2nd line XRT in recurrent GBM |
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E.2.2 | Secondary objectives of the trial |
1. To assess the maximum tolerated dose (MTD) of 131I -IPA administered concomitantly to 2nd line XRT in recurrent GBM 2. To evaluate the feasibility of a fractionated administration of 131I-IPA 3. To evaluate the radiation absorbed dose to tumour from 131I-IPA 4. To explore the antineoplastic effect of 131I-IPA + XRT combination therapy 5. To explore a possible influence of MGMT promoter methylation status on the biological response to 131I-IPA + XRT combination therapy 6. To explore the occurrence and frequency of pseudo-progression (PP) in response to 131I-IPA + XRT combination therapy 7. To explore the cognitive function before, during and after therapy
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Previously confirmed histological diagnosis of GBM, with current clinical or imaging evidence for first recurrence according to modified RANO criteria (2017). History of GBM standard therapy (debulking surgery, followed by radio-chemotherapy (50–60 Gy in 2 Gy fractions, temozolomide) 2. Interval since end of 1st line XRT ≥6 months 3. Amino acid-based molecular imaging (preferably 18F-FET-PETor 11C-methionine, as institutionally established) indicating pathologically increased amino acid uptake inside or in the vicinity of the tumour, clearly discernible from background activity. 4. Current indication for repeat radiation therapy as discussed at the multidisciplinary neuro-oncological tumour board meeting, planned as standard fractionated dose schedule (18*2 Gy) 5. Gross tumour volume (GTV) of up to 4.8 cm diameter, clinical target volume (CTV) 0.5 cm margin and planning target volume (PTV) ≤0.5 cm margin 6. Male or female ≥18 years of age. 7. Karnofsky performance status (KPS) ≥70. Life expectancy of at least 16 weeks. 8. Haematological, liver and renal function test results as follows: • WBC: >3*109/L • Haemoglobin >80 g/L • PLT >100*109/L • ALT, ALP, AST: ≤5 times upper international limit of normal (UILN) • Bilirubin ≤3 times UILN • Serum creatinine: within normal limits or <120 μmol/L for patients aged 60 years or older • Urine protein dipstick: no protein 9. Female patients surgically sterile or postmenopausal for at least 2 years. Participants of generative potential agreeing to use effective contraception during the period of therapy and 6 months after the end of study. 10. Written informed consent
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E.4 | Principal exclusion criteria |
1. Primary XRT dose >60 Gy 2. Doses to organs at risk defined by Yasar and Tugrul (2005) exceeded or reached by prior radiation therapy; e.g. cumulative total dose on the optical chiasm >54 Gy for 2 Gy/fraction, alpha/beta=2 3. Multifocal distant recurrence, defined as tumour lesion outside the primary XRT field, as evidenced by amino acid-based PET imaging 4. Prior treatment with brachytherapy 5. Prior treatment with bevacizumab 6. History or evidence of delayed-type hypersensitivity (DTH)-dependent chronic infection (e.g. tuberculosis, systemic fungal or parasitic infection), potentially exacerbating under systemic corticoid therapy 7. Localisation of tumour related to brain stem or axis, unless sufficient reserve capacity (e.g. remnant resection cavity, marked atrophy) to accommodate possible post–procedural tissue reactions, or pre-therapeutic consent for emergency trepanation 8. Haemostaseologic conditions, precluding catheterisation or invasive procedures 9. Clinically significant illness or clinically relevant trauma within 2 weeks before the administration of the investigational product 10. Known impairment of liver or kidney function or known liver or kidney disease, such as hepatitis, cirrhosis, renal failure 11. Known human immunodeficiency virus (HIV) positive serology or chronically active hepatitis B or C 12. Ongoing toxicity > grade 2 NCI-CTC (version 4.03) from previous standard or investigational therapies 13. Administration of another investigational medicinal product within 90 days prior to screening 14. Expected non-compliance with longer-term admission at isolated nuclear medicine ward 15. In pre-menopausal women: Pregnant as evidenced by a positive pregnancy test, or breast-feeding 16. Patients with known phenylketonuria
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E.5 End points |
E.5.1 | Primary end point(s) |
a) Safety as assessed by the frequency of occurrence and severity of abnormal findings in safety investigations (physical examination, vital signs, 12-lead ECG, clinical laboratory, adverse events, concomitant medication)
b) Tolerability as assessed by Health-Related Quality of Life (HRQOL) total scores on European Organisation for Research and Treatment of Cancer – EORTC QLQ-C30 and EORTC-BN20 questionnaires (Aaronson et al. 1993; Osoba et al. 1996)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
3 monthly scans for 12 months. |
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E.5.2 | Secondary end point(s) |
Whole body biodistribution and dosimetry (safety dosimetry) a) Residence times for discernible organs (MBq*h) b) Organ and whole body absorbed radiation doses (µSv/MBq)
Tumour dosimetry of 131I-IPA following systemic administration (therapeutic dosimetry) a) Cmax (maximum activity concentration in tumour Bq/cm³) b) tmax (time point of maximum activity concentration in tumour) c) TAC (time activity curve) for metabolic tumour volume (MTV) defined by BL 18F-FET PET and 131I-IPA SPECT d) Tumour absorbed radiation dose (µGy/MBq)
Efficacy a) Radiological and clinical response according to the current RANO criteria b) Metabolic tumour response: SUVmax, SUVmean, MTV c) Survival: PFS, OS
Dosing schedule a) Proportion of subjects (%) with reduction morphological, contrast, and metabolic tumour volume reduction, analysed by dose level and dosing schedule b) Extent of morphological, contrast, and metabolic tumour volume reduction (mL), analysed by dose level and dosing schedule c) Duration (months) of morphological, contrast, and metabolic tumour volume reduction, analysed by dose level and dosing schedule
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoint 1: Evaluated on Patient by Patient Basis by an analysis of Adverse events Endpoint 2: Evaluated on Patient by Patient Basis by an analysis of Adverse events Endpoint 3: conducted by Imaging, four images to evaluate uptake excretion to determine the radiation absorbed dose in the Tumor Endpoint 4: Analyzing functional and metabolic response based on the 3 monthly image aqquisition Endpoint 5: Remote analysis after end of study Endpoint 6: Analyzing functional and metabolic response based on the 3 monthly image aqquisition Endpoint 7: Quarterly analysis of Patient completed and physician completed Quality of Life documents |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Information not present in EudraCT |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Belgium |
Netherlands |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
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 | 2 |
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 |