Radioimmunothérapie avec des fragments Fab 6A10 marqués au Lu-177 chez des patients atteints de glioblastome après un traitement standard (RIT in GBM)
Un essai de phase I pour déterminer la dose maximale tolérée et la dosimétrie spécifique au patient de la radioimmunothérapie intracavitaire fractionnée avec des fragments Fab 6A10 marqués au Lu-177 chez des patients atteints de glioblastome après un traitement standard
Locoregional, intracavitary radioimmunotherapy (iRIT) with a newly developed radioimmunoconjugate (Lu-177 labeled 6A10-Fab-fragments) will be used to prevent or postpone tumour recurrence in patients with GBM following standard therapy .
Following study objectives will be analyzed:
- Determining the Maximum Tolerated Dose (MTD)
- Determining safety by assessing all new neurological, hematological and other AEs CTC grade 2 or higher
- Determining absorbed dose to the 2 cm shell of the resection cavity (based on a series of SPECT/CTs of the head 2h,24h,48h, 72h p.i. and on day 5-7)
- Determining absorbed dose values for the kidneys, the liver, the active marrow (based on a series of SPECT/CTs of the abdomen 2h,24h,48h, 72h p.i. and on day 5-7)
- Determining 24 weeks Progression-Free-Survival (PFS), defined from the day of inclusion
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Description détaillée
In glioblastoma (GBM), tumour recurrence occurs adjacent to the initial tumor resection cavity in about 85% of cases (Albert et al., 1994; Bashir et al., 1988; Nestler et al., 2015). Therefore, local treatment concepts seem crucial for effective recurrence treatment strategies. We consider locoregional, intracavitary radioimmunotherapy (iRIT) to be a new therapeutic approach to delay or prevent the development of local tumour regrowth in GBM patients. By applying a radioimmunoconjugate (RIC) into the surgically created resection cavity (RC) the blood-brain barrier can effectively be by-passed, allowing the a deposit of high radiation doses locally while sparing sensitive organs like the bone marrow and the kidneys. LuCaFab (Lu-177 labeled 6A10- Fab-fragment) is a carbonic anhydrase XII-specific antibody Fab fragment developed by Helmholtz Munich, labeled with ITM's highly pure medical radioisotope, lutetium-177. (ITM IsotopeTechnologies Munich SE). Patients with GBM after standard therapy (surgery by radio-chemotherapy concomitant and adjuvant chemotherapy) Are eligible for the study. Patients will receive the calculated total doses of Lu-177-labeled 6A10-Fabs in three fractions with an interval of 4 weeks between injections, administered into the tumour cavity via an implanted reservoir. A patient specific dosing strategy will be applied and will depend on the individual RC volume. This investigator-initiated trial is sponsored by the University Hospital Münster, conducted in hospitals in Münster, Essen, Cologne, and Wuerzburg, and supported by ITM and Helmholtz Munich.
Type d'étude
Inscription (Réel)
Phase
- La phase 1
Contacts et emplacements
Lieux d'étude
-
-
-
Cologne, Allemagne, 50937
- Klinik für Allgemeine Neurochirurgie des Universitätsklinikums Köln
-
Cologne, Allemagne, 50937
- Klinik für Nuklearmedizin des Universitätsklinikums Köln
-
Essen, Allemagne, 45147
- Klinik für Neurochirurgie des Universitätsklinikums Essen
-
Essen, Allemagne, 45147
- Klinik für Nuklearmedizin, Strahlenklinik des Universitätsklinikums Essen
-
Münster, Allemagne, 48149
- Klinik für Nuklearmedizin der Universität Münster
-
Würzburg, Allemagne, 97080
- Universitätsklinikum Würzburg - Neurochirurgie
-
Würzburg, Allemagne, 97080
- Universitätsklinikum Würzburg - Nuklearmedizin
-
-
Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
La description
Inclusion Criteria:
- Written patient consent after comprehensive information
- Age between 18 and 80 years
- Primary supratentorial high grade glioma after standard therapy (fluorescence-guided surgery, radio-chemotherapy, concomitant + adjuvant chemotherapy), with no or stable small tumor residue (residual contrast enhancement of up to 5cm3) at earliest 6 weeks after completion of radiotherapy
- Histological verification of glioblastoma and CA 12-expression of tumor cells confirmed
- Karnofsky-score ≥ 60
- Volume of resection cavity 2,5-25 cm3
- Male and female patients with reproductive potential must use an approved contraceptive method
- Pre-menopausal female patients with childbearing potential: a negative serum pregnancy test must be obtained prior to treatment start
- Adequate bone marrow reserve: white blood cell (WBC) count ≥3000/μl, granulocyte count >1500/μl, platelets ≥100000/μl, hemoglobin ≥ 10 g/dl
- Adequate liver function: bilirubin < 1.5 times above upper limit of normal range (ULN), alanine transaminase (ALT/SGPT) and aspartate transaminase (AST/SGOT) < 3 times ULN. In the case of documented or suspected Gilbert's disease bilirubin < 3 times ULN.
- Blood clotting: INR (=PT) and PTT within acceptable limits according to the investigator
- Adequate renal function: creatinine < 3 times above ULN; eGFR > (or equal) 60 ml/min
Exclusion Criteria:
- Patient unable to undergo imaging by CT, PET or contrast-enhanced MRI for whatever reason (i.e., pacemaker)
- Resection cavity with intraventricular access
- Significant leakage of radioactivity into CSF spaces or ventricles
- Other actively treated invasive malignancy
- Breastfeeding women
- Past medical history of diseases with poor prognosis, e.g., severe coronary heart disease, heart failure (NYHA III/IV), severe and poorly controlled diabetes, immune deficiency, residual deficits after stroke, severe mental retardation, pre-existing neurological diseases except those related to glioblastoma or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator)
- Any active infection (at the discretion of the investigator)
- Previous participation in a registered clinical trial with therapeutic intervention less than 6 weeks prior to enrolment (date of informed consent)
- Allergy against known constituents of study medication
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: N / A
- Modèle interventionnel: Affectation séquentielle
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
|---|---|
|
Expérimental: Lu-177-labeled-6A10Fab-fragments
The patient will receive a predetermined dose of Lu-177-labeled- 6A10Fab-fragments via the intracavitary reservoir. Patients will receive 3 RIT-cycles with an interval of 4 weeks. The total activity, adjusted to the volume of the RC, will be injected in 3 fractions with 50%, 25% and 25% of the total activity to achieve the desired boost to the 2 cm margin. |
The antibody 6A10 is a specific CA12 Inhibitor, a highly specific glioma cell-associated enzyme; all tumor cells are CA12-positive, while its expression in normal brain is very low, and Lu-177 has a comparable β-emission, but a significantly low γ-Emission. |
Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Maximum Tolerated Dose (MTD)
Délai: Through study completion, ca 1 ½ years
|
Determine maximum tolerated dose (MTD) and safety of adjuvant radio-immunotherapy (RIT) with Lu-177 labeled 6A10-Fab-fragments |
Through study completion, ca 1 ½ years
|
|
Safety of the adjuvant radio-immunotherapy
Délai: Through study completion, ca 1 ½ years
|
Determining safety by assessing all new neurological, hematological and other AEs CTC grade 2 or higher |
Through study completion, ca 1 ½ years
|
Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Evaluation of pharmacokinetics of Lu-177 labeled 6A10 Fab fragments
Délai: After first application: 2 ,24 ,48, 72 hours post injection and on day 5-7. After second and third application.
|
Determining absorbed dose to the 2 cm shell of the resection cavity (based on a series of SPECT/CTs of the head 2 ,24 ,48, 72 hours post injection and on day 5-7). Determining absorbed dose values for the kidneys, the liver, the active marrow (based on a series of SPECT/CTs of the abdomen 2 ,24 ,48, 72 hours post injection and on day 5-7) |
After first application: 2 ,24 ,48, 72 hours post injection and on day 5-7. After second and third application.
|
|
Progression-free survival (PFS)
Délai: Through study completion, an average of 18 months
|
Determining 24 weeks Progression-Free-Survival (PFS), defined from the day of inclusion |
Through study completion, an average of 18 months
|
Autres mesures de résultats
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Overall survival (OS)
Délai: 2 years from the day of inclusion
|
OS is defined as the period of time from the start of a study or the treatment in a study until the death of the patient |
2 years from the day of inclusion
|
Collaborateurs et enquêteurs
Parrainer
Collaborateurs
Les enquêteurs
- Chercheur principal: Walter Stummer, Prof., University Hospital Muenster, Klinik und Poliklinik für Neurochirurgie
Publications et liens utiles
Publications générales
- Fiedler L, Kellner M, Gosewisch A, Oos R, Boning G, Lindner S, Albert N, Bartenstein P, Reulen HJ, Zeidler R, Gildehaus FJ. Evaluation of 177Lu[Lu]-CHX-A''-DTPA-6A10 Fab as a radioimmunotherapy agent targeting carbonic anhydrase XII. Nucl Med Biol. 2018 May;60:55-62. doi: 10.1016/j.nucmedbio.2018.02.004. Epub 2018 Mar 4.
- Alterio V, Kellner M, Esposito D, Liesche-Starnecker F, Bua S, Supuran CT, Monti SM, Zeidler R, De Simone G. Biochemical and Structural Insights into Carbonic Anhydrase XII/Fab6A10 Complex. J Mol Biol. 2019 Dec 6;431(24):4910-4921. doi: 10.1016/j.jmb.2019.10.022. Epub 2019 Nov 1.
- Battke C, Kremmer E, Mysliwietz J, Gondi G, Dumitru C, Brandau S, Lang S, Vullo D, Supuran C, Zeidler R. Generation and characterization of the first inhibitory antibody targeting tumour-associated carbonic anhydrase XII. Cancer Immunol Immunother. 2011 May;60(5):649-58. doi: 10.1007/s00262-011-0980-z. Epub 2011 Feb 5.
- Gondi G, Mysliwietz J, Hulikova A, Jen JP, Swietach P, Kremmer E, Zeidler R. Antitumor efficacy of a monoclonal antibody that inhibits the activity of cancer-associated carbonic anhydrase XII. Cancer Res. 2013 Nov 1;73(21):6494-503. doi: 10.1158/0008-5472.CAN-13-1110. Epub 2013 Sep 12.
- Proescholdt MA, Mayer C, Kubitza M, Schubert T, Liao SY, Stanbridge EJ, Ivanov S, Oldfield EH, Brawanski A, Merrill MJ. Expression of hypoxia-inducible carbonic anhydrases in brain tumors. Neuro Oncol. 2005 Oct;7(4):465-75. doi: 10.1215/S1152851705000025.
- Supuran CT. Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors. Expert Opin Investig Drugs. 2018 Dec;27(12):963-970. doi: 10.1080/13543784.2018.1548608. Epub 2018 Nov 22.
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Réel)
Achèvement primaire (Réel)
Achèvement de l'étude (Réel)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Réel)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Autres numéros d'identification d'étude
- UKM15_0027
Plan pour les données individuelles des participants (IPD)
Prévoyez-vous de partager les données individuelles des participants (DPI) ?
Informations sur les médicaments et les dispositifs, documents d'étude
Étudie un produit pharmaceutique réglementé par la FDA américaine
Étudie un produit d'appareil réglementé par la FDA américaine
produit fabriqué et exporté des États-Unis.
Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .