Glioblastom WHO Grade 4
Conditions
Keywords
Carbonic anhydrase XII (CA XII), Intracavitary radioimmunotherapy, Fab fragment 6A10
Brief summary
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
Detailed description
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.
Interventions
DRUGLu-177 labeled 6A10-Fab-fragments
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.
Sponsors
University Hospital Muenster
Isotope Technologies Munich (ITM) Oncologics
Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A modified 3+3 design is used. The applied dose of Lu-177-labeled-6A10Fab-fragments to the resection cavity will be escalated in three cohorts until the maximum tolerated dose (MTD) is determined.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | 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 |
| Safety of the adjuvant radio-immunotherapy | Through study completion, ca 1 ½ years | Determining safety by assessing all new neurological, hematological and other AEs CTC grade 2 or higher |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of pharmacokinetics of Lu-177 labeled 6A10 Fab fragments | 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) |
| Progression-free survival (PFS) | Through study completion, an average of 18 months | Determining 24 weeks Progression-Free-Survival (PFS), defined from the day of inclusion |
Countries
Germany
Contacts
PRINCIPAL_INVESTIGATORWalter Stummer, Prof.
University Hospital Muenster, Klinik und Poliklinik für Neurochirurgie
Outcome results
None listed