Radioimmunotherapy With Lu-177 Labeled 6A10 Fab-fragments in Patients With Glioblastoma After Standard Treatment

Study Purpose

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

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 80 Years
Gender	All

More Inclusion & Exclusion Criteria

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

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT05533242
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	University Hospital Muenster
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Walter Stummer, Prof.
Principal Investigator Affiliation	University Hospital Muenster, Klinik und Poliklinik für Neurochirurgie
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	Germany
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Glioblastom WHO Grade 4

Additional Details

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 the Grosshadern Hospital Munich, and supported by ITM and Helmholtz Munich.

Arms & Interventions

Arms

Experimental: 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.

Interventions

Drug: - Lu-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.

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