Clinical trial NCT05533242: Radioimmunotherapy with Lu-177 Labeled 6A10 Fab-fragments in Patients with Glioblastoma After Standard Treatment
Official title: A Phase I Trial to Determine the Maximum Tolerated Dose and Patient-specific Dosimetry of Fractionated Intracavitary Radioimmunotherapy with Lu-177 Labeled 6A10 Fab-fragments in Patients with Glioblastoma After Standard Treatment
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Glioblastom WHO Grade 4
Keywords: Carbonic anhydrase XII (CA XII)
Intracavitary radioimmunotherapy
Fab fragment 6A10
Lead sponsor: University Hospital Muenster
Sponsor class: OTHER
Collaborators: name: Isotope Technologies Munich (ITM) Oncologics
name: Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)
First posted: 2022-09-08
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: Through study completion, ca 1 ½ years
measure: Safety of the adjuvant radio-immunotherapy
timeFrame: Through study completion, ca 1 ½ years
Secondary outcomes:
measure: Evaluation of pharmacokinetics of Lu-177 labeled 6A10 Fab fragments
timeFrame: After first application: 2 ,24 ,48, 72 hours post injection and on day 5-7. After second and third application.
measure: Progression-free survival (PFS)
timeFrame: Through study completion, an average of 18 months
Other outcomes:
measure: Overall survival (OS)
timeFrame: 2 years from the day of inclusion
Locations:
city: Essen
country: Germany
facility: Klinik für Neurochirurgie des Universitätsklinikums Essen
city: Essen
country: Germany
facility: Klinik für Nuklearmedizin, Strahlenklinik des Universitätsklinikums Essen
city: Köln
country: Germany
facility: Klinik für Allgemeine Neurochirurgie des Universitätsklinikums Köln
city: Köln
country: Germany
facility: Klinik für Nuklearmedizin des Universitätsklinikums Köln
city: Münster
country: Germany
facility: Klinik für Nuklearmedizin der Universität Münster
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg - Neurochirurgie
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg - Nuklearmedizin
Study officials:
affiliation: University Hospital Muenster, Klinik und Poliklinik für Neurochirurgie
name: Walter Stummer, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
citation: 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.