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

Phase 1Active Not RecruitingNCT05533242

University Hospital Muenster15 enrolled

Overview

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

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.

Study Type

INTERVENTIONAL

Allocation

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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

Locations (7)

Klinik für Allgemeine Neurochirurgie des Universitätsklinikums Köln

Cologne, Germany

Klinik für Nuklearmedizin des Universitätsklinikums Köln

Cologne, Germany

Klinik für Neurochirurgie des Universitätsklinikums Essen

Essen, Germany

Klinik für Nuklearmedizin, Strahlenklinik des Universitätsklinikums Essen

Essen, Germany

Klinik für Nuklearmedizin der Universität Münster

Münster, Germany

Universitätsklinikum Würzburg - Neurochirurgie

Würzburg, Germany

Universitätsklinikum Würzburg - Nuklearmedizin

Würzburg, Germany

Outcomes

Primary Outcomes

Maximum Tolerated Dose (MTD)

Determine maximum tolerated dose (MTD) and safety of adjuvant radio-immunotherapy (RIT) with Lu-177 labeled 6A10-Fab-fragments

Time frame: Through study completion, ca 1 ½ years

Safety of the adjuvant radio-immunotherapy

Determining safety by assessing all new neurological, hematological and other AEs CTC grade 2 or higher

Time frame: Through study completion, ca 1 ½ years

Secondary Outcomes

Evaluation of pharmacokinetics of Lu-177 labeled 6A10 Fab fragments

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)

Time frame: After first application: 2 ,24 ,48, 72 hours post injection and on day 5-7. After second and third application.

Progression-free survival (PFS)

Determining 24 weeks Progression-Free-Survival (PFS), defined from the day of inclusion

Time frame: Through study completion, an average of 18 months