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

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ClinicalTrials.gov Identifier: NCT05533242
Recruitment Status : Recruiting
First Posted : September 8, 2022
Last Update Posted : October 20, 2022
Sponsor:
Collaborators:
Isotope Technologies Munich (ITM) Oncologics
Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)
Information provided by (Responsible Party):
University Hospital Muenster

Study Description
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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

Condition or disease Intervention/treatment Phase
Glioblastom WHO Grade 4 Drug: Lu-177 labeled 6A10-Fab-fragments Phase 1

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 the Grosshadern Hospital Munich, and supported by ITM and Helmholtz Munich.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: N/A
Intervention Model: Sequential Assignment
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.
Masking: None (Open Label)
Primary Purpose: 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
Estimated Study Start Date : October 2022
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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.
 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.


Outcome Measures
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Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: 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

  2. Safety of the adjuvant radio-immunotherapy [ Time Frame: Through study completion, ca 1 ½ years ]
    Determining safety by assessing all new neurological, hematological and other AEs CTC grade 2 or higher


Secondary Outcome Measures :
  1. Evaluation of pharmacokinetics of Lu-177 labeled 6A10 Fab fragments [ Time Frame: 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)

  2. Progression-free survival (PFS) [ Time Frame: Through study completion, an average of 18 months ]
    Determining 24 weeks Progression-Free-Survival (PFS), defined from the day of inclusion


Other Outcome Measures:
  1. Overall survival (OS) [ Time Frame: 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


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written patient consent after comprehensive information
  • Age between 18 and 70 years
  • Primary supratentorial glioblastoma, after standard therapy (fluorescence-guided surgery, radio-chemotherapy, concomitant + adjuvant chemotherapy), with no or minimal tumor residue (tumor volume less than 1.0 cm3) at least 6 months after surgery
  • Histological verification of glioblastoma and CA 12-expression of tumor cells confirmed
  • Karnofsky-score ≥ 70
  • Volume of resection cavity 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)
  • GBM with intraventricular access
  • Significant leakage of radioactivity into CSF spaces or ventricles
  • Other invasive malignancy within 2 years (except for non-invasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured)
  • 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)
  • Participation in another clinical trial with therapeutic intervention or use of any other therapeutic interventional agent other than the standard therapy since diagnosis of glioblastoma
  • Allergy against known constituents of study medication
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05533242


Contacts
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Contact: Walter Stummer, Prof. Dr. 0049251/83-47472 walter.stummer@ukmuenster.de
Contact: Nils Warneke, Dr. med.

Locations
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Germany
Klinik für Neurochirurgie des Universitätsklinikums Essen Recruiting
Essen, Germany, 45147
Klinik für Nuklearmedizin, Strahlenklinik des Universitätsklinikums Essen Recruiting
Essen, Germany, 45147
Klinik für Allgemeine Neurochirurgie des Universitätsklinikums Köln Recruiting
Köln, Germany, 50937
Klinik für Nuklearmedizin des Universitätsklinikums Köln Recruiting
Köln, Germany, 50937
Klinik für Nuklearmedizin der Universität Münster Recruiting
Münster, Germany, 48149
Sponsors and Collaborators
University Hospital Muenster
Isotope Technologies Munich (ITM) Oncologics
Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)
Investigators
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Principal Investigator: Walter Stummer, Prof. University Hospital Muenster, Klinik und Poliklinik für Neurochirurgie
More Information
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Publications:

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Responsible Party: University Hospital Muenster
ClinicalTrials.gov Identifier: NCT05533242    
Other Study ID Numbers: UKM15_0027
First Posted: September 8, 2022    Key Record Dates
Last Update Posted: October 20, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by University Hospital Muenster:
Carbonic anhydrase XII (CA XII)
Intracavitary radioimmunotherapy
Fab fragment 6A10
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
 Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Immunoglobulin Fab Fragments
Immunologic Factors
Physiological Effects of Drugs