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

• ClinicalTrials.gov Identifier: NCT05533242
• Recruitment Status: Recruiting
• First Posted: September 8, 2022
• Last Update Posted: May 17, 2023
• Sponsor: University Hospital Muenster
• Collaborators: Isotope Technologies Munich (ITM) Oncologics; Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)
• Information provided by (Responsible Party): University Hospital Muenster

Tracking Information

• First Submitted Date: July 25, 2022
• First Posted Date: September 8, 2022
• Last Update Posted Date: May 17, 2023
• Estimated Study Start Date: June 2023
• Estimated Primary Completion Date: September 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 5, 2022)

• 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
• 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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 5, 2022)

• 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)
• 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

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: September 5, 2022)

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

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: 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

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 the Grosshadern Hospital Munich, and supported by ITM and Helmholtz Munich.
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

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

• Condition: Glioblastom WHO Grade 4

Intervention

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.

Study 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.

Intervention: Drug: Lu-177 labeled 6A10-Fab-fragments

Publications *

• Fiedler L, Kellner M, Gosewisch A, Oos R, Boning G, Lindner S, Albert N, Bartenstein P, Reulen HJ, Zeidler R, Gildehaus FJ. Evaluation of 177Lu[Lu]-CHX-A''-DTPA-6A10 Fab as a radioimmunotherapy agent targeting carbonic anhydrase XII. Nucl Med Biol. 2018 May;60:55-62. doi: 10.1016/j.nucmedbio.2018.02.004. Epub 2018 Mar 4.
• Alterio V, Kellner M, Esposito D, Liesche-Starnecker F, Bua S, Supuran CT, Monti SM, Zeidler R, De Simone G. Biochemical and Structural Insights into Carbonic Anhydrase XII/Fab6A10 Complex. J Mol Biol. 2019 Dec 6;431(24):4910-4921. doi: 10.1016/j.jmb.2019.10.022. Epub 2019 Nov 1.
• Battke C, Kremmer E, Mysliwietz J, Gondi G, Dumitru C, Brandau S, Lang S, Vullo D, Supuran C, Zeidler R. Generation and characterization of the first inhibitory antibody targeting tumour-associated carbonic anhydrase XII. Cancer Immunol Immunother. 2011 May;60(5):649-58. doi: 10.1007/s00262-011-0980-z. Epub 2011 Feb 5.
• Gondi G, Mysliwietz J, Hulikova A, Jen JP, Swietach P, Kremmer E, Zeidler R. Antitumor efficacy of a monoclonal antibody that inhibits the activity of cancer-associated carbonic anhydrase XII. Cancer Res. 2013 Nov 1;73(21):6494-503. doi: 10.1158/0008-5472.CAN-13-1110. Epub 2013 Sep 12.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 5, 2022): 15
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2023
• Estimated Primary Completion Date: September 2023 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Walter Stummer, Prof. Dr.; 0049251/83-47472; walter.stummer@ukmuenster.de

Contact: Nils Warneke, Dr. med.

• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT05533242
• Other Study ID Numbers: UKM15_0027
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University Hospital Muenster
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital Muenster
• Original Study Sponsor: Same as current

Collaborators

• Isotope Technologies Munich (ITM) Oncologics
• Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)

Investigators

• Principal Investigator: Walter Stummer, Prof.; University Hospital Muenster, Klinik und Poliklinik für Neurochirurgie

• PRS Account: University Hospital Muenster
• Verification Date: May 2022