Treatment of Recurrent or Progressive Meningiomas With the Radiolabelled Somatostatin Antagonist 177Lu-satoreotide

Study Purpose

Meningiomas are known to be the most frequent intracranial neoplasms and account for approx. 25-33% of all intracranial tumours.Targeted radionuclide therapy with radiolabelled somatostatin analogues, also called Peptide Receptor Radionuclide Therapy (PRRT), has proven to be an effective treatment in metastatic intestinal neuroendocrine tumours and is currently used in advanced, recurrent or progressive meningiomas with promising results. In this study, the therapeutic index of a standard and newly developed radiolabelled somatostatin antagonist will be evaluated and compared in PRRT. In a second step, safety and efficacy of the latter will be assessed.

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 and Over
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

- Informed Consent as documented by signature.

- Participants of any gender and of age > 18 years.

- Female participants capable of giving birth (who are not surgically sterilized or are less than 2 years in their menopause) must use a medically accepted contraceptive and must agree to use it during and till 3 months after the treatment.

As acceptable contraceptive count sexual abstinence or double contraceptive methods: hormonal contraceptive (oral, transdermal, implants or injections) in combination with barrier methods (spiral, condom, diaphragm)

- Male participants must use medically accepted contraceptive during and till 3 months after treatment.

- The participants' Karnofsky Performance Status must be ≥ 60.

- The participants must be patients with a histologically or clinically confirmed (MRI + somatostatin receptor imaging) recurrent or progressive meningioma.

- There must be no other standard therapeutic alternatives for the participants.

- The participants tumour must be measurable according to RECIST v1.1 with a minimal diameter of 1.0 cm.

- The participants must have a confirmed expression of somatostatin receptor (SSTR) on 68Ga- DOTATOC positron emission computed tomography (PET)/CT scan.

- Blood parameter criteria are: h) Leucocytes ≥ 3*109/L i) Haemoglobin ≥ 80 g/L j) Thrombocytes ≥ 90*109/L k) Estimated glomerular filtration rate ≥ 50 ml/min l) Albumin > 25g/L m) alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP): ≤ 5 times upper standard value n) Bilirubin ≤ 2 times upper standard value.

Exclusion Criteria:

- Known intolerance against 177Lu, DOTA, JR11, TOC or against one of the components of 177Lu-DOTA-JR11 or 177Lu-DOTATOC.

- Ongoing infection at the screening visit or a serious infection in the past 4 weeks.

- Administration of another investigational product in the last 60 days before Visit 1 Day 1.

- Prior or planed administration of a therapeutic radio-pharmaceutical during 8 half-lives of the used radio-pharmaceutical's radionuclide, also during the ongoing study.

- Any extensive Radiotherapy involving bone marrow over the last 3 months before inclusion to the study.

- Chemotherapy in the last 2 months before inclusion.

- Pregnant or breastfeeding female patients.

A pregnancy test will be performed in all women of child bearing potential.

- Any uncontrolled significant medical, psychiatric or surgical condition (active infection, unstable angina pectoris, cardiac arrhythmia, poorly controlled hypertension, poorly controlled diabetes mellitus [HbA1c ≥ 9%], uncontrolled congestive heart disease, etc.) or laboratory findings that might jeopardize the patient's safety or that would limit compliance with the objectives and assessments of the study.

Any mental conditions which prevent the patient from understanding the type, extent and possible consequences of the study and/or an uncooperative attitude from the patient.

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.	NCT04997317
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.	Early 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, Basel, Switzerland
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Dominik Cordier, PD Dr. med.
Principal Investigator Affiliation	University Hospital, Basel, Switzerland
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	Switzerland
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Meningioma

Additional Details

The somatostatin receptor subtype 2 (sstr2) has been identifies as a peptide hormone receptor that is highly expressed in 70

- 100% of meningiomas representing an attractive target for so called "theranostic" applications combining molecular imaging and targeted radionuclide therapy with radiolabelled somatostatin analogues.

The newly developed radiolabelled somatostatin antagonist 177Lu-DOTA-JR11 has been shown to exert a high binding affinity to sstr2 suggesting a higher efficacy in the treatment of advanced meningiomas than the currently available somatostatin analogues (e.g. 177Lu-DOTATOC, 177Lu-DOTATATE).Therefore, the hypothesis has been postulated that 177LuDOTA-JR11 has an improved therapeutic index (tumour-to-dose limiting organ dose ratios) compared to 177Lu-DOTATOC, and that it can be safely used for PRRT in patients with advanced, recurrent or progressive meningiomas. The aim of this 2-step Phase 0 / Phase I/II study is to a) evaluate in the same meningioma patients the therapeutic index (tumour-to-dose limiting organ dose ratios) of 177Lu-DOTA-JR11 in comparison to 177Lu-DOTATOC and b) based on the previous results, to evaluate safety and preliminary efficacy of PRRT with 177Lu-DOTA-JR11.

Arms & Interventions

Arms

Active Comparator: Phase 0: Group A

Cycle 1: 4.5 GBq 177Lu-DOTA-JR11 (300-1300 μg) will be administered once intravenously. Cycle 2: 4.5 GBq 177Lu-DOTATOC (≈200 μg) will be administered once intravenously (following a cross-over design). Cycle 3 and Cycle 4 will be performed for group A patients with 7.4 GBq 177Lu-DOTATOC (clinically established amount of activity). Cycle 3 and 4 are standard of care (i.e. not part of the study).

Active Comparator: Phase 0: Group B

Cycle 1: 4.5 GBq 177Lu-DOTATOC (≈200 μg) will be administered once intravenously. Cycle 2: 4.5 GBq 177Lu-DOTA-JR11 (300-1300 μg) will be administered once intravenously (following a cross-over design). Cycle 3 and Cycle 4 will be performed for group B patients with 7.4 GBq 177Lu-DOTATOC (clinically established amount of activity). Cycle 3 and 4 are standard of care (i.e. not part of the study).

Active Comparator: Phase I/II

3 cycles of 177Lu-DOTA-JR11 will be administered with an activity of 4.5-7.4 GBq. Two additional 177Lu-DOTA-JR11 treatment cycles can be performed if clinically indicated

Interventions

Drug: - 177Lu-DOTA-JR11 (Phase 0); Cycle 1 and Cycle 2 (cross-over)

177Lu-DOTA-JR11 has three main components, namely the somatostatin analogue JR11, the chemical chelator group DOTA and the beta emitter 177Lutetium (177Lu). In the Phase 0 part of the study 177Lu-DOTA-JR11 will be administered once intravenously. The activity of the first 2 cycles will be capped at 4.5 GBq (range: 4.2-4.6 GBq).

Drug: - 177Lu-DOTATOC (Phase 0); Cycle 1 and Cycle 2 (cross-over), Cycle 3 and 4

177Lu-DOTATOC is a therapeutic medicinal product and has 3 main components (a) 177Lutetium (177Lu), a beta-emitting radionuclide with a half-life of 6.64 days; (b) DOTA, a chemical chelator group; and (c) TOC (= [Tyr]3-octreotide) an agonistic somatostatin analogue which binds to sstr2 and sstr5 receptors. In the Phase 0 part of the study 177Lu-DOTATOC will be administered once intravenously. The activity of the first 2 cycles will be capped at 4.5 GBq (range: 4.2-4.6 GBq). The remaining 2 cycles will be performed with an activity of 7.4 GBq 177Lu-DOTATOC (total number of cycles = 4).

Drug: - 177Lu-DOTA-JR11 (Phase I/II)

In the phase I/II part of the study: 3 cycles of 177Lu-DOTA-JR11 will be administered with an activity of 4.5-7.4 GBq. Two additional 177Lu-DOTA-JR11 treatment cycles can be performed if clinically indicated

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