Phase II Randomized Study of [177Lu]Lu-DOTATATE in Recurrent Meningioma Lacking Surgical or Radiotherapeutic Options
- Trial ID
- 2024-513443-93-00
- Protocol
- EORTC 2334-BTG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized phase II trial is to evaluate whether **[177Lu]Lu-DOTATATE** demonstrates sufficient antitumor activity in patients with recurrent meningioma, a condition where local treatment options such as surgery or radiotherapy are not viable. This assessment is crucial for determining the potential of **[177Lu]Lu-DOTATATE** as a therapeutic option, which could lead to further clinical investigations and potentially offer a new treatment avenue for this patient population.
Secondary objectives include:
- Assessing the impact of **[177Lu]Lu-DOTATATE** on radiological response compared to the local standard of care.
- Evaluating its effect on overall survival in comparison to standard treatments.
- Determining the safety profile of **[177Lu]Lu-DOTATATE** relative to existing care standards.
- Investigating its impact on four key health-related quality of life (HRQoL) domains at week 24.
- Assessing its effect on neurological function.
- Evaluating the tolerability of **[177Lu]Lu-DOTATATE**.
Participants
The clinical trial involves participants diagnosed with **recurrent meningioma** without local treatment options such as surgery or radiotherapy. The study population includes both male and female adults aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of meningioma, with all grades (1-3 per WHO CNS5) being eligible. The trial population was selected based on specific criteria, including a WHO performance status of 0-2, measurable disease on cranial MRI, and radiologically documented progression of existing tumors or the appearance of new lesions. Additionally, participants must have somatostatin receptor-positive status confirmed by PET imaging. Adequate liver, renal, and hematological function is required, and participants must have undergone at least one prior surgery and one line of external beam radiotherapy for meningioma, if technically feasible. The trial includes individuals from a vulnerable population, and both genders are represented. However, the sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified, but participants of childbearing potential must adhere to strict birth control measures during and after the study treatment period. The trial ensures that all participants provide written informed consent in accordance with ICH/GCP and national/local regulations.
Plans and Procedures
The clinical trial is a **randomized**, phase II study designed to evaluate the efficacy of **[177Lu]Lu-DOTATATE** in patients with recurrent meningioma who have no local treatment options such as surgery or radiotherapy. The trial aims to assess the antitumor activity of the investigational product to determine its potential for further investigation. The study is structured as a **double-blind** and **controlled** trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias. The trial is expected to commence recruitment in February 2025 and conclude by July 2029, with an estimated duration of participant involvement of up to 16 months.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age, performance status, and prior treatment history. The screening process will also involve imaging studies to document disease progression and confirm somatostatin receptor positivity. Following randomization, participants will receive the investigational product or comparator treatments, with follow-up visits scheduled to monitor safety, tolerability, and treatment efficacy. These visits will include assessments of progression-free survival, overall survival, and changes in quality of life and neurological function. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participants are expected to remain in the study for the full treatment period unless specific conditions necessitate early withdrawal. These conditions include significant adverse events, disease progression, or withdrawal of consent. The primary endpoint of the study is progression-free survival, assessed using MRI-based RANO meningioma response criteria. Secondary endpoints include best overall response, overall survival, safety, and changes in health-related quality of life. The trial will adhere to rigorous ethical standards, with informed consent obtained from all participants prior to enrollment.
Treatment
The clinical trial involves the administration of **Lutathera** (370 MBq/mL solution for infusion), which contains the active substance **lutetium (177Lu) oxodotreotide**. This experimental medication is provided in the form of a solution for infusion and is administered via **intravenous infusion**. The maximum daily dose is 7.4 GBq, with a total maximum dose of 29.6 GBq over a treatment period of 16 weeks. Lutathera is classified as an orphan drug and is specifically designed for the treatment of recurrent meningioma.
**Bevacizumab** is used as a comparator treatment in this study. It is administered as an **intravenous infusion** with a maximum daily dose of 15 mg/kg and a total maximum dose of 510 mg/kg over a 24-week period. Bevacizumab is a protein-based therapeutic agent, known for its role in inhibiting angiogenesis in various cancer types.
**Everolimus** is another comparator treatment, provided in an oral pharmaceutical form. The maximum daily dose is 10 mg, with a total maximum dose of 7320 mg over 24 weeks. Everolimus is a chemical compound that acts as an mTOR inhibitor, commonly used in cancer therapy.
**Hydroxycarbamide**, also known as hydroxyurea, is administered orally with a maximum daily dose of 30 mg/kg and a total maximum dose of 21960 mg/kg over 24 weeks. This chemical compound is utilized for its antineoplastic properties in various hematological conditions.
**Octreotide acetate** is administered via **intramuscular injection** as a comparator treatment. The maximum daily dose is 30 mg, with a total maximum dose of 720 mg over 24 weeks. Octreotide is a protein-based therapeutic agent used for its somatostatin-like effects in managing hormone-secreting tumors.
**Sunitinib** is provided in an oral form, with a maximum daily dose of 50 mg and a total maximum dose of 24000 mg over 24 weeks. Sunitinib is a chemical compound that functions as a multi-targeted receptor tyrosine kinase inhibitor, used in the treatment of various malignancies.
Efficacy
Efficacy in this clinical trial will be assessed using several key endpoints. The primary endpoint is **progression-free survival (PFS)**, which will be computed based on MRI-based RANO meningioma response criteria as assessed by the local investigator. Secondary endpoints include the best overall response (BOR), which encompasses complete response (CR), minor response (MR), or partial response (PR) during the study treatment. The objective response rate and median duration for CR, MR, and PR will also be evaluated. Additionally, overall survival (OS) will be measured, including OS probability at 6 and 12 months, and median OS.
Safety and tolerability of **[177Lu]Lu-DOTATATE** will be monitored using CTCAE v.5.0 criteria. Changes from baseline in health-related quality of life (HRQoL) will be assessed in terms of global QoL, cognitive functioning, social functioning, and fatigue at week 24. Neurological function changes will be evaluated using the NANO scale from baseline during the study treatment. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the antitumor activity of **[177Lu]Lu-DOTATATE** in patients with recurrent meningioma.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult patient ≥ 18 years of age
- Histologically confirmed diagnosis of meningioma (all grades, 1-3 per WHO CNS5, are eligible)
- WHO performance status 0-2
- Measurable disease (at least 10 x 10 mm contrast enhancing lesion) on cranial MRI no more than two weeks prior to enrolment
- Radiologically documented progression of any existing tumour (growth > 25% in the last two years) or appearance of new lesions (including intra- and extracranial manifestations)
- Somatostatin receptor (SSTR)-positive confirmed by PET imaging with scan performed within four weeks before randomization (baseline SSTR-PET is considered as positive when meningioma uptake intensity exceeds a SUVmax of 2.3).
- At least one prior surgery and one line of external beam radiotherapy for meningioma, if technically feasible
- Adequate liver, renal and haematological function within four weeks prior to enrolment
- Participants must have the following electrolyte values within normal limits or corrected to be within normal limits with supplements prior to first dose of study medication: • Potassium (potassium level of up to 6.0 mmol/L is acceptable at study entry if associated with creatinine clearance ≥ 60 mL/min calculated using CKD-EPI formula). Mild decrease below lower limit of normal (LLN) is acceptable at study entry if considered not clinically significant by investigator. • Total magnesium, with the exception of magnesium level > ULN – 3.0 mg/dL (1.23 mmol/L) associated with creatinine clearance ≥ 60 mL/min calculated using CKD-EPI formula. Mild decrease below LLN is acceptable at study entry if considered not clinically significant by Investigator. • Total calcium (corrected for serum albumin) level of up to 12.5 mg/dL (3.1 mmol/L) is acceptable at study entry if associated with creatinine clearance ≥ 60 mL/min calculated using CKD-EPI formula. Mild decrease below LLN is acceptable at study entry if considered not clinically significant by Investigator. • Patients who are receiving corticosteroid treatment with dexamethasone, must be treated with a dose of ≤4 mg/day (or other corticosteroids equivalent dose) for a minimum of 7 days prior to the initiation of study treatment. • Women of childbearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 72 hours prior to enrolment. A positive urine pregnancy test result must immediately be confirmed using a serum test. A pregnancy test will have to be reported within 7 days prior to the first dose of the study treatment.
- Patients of childbearing / reproductive potential should use adequate birth control measures during the study treatment period and for at least 7 months after the last dose of treatment. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly.
- Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 7 months after the last study treatment.
- Before patient 's enrolment, written informed consent must be given according to ICH/GCP, and national/local regulations.
Exclusion Criteria
- Local therapy (surgery and / or radiotherapy) indicated per local investigator. Note: in case of patients with multiple meningioma lesions, in whom resection and / or radiotherapy of individual lesions is indicated, patients may be included after local therapy (with a 4-week gap between surgery / end of radiotherapy and start of treatment), if at least one remaining lesion fulfils the inclusion criteria.
- Any prior systemic treatment regardless of the timing.
- Life expectancy is less than nine weeks.
- Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the study treatment.
- Contraindication to MRI, CT or PET
- Unstable cardiac conditions (congestive heart failure, angina pectoris, myocardial infarction within one year before enrolment, uncontrolled hypertension, clinically significant arrhythmias)
- Psychological, familial, sociological, or geographical conditions could potentially hamper compliance with the study protocol and follow-up schedule.
- Known hypersensitivity to the active substance or to any excipients.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 01 Feb 2025 | 5 |
 Denmark | Recruiting | 01 Feb 2025 | 5 |
 France | Recruiting | 01 Feb 2025 | 28 |
 Germany | Recruiting | 01 Feb 2025 | 12 |
 Italy | Recruiting | 01 Feb 2025 | 33 |
 The Netherlands | Recruiting | 01 Feb 2025 | — |
 Norway | Recruiting | 01 Feb 2025 | 3 |
 Spain | Recruiting | 01 Feb 2025 | 8 |
| Netherlands | — | — | 12 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
HYDROXYCARBAMIDE | Comparator | PHF00082MIG | ORAL | 30 | 24 | SCP137277 |
BEVACIZUMAB | Comparator | PHF00230MIG | INTRAVENIOUS INFUSION | 15 | 24 | SCP29096188 |
SUNITINIB | Comparator | PHF00006MIG | ORAL | 50 | 24 | SCP185293 |
OCTREOTIDE | Comparator | PHF00231MIG | INTRAMUSCULAR INJECTION | 30 | 24 | SCP132132 |
EVEROLIMUS | Comparator | PHF00170MIG | ORAL | 10 | 24 | SCP159587 |
Lutathera 370 MBq/mL solution for infusion | Test | SOLUTION FOR INFUSION | IV INFUSION | 7.4 | 16 | PRD5434501 |