Recent FDA feedback requiring a study amendment.

This is an open-label, multicenter, randomized, phase 2 clinical study to evaluate the efficacy of [177Lu]Lu-DOTATATE in patients with progressive grade 1-3 intracranial meningioma.

Study participants will be randomized by a 2:1 ratio to receive either [177Lu]Lu-DOTATATE or standard of care therapy as deemed appropriate by the local investigator. At time of progression, participants on the standard of care arm may cross-over to the [177Lu]Lu-DOTATATE alternative treatment arm.

Inclusion Criteria:

STEP 1 REGISTRATION

• Aged >= 18 years

• Histologically confirmed diagnosis of WHO grade 1-3 meningioma

• Presence of measurable contrast-enhancing disease on gadolinium-enhanced MRI brain scan defined as at least one lesion with two perpendicular diameters measuring ≥10 mm on two or more axial slices (≤ 5 mm interslice thickness, ≤ 1 mm interslice gap) per current RANO meningioma criteria

• Progression of disease determined by local radiology review per current RANO meningioma criteria, defined as

  • ≥ 15% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 6 months, or
  • ≥ 25% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 12 months, or
  • Development of a new measurable lesion

• The following scans must be available for submission for central radiology review:

  • Pre-progression gadolinium-enhanced MRI brain scan
  • Progression gadolinium-enhanced MRI brain scan

STEP 2 REGISTRATION

• Progression of disease determined by central radiology review per current RANO meningioma criteria, defined as

  • ≥ 15% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 6 months, or
  • ≥ 25% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 12 months, or
  • Development of a new measurable lesion.

• [68Ga]Ga-DOTATATE uptake on PET-CT. Positive uptake is defined as uptake at least as high as liver, based on the uptake in at least one target lesion.

• If randomized to the control (standard of care) arm, both the patient and investigator must agree NOT to receive SSTR2-targeted therapy, surgical resection, or radiation therapy.

• Patients must be willing and able to undergo regular MRI scans of the brain and [68Ga]Ga-DOTATATE PET-CT imaging during the study.

• Patients must have recovered to CTCAE grade ≤1 or pretreatment baseline from clinically significant adverse events related to prior therapy (exclusions include alopecia, lymphopenia, sensory neuropathy ≤ grade 2, or other ≤ grade 2 not constituting a safety risk based on the investigator's judgment).

• Adequate organ and bone marrow function as defined below (within 28 days prior to step 2 registration):

  • Absolute neutrophil count (ANC) ≥ 1500/mm3
  • Platelet count ≥ 75,000/mm3
  • Hemoglobin ≥ 8 g/dL
  • Creatinine clearance (calculated by the Cockroft-Gault method) ≥40mL/min
  • Total serum bilirubin ≤ 3 x ULN (except participants with Gilbert's Syndrome, who can have a total bilirubin ≤ 5 x ULN)
  • Potassium within normal limits.

Exclusion Criteria:

• Patients with a clinical diagnosis of NF2-related schwannomatosis or with a known molecular diagnosis of NF2-related schwannomatosis.

• Patients with radiation-associated meningiomas.

• Patients with known intraspinal meningiomas or meningioma metastases outside the skull/spinal column.

• Prior SSTR2-targeted therapy, e.g. Somatostatin LAR or short-acting Octreotide.

• Unstable neurological symptoms requiring steroids to control symptoms at a dose of >2 mg of dexamethasone (or equivalent) daily within 28 days prior to step 2 registration.

• Patients requiring immediate local therapy (e.g. surgical resection).

• Surgical procedure within the timeframes listed below, prior to step 2 registration.

  • 28 days from any prior craniotomy
  • 7 days from stereotactic biopsy Note: There is no limit to the number of prior surgical interventions

• Treatment within the timeframes specified below, prior to step 2 registration.

  • 28 days (or 5 half-lives, whichever is longer) for cytotoxic chemotherapy, biologic agent, investigational agent or any other systemic agent prescribed for the purpose of treating meningioma
  • 6 weeks from nitrosoureas Note: There is no limit to the number of prior systemically administered therapeutic agents.

• Prior external beam radiation, interstitial brachytherapy or stereotactic radiosurgery cumulative radiation dose of > 70 Gy or the last dose of radiotherapy < 24 weeks (6 months) prior to step 2 registration

• Peptide receptor radionuclide therapy at any time prior to registration.

• Known hypersensitivity to somatostatin analogues or any component of the [68Ga]Ga- DOTATATE or [177Lu]Lu-DOTATATE formulations.

• Active infection requiring current use of intravenous therapy with antibiotics.

• Active cardiovascular disease: cerebral vascular accident/stroke (≤ 6 months prior to registration), myocardial infarction (≤ 6 months prior to registration), congestive heart failure (≥ NYHA class II), unstable angina pectoris, or serious cardiac arrhythmia requiring medication.

• An active malignancy ≤ 3 years. Note: Patients with a malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• Pregnant and/or breastfeeding patients who are unwilling to discontinue breast feeding.

• Participants of childbearing potential must have a negative pregnancy test within 14 days of study entry.