Lutathera for the Treatment of Inoperable, Progressive Meningioma After External Beam Radiation Therapy

Study Overview
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Brief Summary
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This phase II trial studies how well lutathera works in treating patients with meningioma that cannot be treated with surgery (inoperable) and is growing, spreading, or getting worse (progressive) after external beam radiation therapy. Lutathera is a radioactive drug administered in the vein that is designed to target and kill cancer cells. The goal of this study is to determine whether this drug is safe and effective in treating meningiomas that progress after radiation treatment. WHO Grade I and Cohort WHO II/III cohorts will be evaluated.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the efficacy of lutetium Lu 177 dotatate (LUTATHERA) treatment in patients with recurrent grade 1 meningioma as measured by 6-month progression-free survival (PFS) rate. II. To estimate the efficacy of LUTATHERA treatment in patients with recurrent grade 2 or 3 meningioma as measured by 6-month PFS rate. SECONDARY OBJECTIVES: I. To determine the overall survival (by grade cohort) of patients with recurrent meningioma during or after treatment of LUTATHERA. II. To determine the progression-free survival (by grade cohort) of patients with recurrent meningioma during or after treatment of LUTATHERA. III. To determine the toxicity of LUTATHERA treatment in patients with recurrent meningioma. CORRELATIVE RESEARCH OBJECTIVES: I. To assess the impact of treatment on the patient's quality of life (QOL) using the Promise-10, Brief Fatigue Inventory (BFI), European Quality of Life Five Dimension Five Level (EQ-5D-5L), and Mayo Patient Survey National Comprehensive Cancer Network (NCCN)-Functional Assessment of Cancer Therapy (FACT) Brain Symptom Index Questionnaire-24 (FBrSI-24) (version 2) instruments. II. To compare the response assessment between standard of care brain magnetic resonance imaging (MRI) and gallium Ga 68-DOTATATE (68Ga-DOTATATE) positron emission tomography (PET) imaging. III. To determine the best objective response (McDonald criteria) of patients with recurrent meningioma during or after treatment of LUTATHERA. IV. To determine the duration of local control with death as a competing risk (by grade cohort) of patients with recurrent meningioma during or after treatment of LUTATHERA. V. To perform a quantitative dosimetric analysis of radiation dose delivered with lutathera: Va. To determine intratherapeutic dosimetry for the target meningioma. Vb. To correlate treatment response of lutathera with target dose received. Vc. To determine intratherapeutic dosimetry for kidneys and other abdominal organs. OUTLINE: Patients receive gallium Ga 68-DOTATATE intravenously (IV) and undergo a PET/MRI before cycles 1 and 4. Patients then receive lutetium Lu 177 dotatate intravenously (IV) over 30-40 minutes. Treatment repeats every 8 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months thereafter.

Official Title
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A Prospective, Phase II Study of Lutetium Lu 177 Dotatate (LUTATHERA®) in Patients With Inoperable, Progressive Meningioma After External Beam Radiation Therapy

Conditions
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Grade 1 Meningioma, Grade 2 Meningioma, Grade 3 Meningioma, Recurrent Meningioma, Unresectable Meningioma

Intervention / Treatment
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* Radiation: Gallium Ga 68-DOTATATE
* Drug: Lutetium Lu 177 Dotatate
* Procedure: Magnetic Resonance Imaging
* Procedure: Positron Emission Tomography
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previous treatment for meningioma including surgery, when possible, and radiation therapy (conventional fractionated or radiosurgery). Pathologic confirmation of meningioma is not required for patients who are not surgical candidates and received radiation therapy based on magnetic resonance imaging (MRI) consistent with meningioma. Patients with prior surgery will have pathologic confirmation of meningioma with either formalin-fixed paraffin-embedded (FFPE) tumor block OR meningioma tissue slides available for submission to central pathology review Radiographic evidence of meningioma progression with measurable disease, defined as an increase in size of the measurable primary lesion on imaging by 15% or more (sum of the bidirectional measurements) in an approximate 6 month time period (i.e., calculated rate of growth 15% / 6 months based on available scans) or by the appearance of a new measurable lesion Previous treatment with either fractionated radiation therapy or stereotactic radiosurgery at the site of progressive meningioma, without safe option for further radiotherapy Willing to undergo 68Ga-DOTATATE PET imaging. 68Ga-DOTATATE PET imaging must be Krenning score must be a score of 2 or higher, suggesting somatostatin receptor expression, to be enrolled on the study Measurable disease Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2 Absolute neutrophil count (ANC) >= 1500/mm (obtained =< 14 days prior to registration) Platelet count >= 100,000/mm (obtained =< 14 days prior to registration) Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration) Direct bilirubin < 1.5 x upper limit of normal (ULN) (or total bilirubin =< 3.0 x ULN with direct bilirubin =< 1.5 x ULN in patients with well-documented Gilbert's syndrome) (obtained =< 14 days prior to registration) Aspartate transaminase (AST) =< 3 x ULN (obtained =< 14 days prior to registration) Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT) =< 1.5 x ULN OR if patient is receiving anticoagulant therapy and PT or PTT is within therapeutic range of intended use of coagulants (obtained =< 14 days prior to registration) Calculated creatinine clearance must be >= 40 ml/min using the Cockcroft-Gault formula (obtained =< 14 days prior to registration) Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only Note: A negative pregnancy test needs to be done within 48 hours of receiving LUTATHERA treatment Note: Patients with surgical sterilization or who have been post-menopausal for at least 2 years are excluded from pregnancy testing, but this must be documented Ability to complete questionnaire(s) by themselves or with assistance Provide written informed consent Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study) Willing to sign consent onto the Mayo Clinic Radiotherapy Patient Outcomes Registry and Biobanking study, IRB number 15-000136 Note: The blood draw is optional Exclusion Criteria: Eligibility for surgical or radiation treatment with curative intent Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Contraindications to or intolerance of MRI Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy Note: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association [NYHA] II, III, IV), unstable angina pectoris, uncontrolled diabetes mellitus (fasting blood glucose > 2 ULN), cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm Note: This includes treatment with somatostatin LAR within 4 weeks prior to enrollment, or any patient receiving treatment with short-acting octreotide that cannot be interrupted for greater than 24 hours before treatment Other active malignancy =< 2 years prior to registration Exceptions: Non-melanotic skin cancer or carcinoma-in-situ of the cervix Note: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias Current spontaneous urinary incontinence making impossible the safe administration of LUTATHERA Significant toxicity related to previous radiation therapy including radiation necrosis, radiation optic neuropathy, or radiation retinopathy Optic nerve sheath meningioma, extracranial meningioma

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (gallium Ga 68-DOTATATE PET/MRI, Lutathera)<br>Patients receive gallium Ga 68-DOTATATE IV and undergo a PET/MRI before cycles 1 and 4. Patients then receive lutetium Lu 177 dotatate IV over 30-40 minutes. Treatment repeats every 8 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. | Radiation: Gallium Ga 68-DOTATATE<br>* Given IV<br>* Other names: Gallium-68 DOTA-DPhe1, Tyr3-octreotate;Drug: Lutetium Lu 177 Dotatate<br>* Given IV<br>* Other names: Lutetium Oxodotreotide Lu-177;Procedure: Magnetic Resonance Imaging<br>* Undergo PET/MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Procedure: Positron Emission Tomography<br>* Undergo PET/MRI<br>* Other names: proton magnetic resonance spectroscopic imaging;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Will be defined as the number of evaluable patients not having progressive disease or death within six months of the first day of treatment divided by the total number of evaluable patients. The proportion of successes in each cohort will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper-Pearson. There will be no formal comparison of rates among the two different grade cohorts of patients. | At 6 months after starting treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The distribution of survival time for both cohorts will be estimated using the method of Kaplan-Meier. No formal comparison will be made among the cohorts. | From the first day of treatment to death due to any cause, assessed up to 5 years | 
| Progression free survival | The distribution of time to progression will be estimated using the method of Kaplan-Meier (Kaplan et. al 1958). No formal comparison will be made among the cohorts. | From the first day of treatment to the earliest date documentation of disease progression, assessed up to 5 years | 
| Incidence of adverse events | Will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. | Up to 24 months |