68Ga/177Lu-PSMA Theranostics in Recurrent Grade 3 and Grade 4 Glioma

Study Overview
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Brief Summary
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This interventional, clinical pilot-study will initiate and evaluate 68Ga/177Lu-PSMA theranostics in Norway as treatment alternative for patients with recurrent grade 3 and grade 4 gliomas. The main goal is to improve existing diagnostic and therapeutic methods in glioma management, and introduce a novel, well-tolerated radionuclide treatment that possibly can increase the overall survival and quality of life for a patient group that today have very short expected survival and no standard recommended therapy.

Detailed Description
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Patients demonstrating a high tumor uptake of 68Ga-PSMA on the diagnostic PET/MRI examination in the screening part of the study are eligible for a standard of 3 cycles, with a possible extension to maximum number of 6 cycles, of 177Lu-PSMA radionuclide therapy sessions. SPECT/CT will be performed after each cycle of treatment for dosimetry calculations, while 68Ga-PSMA PET/MRI, quality-of-life schemes and clinical examinations will be used to monitor therapeutic effects during the therapy cycles and up to 1.5 year after treatment initiation. The main endpoints of the study are progression-free survival and overall survival.

Official Title
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68Ga/177Lu-PSMA Theranostics in Recurrent Grade 3 and Grade 4 Glioma

Conditions
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High Grade Glioma

Intervention / Treatment
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* Radiation: 177Lu-PSMA I&T


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A previous diagnosis of histologically confirmed WHO grade 3 or grade 4 glioma Radiologically (MRI) confirmed tumor relapse/progression ≥ 12 weeks since completed radiotherapy or suspicion of recurrence where inclusion in the theranostic part of study could be indicated Must be ≥ 18 years old Written informed consent for study participation Negative pregnancy test no longer than 14 days prior to enrollment Life expectancy > 12 weeks Karnofsky performance status ≥ 70% (must be able to care for self after radionuclide therapy) High tumor uptake on diagnostic imaging with 68Ga -PSMA. Tumor not amendable for radiotherapy or surgery, and treating oncologist think that there are no other preferable systemic therapy options (e.g temozolomide, PCV or lomustine monotherapy). Women of childbearing potential (WOCBP) defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile must use adequate contraception. Permanent sterilization methods include hysterectomy, bilateral salpingectomy or bilateral oophorectomy. Adequate contraception in the current study will be the following: o Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: Intravaginal transdermal Progestogen-only hormonal contraception associated with inhibition of ovulation: oral injectable implantable intrauterine device (IUD) intrauterine hormone-releasing system ( IUS) bilateral tubal occlusion vasectomised partner sexual abstinence Patient accept not to receive any other tumor directed treatment before 8 weeks after each 177Lu-PSMA injection. Exclusion Criteria: Estimated GFR < 30 mL/min Platelet count <75 x109 /L White blood cells ≤ 2.5 x 109/L Neutrophil count < 1.5 x109 /L Hb < 8.0 g/dL Albumin ≤ 25 g/L Uncontrollable symptomatic epilepsy refractory to standard medication Pacemakers or defibrillators not compatible with 3T MRI No ability to obtain informed consent (e.g. due to severe dysphasia or cognitive deficits). Breastfeeding Pregnancy Hypersensitivity to the active substance or to any of the excipients Urinary and fecal incontinence (patient cannot have diaper needs) Significant medical or psychiatric illness that, in the investigator's opinion, would compromise the patient's ability to tolerate this therapy If previous radiotherapy and/or radionuclide therapy have resulted in absorbed doses >=23 Gy to any of the kidneys, or >= 25 Gy to any of the parotids, an individual assessment will be made by the nuclear medicine physician and medical physicist if patient can be included to the therapy part of the study. Concurrent investigational drugs or experimental therapy must be stopped at least 4 weeks prior to study entry Unwilling to accept potential challenge with xerostomia

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
Interventional Model Description: Patients with recurrent grade 3 and grade 4 glioma will be recruited for treatment with 177Lu-PSMA.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 68Ga/177Lu-PSMA theranostics in recurrent grade 3 and grade 4 glioma<br>Patients demonstrating a high tumor uptake of 68Ga-PSMA on the diagnostic PET/MRI examination in the screening part of the study are eligible for a standard of 3 cycles, with a possible extension to maximum number of 6 cycles, of 177Lu-PSMA radionuclide therapy sessions. SPECT/CT will be performed after each cycle of treatment for dosimetry calculations, while 68Ga-PSMA PET/MRI, quality-of-life schemes and clinical examinations will be used to monitor therapeutic effects during the therapy cycles and up to 1.5 year after treatment initiation. The main endpoints of the study are progression-free survival and overall survival. | Radiation: 177Lu-PSMA I&T<br>* Patients demonstrating a high tumor uptake of 68Ga-PSMA on the diagnostic PET/MRI examination in the screening part of the study are eligible for a standard of 3 cycles, with a possible extension to maximum number of 6 cycles, of 177Lu-PSMA radionuclide therapy sessions. SPECT/CT will be performed after each cycle of treatment for dosimetry calculations, while 68Ga-PSMA PET/MRI, quality-of-life schemes and clinical examinations will be used to monitor therapeutic effects during the therapy cycles and up to 1.5 year after treatment initiation. The main endpoints of the study are progression-free survival and overall survival.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Type, frequency and severity of adverse events assessed with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. | 6 months after end of therapy | 
| Evaluation of efficacy of 177Lu- PSMA | Progression free survival (6 months) determined from date of commencement of 177Lu-PSMA therapy | 6 months after commencement of therapy | 
| Evaluation of efficacy of 177Lu- PSMA | Overall survival (1 year) determined from date of commencement of 177Lu-PSMA therapy | 1 year after commencement of therapy | 
| Adverse events | Change in score in the modified RAI-6 questionnaire. | Day 1 and 6 months after end of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate radiation dose to tumor and critical organs | Calculation of absorbed doses to the tumor and kidneys, parotid glands, sublingual glands, submandibular glands, lacrimal glands, liver, spleen and red marrow for each therapy cycle as well as accumulated doses for all therapy cycles. | 7 days after commencement of therapy | 
| Tumor response | Tumor responses as assessed by contrast enhanced MRI according to response assessment in neuro oncology (RANO) criteria (50) (Attachment 3) and volume measurements. | 8 weeks | 
| Nano score | Neurologic exam (nano score) | 8 weeks | 
| Health related quality of life | Health-related quality of life EQ-5D scores | 8 weeks | 
| Karnofsky performance status | Karnofsky performance status | 8 weeks | 
| PSMA uptake versus progression free survival | Correlate 68Ga-PSMA uptake (SUV) to overall and image-based progression free survival. | 8 weeks | 
| Pretherapeutic PSMA uptake versus accumulated doses | Evaluate the possible correlation between the pretherapeutic uptake of 68Ga -PSMA (SUV) in tumors and salivary glands to accumulated doses received from therapeutic 177Lu-PSMA. | 8 weeks | 
| Tumor-to-parotis ratio threshold for indication of 177Lu-PSMA therapy | Establish an appropriate indication for 177Lu-PSMA therapy by measuring tumor:parotis-ratios in 68Ga-PSMA PET scans. | 8 weeks | 
| Change in PSMA uptake during treatment period versus overall survival | Measure changes in uptake (SUV) of 68Ga-PSMA during the treatment period and correlate to overall survival in order to evaluate the role of post-therapeutic 68Ga-PSMA PET in monitoring disease. | 8 weeks |