Novel Targeted Radiotherapy in Pediatric Patients With Inoperable Relapsed or Refractory HGG

Study Overview
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Brief Summary
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The purpose of this dose finding study is to evaluate the safety and efficacy of 2 different dose levels of CLR 131 in children, adolescents and young adults with relapsed or refractory high-grade glioma (HGG).

Detailed Description
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This study is designed to further evaluate the safety and tolerability of CLR 131 at the selected doses in children, adolescents and young adults with relapsed or refractory malignant high-grade glioma. It will also determine the therapeutic activity defined as progression free survival and overall survival, antitumor activity (treatment response) defined as the reduction in tumor volume and identify the recommended Phase 2/3 dose of CLR 131 in children, adolescents and young adults with relapsed or refractory HGG.

Official Title
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A Phase 1b, Open-Label, Study of a Novel Targeted Radiotherapy in Children, Adolescents and Young Adults With Inoperable Relapsed or Refractory High-Grade Glioma

Conditions
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High-Grade Glioma

Intervention / Treatment
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* Drug: CLR 131


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously confirmed (histologically or cytologically) high grade glioma that is clinically or radiographically suspected to be relapsed, refractory, or recurrent ≥ 10 years of age and ≤ 25 years of age at time of consent/assent If ≥ age 16 years, Karnofsky performance status of ≥ 60. If < age 16 years, Lansky performance status ≥ 60 Platelets ≥ 75,000/μL (last transfusion, if any, must be at least 1 week prior to study registration, and, unless deemed medically necessary, no transfusions are allowed between registration and dosing) Absolute neutrophil count ≥ 750/μL Hemoglobin ≥ 8 g/dL (last transfusion must be at least 1 week prior to study registration, and, unless deemed medically necessary, no transfusions are allowed between registration and dosing) Using the bedside Schwartz formula, estimated GFR (creatinine clearance) > 60 ml/min/1.73m2 Alanine aminotransferase < 3 × ULN Bilirubin < 2 × ULN At least 1 measurable intracranial lesion with longest diameter of at least 10 mm on any imaging sequence. Patients with previously known neurological deficits must be clinically stable at time of enrollment and able to complete all study related procedures. Patients with documented or newly diagnosed neurological deficits will be enrolled at the investigator's discretion. If patient receives steroids for neurological symptom control, the dose must be stable (unchanged for three weeks prior to registration) or on a steroid tapering regimen. Initiation of steroids per routine care immediately prior to CLR 131 dosing is acceptable Patient or his or her legal representative is judged by the Investigator to have the initiative and means to be compliant with the protocol. Patient or his or her legal representative has the ability to read, understand, and provide written informed consent for the initiation of any study-related procedures. Female patients of childbearing potential must have a negative pregnancy test at screening and within 24 hours of dosing. It is recommended that female caregivers of childbearing potential have a negative pregnancy test within one week of dosing. Patients of childbearing potential must practice an effective method of birth control while participating on this study to avoid possible harm to the fetus. Exclusion Criteria: Antitumor therapy or investigational therapy, within 3-half-lives of the agent preceding the present study. For certain types of radiation (craniospinal, total abdominal, whole lung [spot irradiation to skull-based metastases is not considered craniospinal radiation for the purposes of this study]), at least 3 months must have elapsed. Palliative focal radiation to non-target lesions should be completed at least 2 weeks prior to dosing. Patients participating in non-interventional clinical trials (i.e., non-drug) are allowed to participate in this trial History of hypersensitivity to thyroid protection medication (e.g., potassium iodide, Lugol's solution, etc.) Any other concomitant serious illness or organ system dysfunction (including cardiac and pulmonary dysfunction) that in the opinion of the Investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug. Major surgery within 6 weeks of enrollment unless delay in therapy poses unacceptable risk to the patient due to clinical progression (enrollment o such patients should be discussed with Medical Monitor) Known history of human immunodeficiency virus or uncontrolled, serious, active infection Pregnancy or breast-feeding

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 25 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: Drug: CLR 131 is a radio-iodinated therapy comprising a core phospholipid ether (PLE) analogue radiolabeled with iodine-131. CLR 131 exploits the tumor-targeting properties of PLEs to provide targeted delivery of radiation to malignant tumor cells and minimizes radiation exposure to normal tissues.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pediatric High-Grade Glioma Patients<br>Two dosing cohorts will be explored; patients in the first arm will receive two doses, 20 mCi/m2 each, separated by 14 days for two cycles, with a third optional cycle. Patients in the second arm will receive two doses, 10 mCi/m2 each, separated by 14 days for three cycles with a fourth optional cycle. | Drug: CLR 131<br>* CLR 131 will be administered IV (intravenously) at a dose based on patients' BSA<br>* Other names: iopofosine I 131;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Evaluation of CLR 131 | Will be assessed by physical examination, performance status, vital signs, laboratory changes over time, and adverse events. Evaluations will use a nonparametric Wilcoxon Signed Rank test and a linear mixed effects modeling will be conducted to evaluate longitudinal changes. | Assessed throughout the study to 1-year post-infusion follow-up period | 
| Efficacy Evaluation for Progression Free Survival | To determine the therapeutic activity defined as Progression Free Survival (PFS) using Kaplan Meier estimator. PFS is defined as the time from arm assignment until disease progression or death. | Day 84 post-infusion follow-up period through 3 years following completion of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Response of CLR 131 | Determine antitumor activity (treatment response) defined as the reduction in tumor volume, measured by MRI scans acquired as FLAIR images and based on the RAPNO criteria for responses. | From date of arm assignment until date of first documented progression or date of death from any cause, whichever comes first, assessed up to 48 months. | 
| Dose Determination for CLR 131 | Identify the recommended Phase 2/3 dose of CLR 131 in relapsed pHGG patients based on both safety and efficacy assessments as defined by the primary endpoints concluded from this study. | From date of arm assignment until date of first documented progression or date of death from any cause, whichever comes first, assessed up to 48 months. | 
| Dosimetry Evaluation for Total Body and Organ | To determine total body and organ dosimetry, together, of CLR 131 in relapsed pHGG patients, measured by conjugate planar whole-body imaging and/or blood collection drawn for radiologic dosimetry analysis for a subset of patients. Organ time/activity integrals will be entered into OLINDA/EXM software to produce total body and organ dosimetry values for CLR 131. | 4 hours post-infusion and concluding 4 weeks post-initial imaging | 
| Tumor Response to CLR 131 | Determine the tumor uptake of CLR 131 and utility of SPECT/CT as a potential diagnostic for response. Images will be reconstructed using quantitative SPECT reconstruction methods with compensation for attenuation, scatter and the full collimator-detector response including septal penetration and scatter. A registered CT image will be used as the attenuation map for the SPECT images. Image data will be converted to activity per cubic centimeters using a sensitivity measurement made using a point source in air. | 4 hours post-infusion and concluding 4 weeks post-initial imaging |