Evaluation of Ascorbate-Meglumine Therapeutic for SRS

Study Overview
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Brief Summary
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Phase 1, Single-Center, Dose-Escalating, Open-Label, Safety Clinical Trial of Parenteral Ascorbate-Meglumine as a Novel Magnetic Resonance Imaging-guided Adjunctive Therapeutic for Stereotactic Radiosurgery (SRS).

Detailed Description
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Phase 1, single-center, open-label study in subjects receiving SRS for brain metastases. The study will consist of 4 principal cohorts (n=3 in each cohort). Each cohort will receive an escalating dose of ascorbate-meglumine as an MRI-detectable adjunctive therapeutic to SRS. Subjects will complete a planning MRI for SRS with gadolinium- diethylenetriamine penta-acetic acid (GD-DPTA) per standard of care for SRS. Forty-eight hours after the planning MRI, the subjects will complete the study MRI with ascorbate-meglumine contrast agent. Each cohort will receive an escalating dose of ascorbate-meglumine by intravenous administration over 1 hour during the MRI. The total dose of ascorbate-meglumine-will escalate from the first cohort to the next cohort in a sequential manner. During ascorbate-meglumine infusion, MRI scans will be performed to evaluate the contrast effect and PK blood draws will occur at defined time points. Patients will return for the SRS procedure within 1 week following the planning MRI per standard of care. During SRS, subjects will receive a second dose of ascorbate-meglumine as an adjunctive therapeutic. Patients will enter into a follow up phase within 2 weeks after the SRS procedure per standard of care. The primary endpoint is to evaluate the safety of parenteral ascorbate-meglumine as a MRI-detectable adjunctive therapeutic to SRS.

Official Title
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Phase 1, Single-Center, Dose-Escalating, Open-Label, Safety Clinical Trial of Parenteral Ascorbate-Meglumine as a Novel Magnetic Resonance Imaging-guided Adjunctive Therapeutic for Stereotactic Radiosurgery

Conditions
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Safety

Intervention / Treatment
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* Drug: Ascorbate-Meglumine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving written informed consent to participate in the study before undergoing any screening procedures Age greater than (>) 18 Life expectancy of at least 3 months GPA score 0.5 or greater A contrast-enhanced brain MRI scan performed within 2 weeks of study registration Imaging demonstrates the presence of 1 to 3 intact (not previously irradiated or resected) brain metastases Maximum tumor diameter ≤ 3 cm for the largest lesion Exclusion Criteria: Primary lesion with radiosensitive histology (i.e., small cell carcinoma, germ-cell tumors, lymphoma, leukemia, and multiple myeloma) Metastases in the brain stem, pons or medulla or within 3 mm of optic apparatus (such that some portion of the optic nerve or chiasm would receive >10Gy) Previous whole-brain radiation (previous SRS to or surgical resection of other brain metastases is permitted if more than 3 months prior to the date of enrollment on this protocol.) Pregnancy History or manifestation of glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency History of oxalate kidney stones History of iron overload or hemochromatosis History of allergy to ascorbic acid Anuria, dehydration, severe pulmonary congestion or pulmonary edema or fixed low cardiac input since all are conditions for which osmotic diuresis are contraindicated and ascorbic acid has high osmolarity Subjects who are on the following drugs and cannot have a drug substitution: flecainide, methadone, amphetamines, quinidine, and chlorpropamide; note: high dose ascorbic acid may affect urine acidification and, as a result, may affect clearance rates of these drugs. Subjects who are on strong inducers, inhibitors or substrates of CYP within 3 days of planned administration of study ascorbate-meglumine. Patients for which MRI is contra-indicated

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: dose escalation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Patients receiving SRS treatment for cancer metastatic to the brain from an extracranial primary site with a contrast-enhanced MRI scan showing 1-3 brain metastases, including post-operative patients with 1-3 residual metastases The first cohort of patients will receive ascorbate-meglumine at a dose administration rate of 0.16 g/min for 60 minutes. | Drug: Ascorbate-Meglumine<br>* Ascorbate, meglumine and sodium salt made by combining 375 mM sodium ascorbate, 125 mM ascorbic acid and 125 mM meglumine in sterile water for injection.<br>* Other names: Vitamin C;|
| Experimental: Cohort 2<br>Patients receiving SRS treatment for cancer metastatic to the brain from an extracranial primary site with a contrast-enhanced MRI scan showing 1-3 brain metastases, including post-operative patients with 1-3 residual metastases The first cohort of patients will receive ascorbate-meglumine at a dose administration rate of 0.31 g/min for 60 minutes. | Drug: Ascorbate-Meglumine<br>* Ascorbate, meglumine and sodium salt made by combining 375 mM sodium ascorbate, 125 mM ascorbic acid and 125 mM meglumine in sterile water for injection.<br>* Other names: Vitamin C;|
| Experimental: Cohort 3<br>Patients receiving SRS treatment for cancer metastatic to the brain from an extracranial primary site with a contrast-enhanced MRI scan showing 1-3 brain metastases, including post-operative patients with 1-3 residual metastases The second cohort of patients will receive ascorbate-meglumine at a dose administration rate of 0.63 g/min for 60 minutes. | Drug: Ascorbate-Meglumine<br>* Ascorbate, meglumine and sodium salt made by combining 375 mM sodium ascorbate, 125 mM ascorbic acid and 125 mM meglumine in sterile water for injection.<br>* Other names: Vitamin C;|
| Experimental: Cohort 4<br>Patients receiving SRS treatment for cancer metastatic to the brain from an extracranial primary site with a contrast-enhanced MRI scan showing 1-3 brain metastases, including post-operative patients with 1-3 residual metastases The third cohort of patients will receive ascorbate-meglumine at a dose administration rate of 1.25 g/min for 60 minutes. | Drug: Ascorbate-Meglumine<br>* Ascorbate, meglumine and sodium salt made by combining 375 mM sodium ascorbate, 125 mM ascorbic acid and 125 mM meglumine in sterile water for injection.<br>* Other names: Vitamin C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, as measured by adverse events | Adverse events will be monitored in patients receiving ascorbate formulated with meglumine during the SRS procedure | 1 week after receiving study drug with SRS |