Arginine and Whole Brain Radiation Therapy for the Treatment of Patients With Brain Metastases

Early Phase 1

Not yet recruiting

• Conditions: Metastatic Malignant Neoplasm in the Brain; Metastatic Malignant Solid Neoplasm
• Interventions: Dietary Supplement: Arginine; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Procedure: Spectroscopy; Radiation: Whole-Brain Radiotherapy

• Registration Number: NCT06328686
• Lead Sponsor: Emory University

Brief Summary

This early phase I trial evaluates different administration techniques (oral or intravenous) for arginine and tests the safety of giving arginine with whole brain radiation therapy in patients who have cancer that has spread from where it first started (primary site) to the brain (brain metastases). Arginine is an essential amino acid. Amino acids are the molecules that join together to form proteins in the body. Arginine supplementation has been shown to improve how brain metastases respond to radiation therapy. The optimal dosing of arginine for this purpose has not been determined. This study measures the level of arginine in the blood with oral and intravenous dosing at specific time intervals before and after drug administration to determine the best dosing strategy.

Detailed Description

PRIMARY OBJECTIVE:

I. Determine the bioavailability of orally-administered arginine (L-arginine).

SECONDARY OBJECTIVES:

I. Test the safety of daily arginine administration with standard-fractionation whole brain radiation therapy (WBRT).

II. Determine the side effect profile of oral and intravenous (IV) L-arginine. III. Quantify frontal cortex blood volume/flow changes following L-arginine (L-arg) administration.

IV. Describe immunological effects of oral versus (vs.) IV arginine. V. Describe the metabolic effects of oral vs. IV arginine.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive L-arginine IV over 10-20 minutes followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) at screening, undergo collection of blood samples and spectroscopy on study, and undergo magnetic resonance imaging (MRI) at screening and follow up.

ARM B: Patients receive L-arginine orally (PO) followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.

After completion of study treatment, patients are followed up at 1 month and then quarterly for 1 year.

Study Timeline

• Study First Submitted: 2024-02-19
• Study First Submitted QC: 2024-03-18
• Study First Posted: 2024-03-25
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-16
• Last Update Posted: 2024-07-18
• Study Start: 2024-08-30
• Primary Completion: 2025-12-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

• Diagnosis of brain metastases from any primary cancer
• Planned to undergo whole-brain radiation therapy (Hippocampal avoidant is ok)
• No systemic anti-neoplastic agent concurrent with WBRT (memantine is ok)
• Not inpatient at the time of treatment start
• Age 18 or older
• Able to consent for self

Exclusion Criteria

• Patient unwilling/unable to receive daily arginine treatment (IV or oral) for the 10 days of WBRT
• Systemic therapy continuing during WBRT
• Creatinine > 1.5 x the upper limit of normal
• Alanine aminotransferase (ALT) > 6x the upper limit of normal
• Patient planned to be treated as an inpatient
• Age < 18 years
• Adult not able to consent for self
• Pregnant
• Prisoners
• Cognitively impaired/impaired decision-making capacity

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B (oral L-arginine, WBRT)	Spectroscopy	Patients receive L-arginine PO followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.
Arm A (IV L-arginine, WBRT)	Biospecimen Collection	Patients receive L-arginine IV over 10-20 minutes followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.
Arm B (oral L-arginine, WBRT)	Whole-Brain Radiotherapy	Patients receive L-arginine PO followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.
Arm A (IV L-arginine, WBRT)	Computed Tomography	Patients receive L-arginine IV over 10-20 minutes followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.
Arm A (IV L-arginine, WBRT)	Magnetic Resonance Imaging	Patients receive L-arginine IV over 10-20 minutes followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.
Arm A (IV L-arginine, WBRT)	Arginine	Patients receive L-arginine IV over 10-20 minutes followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.
Arm A (IV L-arginine, WBRT)	Spectroscopy	Patients receive L-arginine IV over 10-20 minutes followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.
Arm A (IV L-arginine, WBRT)	Whole-Brain Radiotherapy	Patients receive L-arginine IV over 10-20 minutes followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.
Arm B (oral L-arginine, WBRT)	Arginine	Patients receive L-arginine PO followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.
Arm B (oral L-arginine, WBRT)	Biospecimen Collection	Patients receive L-arginine PO followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.
Arm B (oral L-arginine, WBRT)	Computed Tomography	Patients receive L-arginine PO followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.
Arm B (oral L-arginine, WBRT)	Magnetic Resonance Imaging	Patients receive L-arginine PO followed by WBRT approximately 1 hour later for up to 10 days of treatment over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening, undergo collection of blood samples and spectroscopy on study, and undergo MRI at screening and follow up.

Primary Outcome Measures

Name	Time	Method
Peak plasma L-arginine (arginine) and arginine metabolite concentration	Within 4 hours of oral and intravenous (IV) dosing of L-arginine	By compartmental pharmacokinetic analysis, the plasma arginine levels at before administration, 10 min, 30 min, 1 hour, 2 hours, and 4 hours post administration will be used to estimate the median time to reach the peak plasma arginine and the mean value of peak. This will be done separately by two arms.

Secondary Outcome Measures

Name	Time	Method
Incidence of adverse events associated with delivering L-arginine with standard fractionation whole brain radiation therapy	At 1 week into radiation and at completion of 2 week course	Will be evaluated using complete metabolic panel and symptom assessment. The descriptive statistics (e.g., summary statistics for numerical measurements and frequency/percentage for categorical measurements) along with data visualization (e.g., box plot repeated by time points) will mainly be considered for all 10 patients or separated by arms. As needed, the comparison between the two arms will be carried out mainly by non-parametric tests (e.g., Wilcoxon sum-rank test, Fisher's exact test). The change before and after treatment can be tested using a paired-test (e.g., Wilcoxon signed rank test). All analyses will be explored for all 10 patients or separated by arms as appropriate.
Side effect profile of oral and IV arginine	On days 1, 5, and 10	Will be evaluated using symptom assessment at time of lab draw. The descriptive statistics (e.g., summary statistics for numerical measurements and frequency/percentage for categorical measurements) along with data visualization (e.g., box plot repeated by time points) will mainly be considered for all 10 patients or separated by arms. As needed, the comparison between the two arms will be carried out mainly by non-parametric tests (e.g., Wilcoxon sum-rank test, Fisher's exact test). The change before and after treatment can be tested using a paired-test (e.g., Wilcoxon signed rank test). All analyses will be explored for all 10 patients or separated by arms as appropriate.
Describe The Immunological Effects of Oral versus IV Arginine	Up to 10 days	Administration of both oral and IV formulations of L-arginine will stimulate T-cell proliferation and expression of effector molecules. A phenotypic analysis of circulating immune cells will be conducted by spectral flow cytometry during treatment.
Frontal cortex blood volume/flow changes with L-arginine administration	Up to 1 year	Cerebral blood flow (CBF) and oxygen utilization will be measured using diffuse optical spectroscopy and diffuse correlation spectroscopy after arginine administration.; The descriptive statistics (e.g., summary statistics for numerical measurements and frequency/percentage for categorical measurements) along with data visualization (e.g., box plot repeated by time points) will mainly be considered for all 10 patients or separated by arms. As needed, the comparison between the two arms will be carried out mainly by non-parametric tests (e.g., Wilcoxon sum-rank test, Fisher's exact test). The change before and after treatment can be tested using a paired-test (e.g., Wilcoxon signed rank test). All analyses will be explored for all 10 patients or separated by arms as appropriate.
Describe The Metabolic Effects of Oral versus IV Arginine	Up to 10 days	Administration of both oral and IV formulations of L-arginine will stimulate T-cell proliferation and expression of effector molecules. Arginine metabolites, including ornithine, citrulline, will have a delayed increase following arginine administration. A phenotypic analysis of circulating immune cells will be conducted by spectral flow cytometry during treatment.

Trial Locations

Locations (1)

Emory University Hospital/Winship Cancer Institute; 🇺🇸 Atlanta, Georgia, United States