Arginine + Radiotherapy for Cancer Spread to the Brain

Overseen By Lisa Sudmeier, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Emory University

Must be taking: Arginine

Must not be taking: Systemic therapy

Disqualifiers: Pregnant, Prisoners, Cognitively impaired, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 2 weeks

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of using arginine, an essential protein building block, with whole-brain radiation therapy for individuals whose cancer has spread to the brain. Researchers aim to determine whether oral or IV administration of arginine enhances radiation treatments. Individuals diagnosed with brain metastases and scheduled for whole-brain radiation may qualify for this study. Participants must not receive any other cancer treatments during the radiation therapy. As an Early Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

Will I have to stop taking my current medications?

The trial requires that you do not take any systemic anti-cancer medications while receiving whole-brain radiation therapy, except for memantine. If you are on such medications, you may need to stop them during the trial.

What prior data suggests that these administration techniques for arginine are safe?

Research has shown that arginine enhances the effects of radiation therapy in patients with cancer that has spread to the brain. This suggests arginine might improve radiation's effectiveness against brain cancer cells. However, the optimal amount of arginine remains under investigation.

Arginine, an amino acid and a building block of proteins in the body, is generally safe as a supplement. This study is in an early stage, so researchers are still gathering initial safety information about using arginine with whole-brain radiation therapy.

In the study, arginine is administered in two ways: through an IV (a tube into the vein) or by mouth. As the study is in its early phase, researchers are still assessing the safety and tolerability of these methods for patients. Those considering participation should consult a healthcare provider about the potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using arginine in conjunction with radiotherapy for brain metastases because it introduces a potentially powerful new approach. Unlike traditional treatments that primarily rely on radiotherapy alone, this approach uses arginine, a naturally occurring amino acid, to potentially enhance the effectiveness of radiotherapy. Arginine can be administered intravenously or orally, providing flexibility and convenience in its delivery. This combination is hoped to improve outcomes by increasing the sensitivity of cancer cells to radiation, potentially leading to better control of cancer spread in the brain.

What evidence suggests that this trial's treatments could be effective for brain metastases?

Research has shown that arginine, a type of protein building block, can help brain tumors respond better to radiation treatment. In this trial, participants will receive arginine either through an IV or by mouth, followed by whole brain radiation therapy (WBRT). Studies have found that arginine can make radiation therapy more effective. Arginine alters how cancer cells use energy, making them more vulnerable to radiation. Specifically, patients who took arginine before receiving WBRT experienced better control of their brain tumors. While researchers continue to determine the best dose, evidence suggests that arginine could enhance the effectiveness of radiation for treating brain tumors. ^{2 3 4 6 7}

Who Is on the Research Team?

Lisa Sudmeier, MD, PhD

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Are You a Good Fit for This Trial?

This trial is for patients with cancer that has spread to the brain. Participants must be able to undergo procedures like CT scans, MRI, and radiation therapy. The study will test if arginine, an essential amino acid, can improve how brain metastases respond to radiation.

Inclusion Criteria

I will not be hospitalized when treatment begins.

Able to consent for self

I am scheduled for brain radiation therapy, avoiding the hippocampus is acceptable.

Exclusion Criteria

I will be treated in the hospital, not at home.

Prisoners

Creatinine > 1.5 x the upper limit of normal

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive L-arginine (IV or oral) followed by whole brain radiation therapy for up to 10 days over 2 weeks

2 weeks

Daily visits for treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

1 visit at 1 month, then quarterly

What Are the Treatments Tested in This Trial?

Interventions

• Arginine
• Whole Brain Radiation Therapy

Trial Overview The trial is evaluating oral or intravenous administration of arginine combined with whole-brain radiotherapy in treating brain metastases from primary cancers. It aims to find the best dosing strategy by measuring blood levels of arginine before and after administration.

How Is the Trial Designed?

Group I: Arm B (oral L-arginine, WBRT) Experimental Treatment 6 Interventions

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.

Group II: Arm A (IV L-arginine, WBRT) Experimental Treatment 6 Interventions

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.

Arginine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as L-arginine for:

• Dietary supplementation
• Angina
• Erectile dysfunction
• High blood pressure

Approved in European Union as L-arginine for:

• Dietary supplementation
• Angina
• Erectile dysfunction
• High blood pressure

Approved in Canada as L-arginine for:

• Dietary supplementation
• Angina
• Erectile dysfunction
• High blood pressure

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The study found that both L-NAME, a nitric oxide synthase inhibitor, and L-arginine, a substrate for nitric oxide production, increased pulmonary metastasis of melanoma and lung carcinoma cells in mice, indicating that inhibiting nitric oxide synthesis can enhance tumor spread.

The combination of L-NAME and L-arginine had a synergistic effect, further increasing the number of metastases and retention of tumor cells in the lungs, suggesting that the relationship between nitric oxide production and tumor metastasis is complex and not straightforward.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of NG-nitro-L-arginine and/or L-arginine on experimental pulmonary metastasis in mice. Yamamoto, T., Terada, N., Nishizawa, Y., et al.[2019]

Arginine deprivation therapy (ADT) significantly inhibits the growth and cell-cycle progression of glioblastoma (GBM) cells in vitro, particularly enhancing the effectiveness of radiation treatment, especially in GBM cells with p53 loss of function.

The combination of ADT and irradiation shows a strong radiosensitizing effect, which remains effective even in three-dimensional environments, suggesting a promising new treatment strategy for GBM patients who are often resistant to conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arginine Deprivation Therapy: Putative Strategy to Eradicate Glioblastoma Cells by Radiosensitization. Hinrichs, CN., Ingargiola, M., Käubler, T., et al.[2020]

L-arginine (Arg) plays a crucial role in synthesizing important substances like nitric oxide and creatine, which can improve cardiovascular health and insulin sensitivity, but its use as a dietary supplement is limited due to safety concerns.

Animal studies show that long-term supplementation of Arg (up to 630 mg/kg body weight per day in pigs and 3.6 g/kg body weight per day in rats) is safe, with no adverse effects observed, suggesting that similar doses may be safe for humans as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Catabolism and safety of supplemental L-arginine in animals. Wu, Z., Hou, Y., Hu, S., et al.[2018]

Supplementing rats with arginine (4% and 6%) significantly reduced the rate of metastatic spread of Walker 256 ascitic tumors, indicating a potential benefit for cancer management.

Arginine supplementation also improved amino acid metabolism and reduced the severity of anemia in tumor-bearing rats, suggesting it may enhance overall health and prognosis in cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic and hematological effects of dietary supplementation with arginine on rats bearing ascitic Walker 256 tumor. Novaes, MR., Lima, LA., Novaes, LC., et al.[2013]

Arginine supplementation at 6% in rats with Walker 256 solid tumors resulted in lower weight gain and less severe anemia compared to a control group, indicating potential benefits in managing some cancer-related symptoms.

The study found that arginine supplementation was associated with a lower rate of metastasis and stimulated amino acid metabolism, as evidenced by increased blood levels of several amino acids, suggesting a pharmacological effect beyond mere nutrition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological effects of arginine supplementation in rats with Walker 256 solid tumor]. Novaes, MR., Lima, LA., Ribeiro, JE., et al.[2016]

HuArg I [Co]-PEG5000 effectively depletes arginine and inhibits tumor growth in certain cancer types, but it has a narrow therapeutic index, causing toxicity in normal cells at higher doses.

The maximum tolerated dose in mice was determined to be 5 mg/kg twice weekly, with weight loss and marrow necrosis as dose-limiting toxicities; however, supplementing with l-citrulline significantly reduced these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant human arginase toxicity in mice is reduced by citrulline supplementation. Mauldin, JP., Zeinali, I., Kleypas, K., et al.[2021]

L-arginine (L-Arg) significantly inhibits the growth of human gastric cancer cells (SGC-7901) and promotes apoptosis, suggesting its potential as an antitumor agent.

The mechanism of L-Arg's antitumor effects involves downregulating antiapoptotic proteins like Bcl-2 and survivin, while upregulating the proapoptotic protein p53, indicating a targeted approach to inducing cancer cell death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulation of apoptosis in human gastric cancer cell line SGC-7901 by L-arginine. Shu, XL., Xu, H., Yu, TT., et al.[2014]

In a study of 81 adult soft tissue sarcomas (STSs), the enzymes arginase (ARG) and inducible nitric oxide synthase (iNOS) were found to be overexpressed in tumor cells, suggesting they may play a role in the biology of these tumors.

Dermatofibrosarcoma protuberans (DFSP) was unique in that it showed little to no expression of ARG and iNOS, indicating a potential difference in tumor biology that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arginine metabolism in soft tissue sarcoma. Yan, X., Takahara, M., Xie, L., et al.[2014]

Paediatric brain tumours, including high-grade gliomas (pHGG), low-grade gliomas (pLGG), ependymomas (EPN), and medulloblastomas (MB), show a significant dependency on extracellular arginine due to deficiencies in key enzymes, indicating they may be susceptible to treatments that deplete arginine.

The study found that a high percentage of these tumours lack enzymes necessary for arginine recycling, suggesting that therapies like pegylated arginase (BCT-100), currently in trials for pHGG, could also be effective for other types of paediatric brain tumours.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterisation of Expression the Arginine Pathway Enzymes in Childhood Brain Tumours to Determine Susceptibility to Therapeutic Arginine Depletion. Bishop, E., Dimitrova, M., Froggatt, A., et al.[2022]

In patients with ulcerative colitis (UC), higher serum levels of L-arginine (L-Arg) were found to correlate with the severity of the disease, indicating that L-Arg may play a role in UC pathology.

Despite increased L-Arg levels in severe colitis, its availability for cellular uptake was not enhanced due to competitive inhibition by other amino acids (L-ornithine and L-lysine), suggesting a defect in L-Arg uptake that could contribute to UC progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased serum levels of L-arginine in ulcerative colitis and correlation with disease severity. Hong, SK., Maltz, BE., Coburn, LA., et al.[2022]

Citations

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Arginine treatment enhances effectiveness of radiation ... Treatment with arginine, one of the amino-acid building blocks of proteins, enhanced the effectiveness of radiation therapy in cancer ...

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L-arginine Enhances Effect of Radiation on Brain Metastases Outcomes improve when patients are pretreated with oral L-arginine before undergoing radiation therapy for unresectable brain metastases, ...

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Arginine and Whole Brain Radiation Therapy for the ... This early phase I trial evaluates different administration techniques (oral or intravenous) for arginine and tests the safety of giving ...

7. irochouston.mdanderson.org irochouston.mdanderson.org/rpc/credentialing/files/RTOG-0933-Master[1].pdf

radiation therapy oncology group rtog 0933 a phase ii trial ... Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 2003;21 ...