Arginine + Radiotherapy for Cancer Spread to the Brain
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase < 1
Recruiting
Sponsor: Emory University
Must be taking: Arginine
Must not be taking: Systemic therapy
Disqualifiers: Pregnant, Prisoners, Cognitively impaired, others
No Placebo Group
Approved in 3 Jurisdictions
Trial Summary
What is the purpose of this trial?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.
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 data supports the effectiveness of the treatment Arginine + Radiotherapy for cancer spread to the brain?
Research suggests that some tumors, including certain brain tumors, may depend on arginine for growth, making them potentially vulnerable to treatments that deplete arginine. This indicates that using arginine in combination with other therapies might help in targeting these tumors.
12345Is L-arginine generally safe for humans?
Animal studies suggest that L-arginine is generally safe, as large amounts were well tolerated in pigs and rats for 91 days without adverse effects. However, more human studies are needed to confirm its long-term safety.
46789What makes the treatment of Arginine combined with radiotherapy unique for cancer spread to the brain?
This treatment is unique because it combines arginine, an amino acid known for its potential to enhance the immune system and possibly improve cancer prognosis, with radiotherapy. Arginine may also increase the sensitivity of cancer cells to radiation, potentially making the radiotherapy more effective.
125910Eligibility Criteria
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.
+3 more
Exclusion Criteria
I will be treated in the hospital, not at home.
Prisoners
Creatinine > 1.5 x the upper limit of normal
+7 more
Trial Timeline
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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Arm B (oral L-arginine, WBRT)Experimental Treatment6 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 Treatment6 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Emory University Hospital/Winship Cancer InstituteAtlanta, GA
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Who Is Running the Clinical Trial?
Emory UniversityLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Metabolic and hematological effects of dietary supplementation with arginine on rats bearing ascitic Walker 256 tumor. [2013]The notion of using supplementary quantities of arginine for nutritional support in patients with cancer has been evaluated not only as supplement intake of nitrogen substrate but also for its immunopharmacological effects capable of improving the patient's prognosis. The aim of the present study is to evaluate the effects of dietary supplementation with arginine on metastatic dissemination, amino acid metabolism, hematological functions of rats with Walker 256 ascitic tumor. Animals were inoculated intraperitoneally with approximately 4 million cells. Nutritional solutions containing 4 or 6% arginine or just a control diet without added arginine, were administered to the animals via esophagic gavages. The rate of metastasis was lower in animals supplemented with arginine at 4 and 6%. Amino acid metabolism was stimulated in tumor-bearing animals after receiving 4 or 6% arginine, demonstrated by significant increase of arginine, ornithine, citrulline, proline and histidine levels in the blood (p
Effects of NG-nitro-L-arginine and/or L-arginine on experimental pulmonary metastasis in mice. [2019]Effects of NG-nitro-L-arginine methyl ester (L-NAME; an inhibitor of nitric oxide (NO) synthase) and/or L-arginine (substrate of NO synthase) on pulmonary metastasis of murine melanoma and Lewis lung carcinoma cells were investigated. L-NAME, L-arginine or both L-NAME and L-arginine was injected i.p. into mice 5, 3, and 1 h before and 1, 3, 5, and 7 h after the injection of tumor cells into mice via a tail vein. The administration of L-NAME (9.3 mumol/mouse) alone or L-arginine alone (46.5 or 186 mumol/mouse) potentiated pulmonary metastasis of highly and poorly metastatic B16 melanoma cells. L-NAME alone also increased the number of pulmonary metastasis of Lewis lung carcinoma cells, but L-arginine (185 mumol/mouse) did not. However, the combination of L-NAME and L-arginine increased the number of pulmonary metastasis of both the melanoma and Lewis lung carcinoma cells synergistically. L-NAME or L-arginine administration enhanced the retention of B16 melanoma cells in the lungs examined 24 h after the tumor cell injection. Synergistic effect of L-NAME and L-arginine was also seen in the tumor cell retention. The present results suggest that the metastatic potentials of the tumor cells do not simply correlate to NO production in vivo.
Arginine metabolism in soft tissue sarcoma. [2014]L-Arginine (L-Arg) is a conditionally essential amino acid for humans, which is the substrate for both arginase (ARG) and the inducible form of nitric oxide synthase (iNOS) enzymes. Whether L-Arg metabolism has detrimental or beneficial influence on the tumor growth depends on local up regulation of the NOS or ARG pathways at the tumor site.
Characterisation of Expression the Arginine Pathway Enzymes in Childhood Brain Tumours to Determine Susceptibility to Therapeutic Arginine Depletion. [2022]Despite significant improvements in treatment and survival in paediatric cancers, outcomes for children with brain tumours remain poor. Novel therapeutic approaches are needed to improve survival and quality of survival. Extracellular arginine dependency (auxotrophy) has been recognised in several tumours as a potential therapeutic target. This dependency is due to the inability of cancer cells to recycle or synthesise intracellular arginine through the urea cycle pathway compared to normal cells. Whilst adult glioblastoma exhibits this dependency, the expression of the arginine pathway enzymes has not been delineated in paediatric brain tumours. We used immunohistochemical (IHC) methods to stain for arginine pathway enzymes in paediatric high-grade glioma (pHGG), low-grade glioma (pLGG), ependymoma (EPN), and medulloblastoma (MB) tumour tissue microarrays (TMAs). The antibodies detected protein expression of the metaboliser arginase (Arg1 and Arg2); recycling enzymes ornithine transcarbamoylase (OTC), argininosuccinate synthetase (ASS1), and argininosuccinate lyase (ASL); and the transporter SLC7A1. Deficiency of OTC, ASS1, and ASL was seen in 87.5%, 94%, and 79% of pHGG samples, respectively, consistent with an auxotrophic signature. Similar result was obtained in pLGG with 96%, 93%, and 91% of tumours being deficient in ASL, ASS1, and OTC, respectively. 79%, 88%, and 85% of MB cases were ASL, ASS1, and OTC deficient whilst ASL and OTC were deficient in 57% and 91% of EPN samples. All tumour types highly expressed SLC7A1 and Arginase, with Arg2 being the main isoform, demonstrating that they could transport and utilise arginine. Our results show that pHGG, pLGG, EPN, and MB demonstrate arginine auxotrophy based on protein expression and are likely to be susceptible to arginine depletion. Pegylated arginase (BCT-100) is currently in phase I/II trials in relapsed pHGG. Our results suggest that therapeutic arginine depletion may also be useful in other tumour types and IHC analysis of patient tumour samples could help identify patients likely to benefit from this treatment.
[Pharmacological effects of arginine supplementation in rats with Walker 256 solid tumor]. [2016]The effects of diet arginine supplementation for those with cancer are controversial. We evaluate the effects of dietetic supplementation with arginine over body weight, growth of tumor, metastatic dissemination, surviving time, amino acid metabolism, haematological changes of the rats with Walker 256 solid tumor. Intragastrical solutions with arginine at 4% and 6%, a standard diet (control) were administered to the animals. The supplementation with arginine was associated with a lower weight gain during the study period (p
Increased serum levels of L-arginine in ulcerative colitis and correlation with disease severity. [2022]L-arginine (L-Arg) is a semi-essential amino acid that is the substrate for both nitric oxide and polyamine synthesis. Cellular uptake of L-Arg is an active transport process that is subject to competitive inhibition by L-ornithine (L-Orn) and L-lysine (L-Lys). We investigated L-Arg utilization in patients with ulcerative colitis (UC).
Catabolism and safety of supplemental L-arginine in animals. [2018]L-arginine (Arg) is utilized via multiple pathways to synthesize protein and low-molecular-weight bioactive substances (e.g., nitric oxide, creatine, and polyamines) with enormous physiological importance. Furthermore, Arg regulates cell signaling pathways and gene expression to improve cardiovascular function, augment insulin sensitivity, enhance lean tissue mass, and reduce obesity in humans. Despite its versatile roles, the use of Arg as a dietary supplement is limited due to the lack of data to address concerns over its safety in humans. Data from animal studies are reviewed to assess arginine catabolism and the safety of long-term Arg supplementation. The arginase pathway was responsible for catabolism of 76-85 and 81-96 % Arg in extraintestinal tissues of pigs and rats, respectively. Dietary supplementation with Arg-HCl or the Arg base [315- and 630-mg Arg/(kg BW d) for 91 d] had no adverse effects on male or female pigs. Similarly, no safety issues were observed for male or female rats receiving supplementation with 1.8- and 3.6-g Arg/(kg BW d) for at least 91 d. Intravenous administration of Arg-HCl to gestating sheep at 81 and 180 mg Arg/(kg BW d) is safe for at least 82 and 40 d, respectively. Animals fed conventional diets can well tolerate large amounts of supplemental Arg [up to 630-mg Arg/(kg BW d) in pigs or 3.6-g Arg/(kg BW d) in rats] for 91 d, which are equivalent to 573-mg Arg/(kg BW d) for humans. Collectively, these results can help guide studies to determine the safety of long-term oral administration of Arg in humans.
Recombinant human arginase toxicity in mice is reduced by citrulline supplementation. [2021]Human recombinant arginase I cobalt coupled to polyethylene glycol 5000 (HuArg I [Co]-PEG5000) achieved potent in vitro depletion of arginine from tissue culture medium and cytotoxicity to many cancer cell lines. The recombinant enzyme also produced tumor growth inhibition of hepatocellular carcinoma and pancreatic carcinoma xenografts. Although these results were promising, the therapeutic index was narrow. Toxicities were seen in normal cells in tissue culture. In vivo normal tissue injury occurred at doses twice the effective dose. The current study was conducted to define, in greater detail, the maximum tolerated dose (MTD), pharmacodynamics, and dose-limiting toxicities (DLTs) of twice-weekly intraperitoneal HuArg I [Co]-PEG5000 in Balb/c mice. Animal weight and survival were monitored, serum arginine levels measured, and complete blood cell counts, chemistries, necropsies, and histologies were performed. In addition, methods to ameliorate the HuArg I [Co]-PEG5000 adverse effects were tested. Supplemental l-citrulline was given concurrently with the arginase drug. The HuArg I [Co]-PEG5000 MTD in mice was 5 mg/kg twice weekly, and DLTs included weight loss and marrow necrosis. No other organ damage or changes in blood cell counts or chemistries were observed. Arginase reduced serum arginine levels from 60 µM to 4 to 6 µM. Supplemental l-citrulline given per os or daily subcutaneously reduced and delayed toxicities, and l-citrulline given twice daily subcutaneously completely prevented animal toxicities. On the basis of these results, we hypothesize that HuArg I [Co]-PEG5000, particularly with supplemental l-citrulline, may be an attractive therapeutic agent for argininosuccinate synthetase-deficient tumors.
Regulation of apoptosis in human gastric cancer cell line SGC-7901 by L-arginine. [2014]L-arginine (L-Arg) is an aminoacid that has immunomodulating and antitumor effects. It is possible that antitumor effects of L-Arg are due to induction of apoptosis in tumor cells. The present study assessed antiproliferating and proapoptotic effects of L-Arg in human gastric cancer cell line SGC-7901.
Arginine Deprivation Therapy: Putative Strategy to Eradicate Glioblastoma Cells by Radiosensitization. [2020]Tumor cells-even if nonauxotrophic-are often highly sensitive to arginine deficiency. We hypothesized that arginine deprivation therapy (ADT) if combined with irradiation could be a new treatment strategy for glioblastoma (GBM) patients because systemic ADT is independent of local penetration and diffusion limitations. A proof-of-principle in vitro study was performed with ADT being mimicked by application of recombinant human arginase or arginine-free diets. ADT inhibited two-dimensional (2-D) growth and cell-cycle progression, and reduced growth recovery after completion of treatment in four different GBM cell line models. Cells were less susceptible to ADT alone in the presence of citrulline and in a three-dimensional (3-D) environment. Migration and 3-D invasion were not unfavorably affected. However, ADT caused a significant radiosensitization that was more pronounced in a GBM cell model with p53 loss of function as compared with its p53-wildtype counterpart. The synergistic effect was independent of basic and induced argininosuccinate synthase or argininosuccinate lyase protein expression and not abrogated by the presence of citrulline. The radiosensitizing potential was maintained or even more distinguishable in a 3-D environment as verified in p53-knockdown and p53-wildtype U87-MG cells via a 60-day spheroid control probability assay. Although the underlying mechanism is still ambiguous, the observation of ADT-induced radiosensitization is of great clinical interest, in particular for patients with GBM showing high radioresistance and/or p53 loss of function. Mol Cancer Ther; 17(2); 393-406. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."