IV Gallium for Cystic Fibrosis and NTM Infections

(ABATE Trial)

Recruiting at 10 trial locations

Overseen By Natallia Cameron

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Chris Goss

Must be taking: Guideline-based antibiotics

Must not be taking: Bisphosphonates, Azithromycin

Disqualifiers: Transplantation, Osteoporosis, Pregnancy, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 11

Duration: 10 days

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

If you are in the treatment-naïve group, you must stop taking azithromycin for the study duration. If you are in the treatment-refractory group, you can continue your current guideline-based antibiotic therapy while participating in the trial.

What data supports the effectiveness of the drug Gallium nitrate for treating cystic fibrosis and NTM infections?

Research shows that Gallium nitrate can help fight lung infections in cystic fibrosis patients by disrupting bacteria's iron uptake, which is essential for their growth. It has shown effectiveness against various bacteria in lab studies and animal models, suggesting it could be a promising treatment for lung infections in cystic fibrosis. ^{1 2 3 4 5}

Is IV Gallium safe for humans?

Gallium nitrate has been tested in humans for various conditions, and the main safety concern is kidney-related side effects, which can be managed with proper hydration. Other side effects include nausea, changes in hearing, and changes in blood minerals like calcium and magnesium. ^{1 2 4 6 7}

How is the drug gallium nitrate different from other treatments for cystic fibrosis and NTM infections?

Gallium nitrate is unique because it mimics iron, disrupting bacterial iron uptake and metabolism, which is crucial for bacterial growth. Unlike traditional antibiotics, it targets a broad range of cystic fibrosis pathogens, including those resistant to other treatments, by interfering with their iron-dependent processes. ^{2 3 5 6 8}

What is the purpose of this trial?

The purpose of this study is to assess the safety and tolerability of two 5-day infusion cycles of IV gallium in adult patients with CF who are infected with NTM. Funding Source - FDA Office of Orphan Products Development (OOPD)

Research Team

Christopher H. Goss, MD, MSc

Principal Investigator

University of Washington, Seattle Children's Hospital

Eligibility Criteria

Adults over 18 with Cystic Fibrosis and NTM infections, who can expectorate sputum and have not been treated for NTM or were treated successfully over 2 years ago. Participants must have a CF diagnosis, two positive NTM cultures from sputum/BAL at least 28 days apart, and be willing to follow the study schedule.

Inclusion Criteria

My health has been stable for the last week.

You have repeatedly tested positive for certain types of bacteria in the sputum or lung fluid samples. This means that the same bacteria species has been found in your samples over time, or that you have had multiple positive test results within certain timeframes.

You can cough up phlegm.

Exclusion Criteria

I have been diagnosed with osteoporosis.

I am currently being treated for NTM disease or will start treatment soon.

My doctor believes my symptoms are due to NTM disease, despite treatment for other infections.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive two 5-day infusion cycles of IV gallium

10 days

Continuous infusion over 5 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

16 weeks

Multiple visits for monitoring between Day 6 and Day 111

Treatment Details

Interventions

• Gallium nitrate

Trial Overview The trial is testing IV gallium nitrate's safety in adults with Cystic Fibrosis infected by NTM. It involves two cycles of a five-day infusion to evaluate how well patients tolerate this treatment.

Participant Groups

Group I: Infusion of IV Gallium Experimental Treatment 1 Intervention

Gallium nitrate will be infused continuously over 5 days at 200 mg/m2/day. Study drug will be administered via a peripheral IV catheter, a peripherally inserted central catheter (PICC) line, midline catheter, or a chronic indwelling vascular access device using an ambulatory infusion pump infused over 24 hours for 5 sequential days for each cycle. There is a maximum of 2 cycles.

Gallium nitrate is already approved in United States for the following indications:

Approved in United States as Ganite for:

• Hypercalcemia of malignancy

Who Is Running the Clinical Trial?

Chris Goss

Lead Sponsor

Trials

5

Recruited

2,300+

Cystic Fibrosis Foundation

Collaborator

Trials

199

Recruited

37,800+

Findings from Research

Intravenous gallium nitrate (GaN) has shown promise against Pseudomonas aeruginosa pneumonia, and a new inhalation formulation using hyaluronic acid/chitosan nanoparticles (Ga_HA/CS NPs) improves lung delivery and reduces systemic exposure.

The engineered mannitol-based formulation (Ga_Man NEM) demonstrated better lung retention of Ga(III) while minimizing kidney accumulation, which is crucial for reducing potential side effects, indicating a safer and more effective delivery method for treating lung infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Boosting lung accumulation of gallium with inhalable nano-embedded microparticles for the treatment of bacterial pneumonia. Costabile, G., Mitidieri, E., Visaggio, D., et al.[2022]

Gallium nitrate has shown promising antitumor activity in various murine tumor models and has demonstrated effectiveness in treating refractory lymphomas and small cell lung carcinoma in limited phase II evaluations, with response rates of 28% and 11%, respectively.

The primary dose-limiting toxicity of gallium nitrate is renal, but this can be managed through hydration and osmotic diuresis, allowing for the administration of effective doses with a low risk of kidney damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gallium nitrate: the second metal with clinical activity. Foster, BJ., Clagett-Carr, K., Hoth, D., et al.[2016]

Gallium nitrate shows promise as an antibacterial treatment against Pseudomonas aeruginosa, with low rates of resistance observed in clinical isolates, making it a potential alternative for treating infections.

In a resistant strain of P. aeruginosa, mechanisms of resistance were linked to increased antioxidant enzyme activity and gallium efflux, indicating that while resistance can develop, the strain still retains the ability to accumulate gallium initially.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of gallium resistance induced in a Pseudomonas aeruginosa cystic fibrosis isolate. Tovar-García, A., Angarita-Zapata, V., Cazares, A., et al.[2020]

Gallium nitrate shows potential as an antitumor agent for small cell lung cancer due to its ability to bind transferrin, which is overexpressed in most small cell carcinoma cell lines.

In a phase I study, the maximum tolerated dose was 400 mg/m2/day, with nausea being the main side effect, along with other effects like elevated serum creatinine and hypocalcemia, indicating a need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of gallium nitrate in previously treated patients with small cell lung cancer. Baselga, J., Kris, MG., Scher, HI., et al.[2019]

Gallium (Ga(III)) compounds show promise as effective antimicrobials against various pulmonary pathogens in cystic fibrosis patients, with all tested pathogens except Streptococcus pneumoniae being susceptible to at least one Ga(III) compound.

The study identified specific Ga(III) compounds that are particularly effective against certain bacteria, suggesting that Ga(III)-based therapies could be developed as a broad-spectrum treatment strategy for lung infections in cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Variable Susceptibility to Gallium Compounds of Major Cystic Fibrosis Pathogens. Visaggio, D., Frangipani, E., Hijazi, S., et al.[2022]

Gallium nitrate (Ganite) shows promise as a treatment for Pseudomonas aeruginosa infections, with research identifying key pathways for how the bacteria take up gallium ions (Ga3+).

The study reveals that Ga3+ and Fe3+ compete for the same binding site in a protein involved in the bacteria's nutrient transport system, providing important insights for developing gallium-based antimicrobial therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification and Characterization of a Metalloprotein Involved in Gallium Internalization in Pseudomonas aeruginosa. Guo, Y., Li, W., Li, H., et al.[2020]

In a phase I-II clinical trial of gallium nitrate involving bolus administration, dose-limiting renal toxicity was observed at doses above 700 mg/m2, while hematological toxicity was minimal, indicating a need for careful dosing to avoid kidney damage.

The phase II trial showed antitumor responses in three patients with soft tissue sarcoma and small cell lung carcinoma, suggesting potential efficacy, especially when administered every 2 weeks with hydration to reduce nephrotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I-II clinical trial of gallium nitrate (NSC-15200). Samson, MK., Fraile, RJ., Baker, LH., et al.[2016]

Intravenous gallium therapy effectively limits the growth of Pseudomonas aeruginosa biofilms in cystic fibrosis patients by competing with iron for binding to siderophores, making it a promising non-antibiotic treatment option.

Research using Density-Functional Theory indicates that gallium cannot easily replace calcium in the biofilm's exopolysaccharide matrix, suggesting that gallium may enter siderophore-deficient bacteria through a novel mechanism, potentially enhancing its therapeutic effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A DFT study of the gallium ion-binding capacity of mature Pseudomonas aeruginosa biofilm extracellular polysaccharide. Hills, OJ., Poskrobko, Z., Scott, AJ., et al.[2023]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Boosting lung accumulation of gallium with inhalable nano-embedded microparticles for the treatment of bacterial pneumonia. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Gallium nitrate: the second metal with clinical activity. [2016]

3. Germany pubmed.ncbi.nlm.nih.gov

Characterization of gallium resistance induced in a Pseudomonas aeruginosa cystic fibrosis isolate. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of gallium nitrate in previously treated patients with small cell lung cancer. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Variable Susceptibility to Gallium Compounds of Major Cystic Fibrosis Pathogens. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Identification and Characterization of a Metalloprotein Involved in Gallium Internalization in Pseudomonas aeruginosa. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Phase I-II clinical trial of gallium nitrate (NSC-15200). [2016]

8. United States pubmed.ncbi.nlm.nih.gov

A DFT study of the gallium ion-binding capacity of mature Pseudomonas aeruginosa biofilm extracellular polysaccharide. [2023]