A Pharmacokinetic and Safety Study of IV Gallium Nitrate (Ganite) in Cystic Fibrosis Patients

Study Overview
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Brief Summary
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The purpose of this research study is to test the pharmacokinetics, safety, and tolerability of an intravenous infusion of a drug called Ganite (gallium nitrate) in patients with cystic fibrosis. We want to see this drug is safe and tolerable and to see if high levels of the drug are found in the sputum. Funding Source - Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD)

Detailed Description
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This is a two center pharmacokinetic and safety dosing study of IV gallium nitrate (Ganite®) in cystic fibrosis (CF) patients. Eighteen subjects are planned. Each subject will be administered a single 5-day infusion of study medication (one of 2 doses). No placebo is used. Each subject will receive 5 days of continuous infusion of the experimental treatment. There will be two dosing cohorts (cohort 1: 100 mg/m2/day and cohort 2: 200 mg/m2/day). Cohort 2 will begin enrollment only after Data Safety Monitoring Committee (DSMC) safety review and approval of cohort 1 data. Study visits occur at baseline (day 1), day 3 (visit 2), day 6 (visit 3), day 8 (visit 4), day 14 (visit 5), day 28 (visit 6), and day 56 (visit 7). Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion criteria and none of the exclusion criteria will be entered into the study. The following treatment regimens will be used: • Experimental treatment continuous infusion of gallium nitrate at the following doses cohort 1: 100 mg/m2/day and cohort 2: 200 mg/m2/day All subjects who receive at least one dose of study medication will be considered evaluable for safety and efficacy analyses. Incidence of adverse events will be monitored during the trial. Primary endpoints will be assessment of pharmacokinetic and safety/tolerability data. Secondary efficacy assessments will be based on changes in lung function and sputum P. aeruginosa density in sputum. Total duration of subject participation will be five weeks. Total duration of the study is expected to be 20 months.

Official Title
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A Pharmacokinetic and Safety Study of IV Gallium Nitrate (Ganite) in Cystic Fibrosis Patients

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: 100 mg/m2 dose
* Drug: 200 mg/m2 dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female, between 18 and 55 years of age Documented chronic colonization with Pseudomonas Aeruginosa (Pa) Confirmed diagnosis of CF: Documented history of > 60 mmol/L chloride concentration in pilocarpine sweat chloride test And/Or Genotype with two identifiable mutations consistent with CF, accompanied by one or more phenotypic features consistent with diagnosis of CF Forced expiratory volume in the first second (FEV1) ≥ 30% of predicted value Able to expectorate sputum Serum liver function tests ≤ 2.5 x upper limit of normal Serum urea nitrogen (BUN) and creatinine ≤ 1.5 x upper limit of normal Serum creatinine ≤ 2.0 mg/dl Hemoglobin ≥ 9 g/dl, platelets ≥ 100,000/mm3, and white blood cells (WBC) ≥ 4,500/mm3 and ≤ 15,000/mm3 Ionized calcium ≥ the lower limit of normal Able to understand and sign the informed consent document, communicate with the Investigator, and comply with the requirements of the protocol If female and of childbearing potential, must have a negative pregnancy test on Day 1 prior to receiving study drug If female and of childbearing potential, is willing to use adequate contraception, as determined by the investigator, for the duration of the study Exclusion Criteria: Acute pulmonary exacerbation requiring antibiotic intervention within 2 weeks prior to screening Osteoporosis defined as the most recent dexa scan within the prior 5 years with a T-score ≤ -2.5 Pregnant or lactating female Known sensitivity to gallium Use of biphosphonates Use of any investigational drug and/or participated in any clinical trial within 3 months prior to screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 100 mg/m2 dose<br>Five day continuous IV Gallium Nitrate (Ganite®) infusion at 100 mg/m2 | Drug: 100 mg/m2 dose<br>* 5 day infusion of gallium nitrate (IV Ganite®) at a dose of 100 mg/m2/day<br>* Other names: gallium nitrate;|
| Experimental: 200 mg/m2 dose<br>Five day continuous IV Gallium Nitrate (Ganite®) infusion at 200 mg/m2 | Drug: 200 mg/m2 dose<br>* 5 day infusion of gallium nitrate (IV Ganite®) at 200 mg/m2/day<br>* Other names: gallium nitrate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Assessment of a 5 Day Infusion of Gallium Nitrate (IV Ganite®) | To assess the summed area under the curves of a 5 day infusion of IV Ga from day 1 to day 28 at two doses: 100 mg/m2/day in adult subjects with CF; 200 mg/m2/day in adult subjects with CF. To assess the safety of a 5 day infusion of IV Ga at two doses: 100 mg/m2/day in adult subjects with CF; 200 mg/m2/day in adult subjects with CF. Safety and tolerability of 5 days of treatment with IV administered gallium nitrate (IV Ganite®) at a doses of 100 mg/m2/day and 200 mg/m2/day. | Day 1 at t=1, 2 and 6 hours, Day 3, Day 6 at t= 1, 2, 8, and 12, Day 14 and Day 28 | 
| Number of Serious Adverse Events | Safety as measured by serous adverse events | 56 days from starting dose | 
| Number of Events When Study Drug Infusion Was Stopped Early | Tolerability as measured by adverse events of a 5 day continuous infusion of IV Gallium as assessed by stopping study drug infusion | 6 days from starting dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Spirometry From Baseline to Day 8 | Change in spirometry as measured by FEV1 in liters from baseline to day 8 | 8 days | 
| Change in Lung Function From Baseline to Day 15 | Change in FEV1 in liters from baseline to day 15 | 15 days from starting dose | 
| Change in Spirometry From Baseline to Day 28 | Change in lung function as measured by FEV1 in liters from baseline to day 28 | 28 days from starting dose | 
| Change in Spirometry From Baseline to Day 56 | Change in lung function as measured by FEV1 in liters from baseline to day 56 | 56 days from starting dose | 
| Change in Spirometry as Measured by FVC From Baseline to Day 8 | Change from baseline in lung function assessed by FVC in liters after treatment with IV Ga at day 8 | 8 days from starting dose | 
| Change in P. Aeruginosa Density From Baseline to Day 8 | Change in sputum microbiology (specifically P. aeruginosa density based on quantitative cultures) from baseline to day 8 | 8 days from starting dose | 
| Change in Sputum P. Aeruginosa Density From Baseline to Day 15 | Change in sputum microbiology (specifically P. aeruginosa density based on quantitative cultures) from baseline to day 15 | 15 days from starting dose | 
| Change in P. Aeruginosa Density From Baseline to Day 56 | Change in sputum microbiology (specifically P. aeruginosa density based on quantitative cultures) from baseline to day 56 | 56 days from starting dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IV Gallium, Gallium, Ganite, Cystic Fibrosis, Gallium Infusion