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)

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.

Inclusion Criteria:

1. Adult male or female, between 18 and 55 years of age

2. Documented chronic colonization with Pseudomonas Aeruginosa (Pa)

3. Confirmed diagnosis of CF:

   1. Documented history of > 60 mmol/L chloride concentration in pilocarpine sweat chloride test And/Or
   2. Genotype with two identifiable mutations consistent with CF, accompanied by one or more phenotypic features consistent with diagnosis of CF

4. Forced expiratory volume in the first second (FEV1) ≥ 30% of predicted value

5. Able to expectorate sputum

6. Serum liver function tests ≤ 2.5 x upper limit of normal

7. Serum urea nitrogen (BUN) and creatinine ≤ 1.5 x upper limit of normal

8. Serum creatinine ≤ 2.0 mg/dl

9. Hemoglobin ≥ 9 g/dl, platelets ≥ 100,000/mm3, and white blood cells (WBC) ≥ 4,500/mm3 and ≤ 15,000/mm3

10. Ionized calcium ≥ the lower limit of normal

11. Able to understand and sign the informed consent document, communicate with the Investigator, and comply with the requirements of the protocol

12. If female and of childbearing potential, must have a negative pregnancy test on Day 1 prior to receiving study drug

13. 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:

1. Acute pulmonary exacerbation requiring antibiotic intervention within 2 weeks prior to screening
2. Osteoporosis defined as the most recent dexa scan within the prior 5 years with a T-score ≤ -2.5
3. Pregnant or lactating female
4. Known sensitivity to gallium
5. Use of biphosphonates
6. Use of any investigational drug and/or participated in any clinical trial within 3 months prior to screening

Patients were adults age 18 years but less than 55 years of age with CF and chronic Pseudomonal infection. Patient had to have a baseline FEV1% of predicted greater than or equal to 30%. They had to have been at least 14 days from the end of treatment with intravenous antibiotics for exacerbation. They could not be lactating or pregnant.

56 days

At study visits, all body systems were assessed for adverse events. Serious adverse events were assessed at all study visits and participants were told to inform their research team of any serious adverse events occurring between study visits.

The primary limitation of our study was that it was uncontrolled without a blinded placebo. Thus, subjective endpoints could have been biased by either the subjects or the investigators.