Open-Label, Dose-Escalation Study Evaluating the Safety of a Single Administration of AdhAQP1, an Adenoviral Vector Encoding Human Aquaporin-1 to One Parotid Salivary Gland in Individuals With Irradiation-Induced Parotid Salivary Hypofunction

Inclusion Criteria

- INCLUSION CRITERIA:

1. 18 years of age or older.

2. Capable of providing informed consent.

3. History of radiation therapy for head and neck cancer, having received > 45Gy to
the parotid gland(s) due to primary or neck radiation.

4. Abnormal parotid gland function in the targeted parotid gland as judged by
absence of unstimulated parotid salivary flow and a stimulated parotid salivary
flow in the targeted parotid gland < 0.2 mL/min/gland after 2% citrate
stimulation.

5. Abnormal (99m)TcO4 scintiscan (reduced or absent uptake of (99m)TcO4) for the
targeted parotid gland in the following circumstance: A (99m)TcO4 scintiscan
will only be performed and used to determine eligibility if the isotope is
available. If the isotope is not available, this inclusion criterion is not
applicable.

6. Abnormal sialogram (an altered ductal network with sialectasis) for the targeted
parotid gland.

7. No current evidence of malignancy by otolaryngology assessment, including a
clinical history, nasopharyngolaryngoscopy, and negative CT or PET scan (e.g.
reference 58).

8. Absence of shedding wild type adenovirus in the saliva sample collected from the
targeted gland at the pre-dose visit 1. Specifically, an aliquot of the
pre-dose visit 1 saliva sample from the target parotid gland will be used to
infect A549 cells to test for the presence of shedding WT Ad virus. If
infectious virus emerges during the subsequent 7-10 day follow-up period, then
the participant will no longer be eligible for treatment and will be withdrawn
from the study. However, if no cytopathic effects are observed over a 7-10 day
period, the participant may be treated provided all other eligibility criteria
are met. If stimulated saliva cannot be collected at the pre-dose visit 1, this
inclusion criterion is not applicable.

9. Must be disease-free for at least 5 years, with the disease-free interval
calculated from date of last cancer treatment (i.e., date of last radiation,
chemotherapy or surgery) to date of pre-dose visit 1.

10. Willingness to practice the required birth control method ("barrier"
contraception, i.e., condoms, diaphragm) until AdhAQP1 is no longer detectable
in their serum or saliva. Women who cannot bear children (post menopausal or
due to a surgical intervention) also will be required to practice barrier birth
control methods until AdhAQP1 is no longer detectable in their serum or saliva.

11. Able to stay at the NIH hospital for the period of time necessary to complete
each on-site phase of the protocol.

12. No history of allergies to any medications or agents to be used in this
protocol.

13. On stable doses of medications (greater than or equal to 2 months from the
pre-dose visit 1) for any underlying medical conditions.

EXCLUSION CRITERIA:

1. Pregnant or lactating women. Women of childbearing potential are required to have a
negative serum pregnancy test at pre-dose visit 1 and a negative urine pregnancy test
within 24 hours of treatment.

2. Any experimental therapy within 3 months of planned AdhAQP1 administration (Day 1).

3. Any active respiratory tract infection in the 3 weeks prior to planned AdhAQP1
administration (Day 1).

4. Active infection that requires the use of intravenous antibiotics and does not
resolve at least 1 week before planned AdhAQP1 administration (Day 1).

5. Evidence of active substance or alcohol abuse or history of substance or alcohol
abuse within two years of pre-dose visit 1.

6. Uncontrolled ischemic heart disease: unstable angina, evidence of active ischemic
heart disease on ECG, congestive heart failure (left ventricular ejection fraction <
45% on MUGA or echo) or cardiomyopathy.

7. Asthma or chronic obstructive pulmonary disease requiring regular inhaled or systemic
corticosteroids.

8. Individuals taking prescription medications (anti-cholinergics, anti-depressants)
likely to result in salivary hypofunction.

9. Individuals with a history of autoimmune diseases affecting salivary glands,
including Sjogren's syndrome, lupus, scleroderma, type 1 diabetes, sarcoidosis,
amyloidosis, and chronic graft versus host disease.

10. Use of systemic immunosuppressive medications, e.g., corticosteroids. Topical
corticosteroids are allowed.

11. History of a second malignancy, within the past 3 years, with the exception of
adequately treated basal cell or squamous cell carcinoma of the skin or in situ
carcinoma of the cervix.

12. Active hepatitis B, hepatitis C or HIV infection tested using blood collected at
pre-dose visit 1.

13. WBC < 3000/microL or ANC < 1500/microL or Hgb < 10.0 g/dL or platelets <
100,000/microL or absolute lymphocyte count less than or equal to 500/microL using
blood collected at pre-dose visit 2.

14. ALT and/or AST > 1.5 times the upper limit of normal (ULN) or alkaline phosphatase >
1.5 times ULN using blood collected at pre-dose visit 2.

15. Serum creatinine > 2 mg/dL using blood collected at pre-dose visit 2.

16. Individuals who are active smokers.

17. Individuals who consume more than one alcoholic beverage/day.

18. Individuals who have an allergy to iodine or shellfish and thus are unable to have
sialographic evaluations.

19. Individuals whose targeted parotid duct is not clinically accessible on screening
sialography evaluations.

20. Individuals who on sialography have a distal stenosis in the targeted parotid gland
that would impede vector delivery.

21. Individuals who likely would require use of a general anesthetic for ultrasound-
guided core needle biopsy (applicable only for participants in dose cohorts 2-5).

22. Significant concurrent or recently diagnosed (< 2 months from Day 1) medical
condition that, in the opinion of the Medically Responsible Investigator, could
affect the participant's ability to tolerate or complete the study.

23. Live vaccines within 4 weeks of first infusion.

24. Previous participation in a rAd5 vector gene transfer study.