Effect of AdhAQP1 on Salivary Flow in Patients Treated With Radiation for Head and Neck Cancer
| Status: | Completed |
|---|---|
| Conditions: | Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 9/13/2018 |
| Start Date: | September 1, 2006 |
| End Date: | September 5, 2018 |
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
This study will examine whether the experimental drug AdhAQP1 can increase salivary flow in
patients whose parotid glands have been exposed to therapeutic radiation for treatment of
head and neck cancer. Radiation may damage the parotid glands (salivary glands located under
the skin in front of the ear), leading to dry mouth, infections, excessive tooth decay, mouth
sores, difficulty swallowing and pain. AdhAQP1 contains the human aquaporin-1 gene, which
codes for a protein that works to transport water across cells, and a virus that normally can
cause colds in humans, but is modified to render it ineffective. In animal experiments,
AdhAQP1 has increased saliva production for a short time.
Patients between 18 years of age or older who received radiation treatment for head and neck
cancer at least 5 years before enrolling in this study, who have no evidence of recurrent
tumor, who have dry mouth and who secrete abnormally low levels of saliva from the parotid
glands may be eligible for this study. Candidates are screened with a medical history,
physical examination, blood, urine and saliva tests, electrocardiogram (EKG), chest x-ray,
MRI exam, gallium scan (a nuclear medicine test to look for inflammation in the salivary
glands), technetium pertechnetate scan (a nuclear medicine test to examine salivary gland
function), parotid sialogram (x-ray of parotid gland), PET and CT scans to look for signs of
tumor and a skin biopsy to collect skin cells for use in immunological tests.
Participants have a salt and sugar solution infused through a catheter (plastic tube) into
both parotid glands. After 10 minutes, the solution drains into the mouth and is swallowed.
Saliva is collected from the parotid glands at 6 and 24 hours after administration of the
salt and sugar solution. Ten to 14 days later, patients are admitted to the NIH Clinical
Center for up to 4 days for the following tests and procedures:
- On the first day, administration, through a catheter, of the study drug AdhAQP1 into one
parotid gland.
- Monitoring over the next 3 days for changes in patients' ability to produce saliva. This
includes medical examinations and several blood, urine and saliva collections.
- Technetium scan on day 2.
- Gallium scan on day 2.
Patients return to NIH for follow-up visits at 1, 2, 4, and 6 weeks after the AdhAQP1
infusion and then 3, 4, 5, 6 and 12 months for a medical examination and blood, urine and
saliva collections. Gallium, technetium and MRI scans are repeated at several of the
follow-up visits, and sialograms are done at 6 and 12 months. Chest x-ray and EKG are
repeated at 4 and 6 months.
patients whose parotid glands have been exposed to therapeutic radiation for treatment of
head and neck cancer. Radiation may damage the parotid glands (salivary glands located under
the skin in front of the ear), leading to dry mouth, infections, excessive tooth decay, mouth
sores, difficulty swallowing and pain. AdhAQP1 contains the human aquaporin-1 gene, which
codes for a protein that works to transport water across cells, and a virus that normally can
cause colds in humans, but is modified to render it ineffective. In animal experiments,
AdhAQP1 has increased saliva production for a short time.
Patients between 18 years of age or older who received radiation treatment for head and neck
cancer at least 5 years before enrolling in this study, who have no evidence of recurrent
tumor, who have dry mouth and who secrete abnormally low levels of saliva from the parotid
glands may be eligible for this study. Candidates are screened with a medical history,
physical examination, blood, urine and saliva tests, electrocardiogram (EKG), chest x-ray,
MRI exam, gallium scan (a nuclear medicine test to look for inflammation in the salivary
glands), technetium pertechnetate scan (a nuclear medicine test to examine salivary gland
function), parotid sialogram (x-ray of parotid gland), PET and CT scans to look for signs of
tumor and a skin biopsy to collect skin cells for use in immunological tests.
Participants have a salt and sugar solution infused through a catheter (plastic tube) into
both parotid glands. After 10 minutes, the solution drains into the mouth and is swallowed.
Saliva is collected from the parotid glands at 6 and 24 hours after administration of the
salt and sugar solution. Ten to 14 days later, patients are admitted to the NIH Clinical
Center for up to 4 days for the following tests and procedures:
- On the first day, administration, through a catheter, of the study drug AdhAQP1 into one
parotid gland.
- Monitoring over the next 3 days for changes in patients' ability to produce saliva. This
includes medical examinations and several blood, urine and saliva collections.
- Technetium scan on day 2.
- Gallium scan on day 2.
Patients return to NIH for follow-up visits at 1, 2, 4, and 6 weeks after the AdhAQP1
infusion and then 3, 4, 5, 6 and 12 months for a medical examination and blood, urine and
saliva collections. Gallium, technetium and MRI scans are repeated at several of the
follow-up visits, and sialograms are done at 6 and 12 months. Chest x-ray and EKG are
repeated at 4 and 6 months.
The treatment of most head and neck cancer patients includes ionizing radiation (IR).
Salivary glands in the IR field suffer irreversible damage. There is no conventional
treatment available to correct this condition. Our research group has been developing the
AdhAQP1 recombinant serotype 5 adenoviral (rAd5) vector based on the hypothesis that a
replication deficient rAd5 vector is capable of safely transferring the human aquaporin-1
(hAQP1) cDNA to parotid glands of adult patients with IR-induced salivary hypofunction,
resulting in an elevated salivary output, albeit transiently. Salivary glands have proven to
be valuable gene transfer targets in numerous pre-clinical animal model studies. hAQP1, the
archetypal water channel, is a plasma membrane protein that facilitates water movement across
lipid bilayers. Rat and minipig studies have clearly shown that the AdhAQP1 strategy for
restoring salivary flow to IR-damaged salivary glands is effective, and studies in rats,
non-human primates and minipigs have shown that AdhAQP1 and similar rAd5 vectors are without
significant untoward effects after salivary gland delivery. The purpose of this clinical
protocol is to test the safety of AdhAQP1, with some measures of efficacy, in adult patients
with established IR-induced parotid gland hypofunction. The targeted tissue site for the
AdhAQP1 vector in the proposed study is a single parotid gland. In this Phase 1
dose-escalation study, safety will be evaluated using conventional clinical and immunological
parameters. The primary outcome measure for biological efficacy will be parotid gland
salivary output.
Salivary glands in the IR field suffer irreversible damage. There is no conventional
treatment available to correct this condition. Our research group has been developing the
AdhAQP1 recombinant serotype 5 adenoviral (rAd5) vector based on the hypothesis that a
replication deficient rAd5 vector is capable of safely transferring the human aquaporin-1
(hAQP1) cDNA to parotid glands of adult patients with IR-induced salivary hypofunction,
resulting in an elevated salivary output, albeit transiently. Salivary glands have proven to
be valuable gene transfer targets in numerous pre-clinical animal model studies. hAQP1, the
archetypal water channel, is a plasma membrane protein that facilitates water movement across
lipid bilayers. Rat and minipig studies have clearly shown that the AdhAQP1 strategy for
restoring salivary flow to IR-damaged salivary glands is effective, and studies in rats,
non-human primates and minipigs have shown that AdhAQP1 and similar rAd5 vectors are without
significant untoward effects after salivary gland delivery. The purpose of this clinical
protocol is to test the safety of AdhAQP1, with some measures of efficacy, in adult patients
with established IR-induced parotid gland hypofunction. The targeted tissue site for the
AdhAQP1 vector in the proposed study is a single parotid gland. In this Phase 1
dose-escalation study, safety will be evaluated using conventional clinical and immunological
parameters. The primary outcome measure for biological efficacy will be parotid gland
salivary output.
- 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
Sj(SqrRoot)(Delta)gren 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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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