a phase 1 open-label, dose escalation study to determine the optimal dose, safety, and activity of aav2haqp1 in subjects with radiation-induced parotid gland hypofunction and xerostomia

Conditions: Radiation-Induced Parotid Gland Hypofunction; Xerostomia Due to Radiotherapy; Head and Neck Cancer

Summary: open-label, non-randomized, dose escalation trial of aav2haqp1 administered via stensen's duct to a single or both parotid glands in subjects with radiation-induced xerostomia the objectives are to evaluate the safety and identify either a maximum tolerated dose or a maximum feasible dose of a single dose of aav2haqp1 infused into one or both parotid glands: to evaluate subject improvement of xerostomia symptoms, to evaluate the increase in parotid gland salivary output after treatment with aav2haqp1, to evaluate additional efficacy outcomes.


Eligibility criteria:
inclusion criteria: 1. male or female subjects ≥18 years of age. 2. history of radiation therapy for head and neck cancer. 3. abnormal parotid gland function as judged by both absence of unstimulated parotid salivary flow and a stimulated parotid salivary flow in the targeted parotid gland \>0 and \<0.3 ml/min/gland after 2% citrate stimulation. 4. no evidence of recurrence of the primary malignancy by an otolaryngology (ears, nose, and throat \[ent\]) assessment. additionally, all subjects must be disease-free of head and neck cancer for at least 5 years following the end of treatment at screening, with the exception of subjects with a history of hpv+ opc (base of tongue, oropharynx, pharynx, soft palate, tonsil) who must be disease free for at least 2 years following the end of treatment. disease status will be determined by negative clinical examinations and computed tomography (ct) scans of the neck and chest. if subjects have had a magnetic resonance imaging (mri) of the neck or a positron emission tomography (pet) scan within 6 months of screening, then a ct scan is not required, except for hpv+ opc subjects who must have scans at 2 years post treatment. 5. female subjects of childbearing potential (i.e., ovulating, pre-menopausal, and not surgically sterile) and all male subjects must use a medically accepted contraceptive regimen during their participation in the study and until all samples collected at 2 consecutive visits following aav2haqp1 administration are negative. acceptable methods of contraception for male subjects include the following: * condoms with spermicide. acceptable methods of contraception for female subjects include the following: * intrauterine device for at least 12 weeks prior to screening. * hormonal contraception (oral, implant, injection, ring, or patch) for at least 12 weeks prior to screening. * diaphragm used in combination with spermicide. exclusion criteria: 1. pregnant or lactating women or women planning to become pregnant. 2. any experimental therapy within 3 months before day 1. 3. active infection that requires the use of intravenous antibiotics and does not resolve at least 1 week before day 1. 4. uncontrolled ischemic heart disease (i.e., unstable angina, evidence of active ischemic heart disease on electrocardiogram \[ecg\]). 5. history of systemic autoimmune diseases affecting the salivary glands. 6. use of systemic immunosuppressive medications (i.e., corticosteroids). o note: topical, inhaled, or intranasal corticosteroids are allowed. 7. malignancy, other than head and neck cancer, within the past 3 years, with the exception of adequately treated basal cell or squamous cell carcinoma of the skin or in situ cervical carcinoma. 8. active infections including, epstein-barr virus (ebv), cytomegalovirus (cmv), hepatitis b (hbv), hepatitis c (hcv), or human immunodeficiency virus (hiv) infection. 9. white blood cell count \<3000/μl, absolute neutrophil count \<1500/μl, hemoglobin \<10.0 g/dl, platelet count \<100,000/μl, or absolute lymphocyte count ≤500/μl. 10. alanine aminotransferase and/or aspartate aminotransferase \>1.5 × the upper limit of normal (uln), alkaline phosphatase \>1.5 × uln, or total bilirubin \>1.5 × uln with any elevation of liver enzymes. 11. estimated glomerular filtration rate \<60 ml/min/1.73 m2 using the modification of diet in renal disease equation. 12. active use of tobacco products as determined by self-reporting. 13. allergy to iodine or shellfish, and thus unable to have sialographic evaluations. 14. allergy or hypersensitivity to glycopyrrolate.