Phase I Randomized Study of Adeno-Associated Virus-CFTR Vector in Patients With Cystic Fibrosis
Phase I Randomized Study of Adeno-Associated Virus-CFTR Vector in Patients With Cystic Fibrosis
OBJECTIVES:

 I. Determine the maximum tolerated dose of recombinant adeno-associated virus-CFTR vector in
 patients with cystic fibrosis.

 II. Assess the safety of this gene therapy in these patients.

 III. Assess the in vivo gene transfer of this vector in these patients.

 IV. Assess the CFTR gene expression and physiologic activity following gene transfer in these
 patients.

 V. Assess the clinical impact of CFTR gene expression following gene transfer in these
 patients.

 VI. Monitor patient immune response directed against CFTR or vector components following
 vector administration.
PROTOCOL OUTLINE:

 This is a randomized, dose escalation, double blind, placebo controlled, multicenter study.
 Patients are randomized to receive either adeno-associated virus-CFTR (AAV-CFTR) vector or
 placebo.

 Patients undergo tests on days -10 to -4 to rule out adenovirus and adeno-associated virus
 infections. Patients then receive AAV-CFTR vector intranasally to the right or left inferior
 turbinates and placebo to the other side of the nose. The next day, patients receive an
 endobronchial dose of AAV-CFTR vector to the superior segment of the right lower lobe.

 Cohorts of 2-4 patients each receive escalating doses of AAV-CFTR vector until the maximum
 tolerated dose (MTD) is determined. The MTD is defined as the dose level immediately
 preceding the dose at which at least 2 subjects develop dose limiting toxicity.

 Patients are followed at day 10, then at 1, 2, 3, 6, 9, and 12 months.
PROTOCOL ENTRY CRITERIA:

 --Disease Characteristics--

 Diagnosis of cystic fibrosis (CF) with mild to moderate lung disease; FVC at least 60%
 predicted; Schwachman-Kulczycki score at least 65; Sweat chloride greater than 60 mEq/L

 All CF genotypes allowed

 No sputum colonization with Burkholderia cepacia or another multiply resistant organism

 No recurrent or intermittent hemoptysis; At least 1 year since significant hemoptysis
 requiring transfusion or embolization OR Coughing of greater than 30 mL of blood more often
 than once a week

 --Prior/Concurrent Therapy--

 At least 30 days since hospitalization or home intravenous antibiotic therapy for pulmonary
 exacerbation

 No concurrent investigational drugs or therapy

 --Patient Characteristics--

 Other: No concurrent cigarette smoking; Not pregnant or nursing; Negative pregnancy test;
 Fertile patients must use effective contraception