Study Design:
This is a phase 1, open-label, dose-escalation trial to assess the safety and feasibility of administering CGD-Grans to adult patients with X-linked CGD and to identify the maximum tolerated dose (MTD). Subjects will undergo granulocyte-enriched apheresis to provide cell product for mRNA-correction and then receive 1 administration of study agent. The first subjects enrolled will receive the study agent at the lowest dose, and when a level has been determined to be safe, the dose level will be increased to a second and then third dose level for subsequent subjects.Subjects will be hospitalized for at least 3 days after study agent administration and will return for a final study visit about 3 months after administration. Blood will be collected regularly for safety and research evaluations. The study hypothesis is that it is safe and feasible to administer mRNA-transfected autologous granulocyte-enriched apheresis product to restore protein expression and phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function in patients with CGD.
Study Agent Description:
The study agent is one administration of autologous CGD mRNA transfected granulocyte-enriched cells, referred to as CGD-Grans. The study agent is derived from apheresis product enriched for granulocytes, which are then transfected with CGD mRNA and administered as an intravenous (IV) infusion. CGD-Grans will be evaluated using the 3+3 modified Fibonacci model at the following 3 escalating dosages:
Dose K: 1 x 10\^6 granulocyte-enriched cells/kg body mass
Dose K+1: 1 x 10\^7 granulocyte-enriched cells/kg body mass
Dose K+2: 1-5 x 10\^8 granulocyte-enriched cells/kg body mass
Each dose will be evaluated in at least 3 subjects. Dose escalation will be managed by a predetermined algorithm depending on the occurrence of drug-related toxicity (DRT). There will be at least 1 week between study agent administration to each subject.
Primary Objectives:
1. Determine the safety and feasibility of CGD-Grans infusion.
2. Determine an MTD for administration.
Secondary Objectives:
1. Assess efficacy of CGD-Grans at restoring NADPH oxidase.
2. Determine the kinetics of CGD-Grans.
Exploratory Objectives:
1. Assess for inflammatory responses to CGD-Grans infusion.
2. Assess for immune responses to protein expressed by the transfected mRNA.
3. Evaluate in vitro bactericidal activity of CGD-Grans.
Primary Endpoints:
1. Determine safety and feasibility by:
Safety: Frequency of grade 3 or greater adverse events (AEs) or serious adverse events (SAEs) related to the study agent.
Feasibility: Recruitment, implementation, and manufacturing of CGD-Grans for infusions.
2. MTD determination based on the rate of AEs. MTD is defined as the highest dose level that does not cause the same grade 3 or 4 AEs in 3 or more patients.
Secondary Endpoints:
1. Determine percent of circulating dihydrorhodamine (DHR) positive granulocytes following study agent infusion.
2. Serial measurement of circulating DHR+ granulocytes from peripheral blood until day 3 following study agent infusion or disappearance of DHR+ granulocytes.
Exploratory Endpoint:
1. Assess for increased expression of inflammation-related genes after study agent infusion.
2. Evaluate for development of antibodies against mRNA-expressed CGDphox.
3. Perform in vitro bactericidal activity of CGD-Grans.
