This is a Phase 1, open-label, single center, dose escalation study to evaluate the safety, tolerability and pharmacokinetic profile of mAb AZD5396 and mAb AZD8076 following delivery of optimized dMAb AZD5396 and dMAb AZD8076 with Hylenex® Recombinant, administered by intramuscular injection (IM) followed immediately by electroporation (EP) using the CELLECTRA™ 2000 with Side Port needle device, in a 2-dose regimen (Days 0 and 3) or a 4-dose regimen (Days 0, 3, 28 and 31) in healthy adults. The hypothesis is that the administration of dMAb AZD5396 and dMAb AZD8076 will be safe and associated with expression of mAb AZD5396 and mAb AZD8076 in serum.
The study will apply a single ascending dose (SAD) modified 3+3 design. Participants will be enrolled sequentially beginning with Cohort A1. The first participant in cohort A1 will be dosed on Day 0. If no stopping event (DLT) is observed after 14 days of the initial dose, the remaining two participants in that cohort will be dosed. If there are 0 DLT events after 14 days of the initial dosing of the third subject, enrollment will be completed, and then cohort A2 will open. Same process will be followed for Cohorts B, C and E. Because cohorts D, F \& G are a similar or lower dose and the safety profile would have been already established in previous cohorts, the 14-day waiting periods will not apply to Cohorts D, F or G. If one dose limiting toxicity (DLT) is observed in the first three participants enrolled in any cohort, an ad hoc DSMB will review the event and make a decision if the study should continue. If the DSMB agrees that the study should continue, the remaining participants will be enrolled in the cohort and dosed, but the next cohort will not open until the 28-day period of safety is completed. However, if any additional DLT occurs (i.e., \>1 DLT in 6 total participants in a given cohort), then that dose will be deemed not tolerated The following Investigational product administration- and/or EP-related adverse events are defined as DLTs: * Grade 3 or greater local injection site erythema, swelling, and/or induration recorded ≥ 1 hour after Investigational product administration * Pain or tenderness at the injection site that requires overnight hospitalization despite proper use of non-narcotic analgesics. * Grade 3 or greater systemic symptoms assessed by the Principal Investigator as related to Investigational product administration. * Grade 3 or greater clinically significant laboratory abnormalities assessed by the Principal Investigator as related to Investigational product administration.
Study Type
INTERVENTIONAL
Participants will receive one injection of dMAb AZD5396 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.
Participants will receive one injection of dMAb AZD8076 with Hylenex into the arm (deltoid)/leg (quadriceps) region followed by EP.
The device will be used to perform electroporation (EP) on each subject immediately after being dosed with dMAb AZD5396 and dMAb AZD8076.
University of Pennsylvania
Philadelphia, Pennsylvania, United States
Frequency and nature of injection site reaction
Injection site reactions occurring up to 7 days after administration of the investigational product
Time frame: 7 days after administration of the investigational products
Frequency and nature of systemic reactions
Systemic reactions occurring up to 7 days after administration of the investigational product.
Time frame: 7 days after administration of the investigational products
Frequency and nature of Serious Adverse Events
SAE will be classified using the CTCAE v5 throughout the study
Time frame: 72 Weeks after administration of the investigational products
Evaluation of the pain experienced by the participant
Visual analogue scale (VAS). A VAS consists of a horizontal line, 10 cm in length, anchored by word descriptors at each end (no pain = 0 cm; worst pain = 10 cm). The VAS score is determined by measuring in centimeters from the left hand end of the line to the point that the patient marks. Absolute initial value and change over time will be described.
Time frame: Immediately after EP, 5 minutes after EP and 10 minutes after EP
Evaluation of laboratory related adverse events
Laboratory AEs will be assessed and graded in accordance with the "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials", issued in September 2007.
Time frame: Up to 7 days after administration of the investigational product
Serum concentration of dMAb AZD5396 nm/mL.
The number and percentage of participants in which detection of monoclonal antibody dMAb AZD5396 in serum is achieved will be summarized with a point estimate and corresponding exact 90% Clopper- Pearson confidence interval. These will be summarized per time point within each cohort. We will also estimate the time to 50% decline from peak concentration.
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Allocation
NON_RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
61
Hylenex® recombinant will be used for dMAb AZD5396 and dMAb AZD8076 dose preparation at the clinical site.
The device will be used to perform electroporation (EP) on each subject immediately after being dosed with dMAb AZD5396 and dMAb AZD8076.
Time frame: Up to 72 Weeks after administration of the investigational products
Serum concentration of dMAb AZD8076 nm/mL.
The number and percentage of participants in which detection of monoclonal antibody dMAb AZD8076 in serum is achieved will be summarized with a point estimate and corresponding exact 90% Clopper- Pearson confidence interval. These will be summarized per time point within each cohort. We will also estimate the time to 50% decline from peak concentration.
Time frame: Up to 72 Weeks after administration of the investigational products