A Phase 1, Open-Label, Single Center, Dose Escalation Study of the Safety and Pharmacokinetics of mAb AZD5396 and mAb AZD8076 Delivered as dMAbs in Healthy Adults
Overview
- Phase
- Phase 1
- Intervention
- dMAb AZD5396
- Conditions
- Healthy Volunteers
- Sponsor
- Pablo Tebas
- Enrollment
- 61
- Locations
- 1
- Primary Endpoint
- Evaluation of the pain experienced by the participant
- Status
- Completed
- Last Updated
- 3 months ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Pablo Tebas
Professor of Medicine. University of Pennsylvania
University of Pennsylvania
Eligibility Criteria
Inclusion Criteria
- •Age 18-60 years.
- •Able to provide consent to participate and having signed an Informed Consent Form (ICF).
- •Able and willing to comply with all study procedures.
- •Body mass index (BMI) between 20 and 31, inclusive.
- •Screening laboratory must be within normal limits or have only Grade 0-1 findings.
- •Normal screening ECG or screening ECG with no clinically-significant findings.
- •Women of child-bearing potential agree to one of the following:
- •use medically effective contraception (oral contraception, barrier methods, spermicide, etc.)
- •have a partner who is sterile from enrollment to 6 months following the last injection
- •have a partner who is medically unable to induce pregnancy Abstinence is acceptable per Investigator discretion and as long as it is documented that the subject will use medically effective contraception when engaging in sexual activities and notifies the study team.
Exclusion Criteria
- •Administration of an investigational compound either currently or within 6 months of first dose.
- •Administration of any vaccine within 4 weeks of first dose.
- •Administration of a SARS-CoV-2 vaccine in the last 14 days or plans to have any standard of care vaccines within 14 days form the last administration of study products.
- •Positive SARS-CoV-2 infection at screening visit.
- •Administration of any monoclonal or polyclonal antibody product within 4 weeks of the first dose.
- •Administration of any blood product within 3 months of first dose.
- •Co-morbid conditions including poorly-controlled diabetes (HbA1C \> 7), poorly-controlled hypertension (BP \> 140/95 repeatedly), asthma, and any cardiovascular disease.
- •Pregnancy or breast feeding or plans to become pregnant during the course of the study.
- •Positive serologic test for hepatitis B surface antigen (HBsAg); or any potentially communicable infectious disease as determined by the Principal Investigator or Medical Director.
- •Positive serologic test for hepatitis C (exception: successful treatment with confirmation of sustained virologic response);
Arms & Interventions
Cohort A1 - 1x 0.5 mg
Participants (n=3) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 0.5 mg of each plasmid.
Intervention: dMAb AZD5396
Cohort A1 - 1x 0.5 mg
Participants (n=3) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 0.5 mg of each plasmid.
Intervention: dMAb AZD8076
Cohort A1 - 1x 0.5 mg
Participants (n=3) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 0.5 mg of each plasmid.
Intervention: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device
Cohort A1 - 1x 0.5 mg
Participants (n=3) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 0.5 mg of each plasmid.
Intervention: Hylenex
Cohort A2 - 1x 1 mg
Participants (n=3) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 1 mg of each plasmid.
Intervention: dMAb AZD5396
Cohort A2 - 1x 1 mg
Participants (n=3) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 1 mg of each plasmid.
Intervention: dMAb AZD8076
Cohort A2 - 1x 1 mg
Participants (n=3) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 1 mg of each plasmid.
Intervention: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device
Cohort A2 - 1x 1 mg
Participants (n=3) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, for a total dose of 1 mg of each plasmid.
Intervention: Hylenex
Cohort B - 2x 0.5 mg
Participants (n=6) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
Intervention: dMAb AZD5396
Cohort B - 2x 0.5 mg
Participants (n=6) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
Intervention: dMAb AZD8076
Cohort B - 2x 0.5 mg
Participants (n=6) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
Intervention: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device
Cohort B - 2x 0.5 mg
Participants (n=6) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
Intervention: Hylenex
Cohort C - 2x 1 mg
Participants (n=6) will be administered 1mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
Intervention: dMAb AZD5396
Cohort C - 2x 1 mg
Participants (n=6) will be administered 1mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
Intervention: dMAb AZD8076
Cohort C - 2x 1 mg
Participants (n=6) will be administered 1mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
Intervention: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device
Cohort C - 2x 1 mg
Participants (n=6) will be administered 1mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
Intervention: Hylenex
Cohort D - 2x 0.25 mg
Participants (n=6) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
Intervention: dMAb AZD5396
Cohort D - 2x 0.25 mg
Participants (n=6) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
Intervention: dMAb AZD8076
Cohort D - 2x 0.25 mg
Participants (n=6) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
Intervention: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device
Cohort D - 2x 0.25 mg
Participants (n=6) will be administered 1 mg of dMAb AZD5396 and 1 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 2 mg of each plasmid.
Intervention: Hylenex
Cohort E - 2x 2 mg
Participants (n=5) will be administered 2 mg of dMAb AZD5396 and 2 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 4 mg of each plasmid.
Intervention: dMAb AZD5396
Cohort E - 2x 2 mg
Participants (n=5) will be administered 2 mg of dMAb AZD5396 and 2 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 4 mg of each plasmid.
Intervention: dMAb AZD8076
Cohort E - 2x 2 mg
Participants (n=5) will be administered 2 mg of dMAb AZD5396 and 2 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 4 mg of each plasmid.
Intervention: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device
Cohort E - 2x 2 mg
Participants (n=5) will be administered 2 mg of dMAb AZD5396 and 2 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0 and D3, for a total dose of 4 mg of each plasmid.
Intervention: Hylenex
Cohort F - 2x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0070 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
Intervention: dMAb AZD5396
Cohort F - 2x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0070 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
Intervention: dMAb AZD8076
Cohort F - 2x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0070 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
Intervention: Hylenex
Cohort F - 2x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0070 parameter on D0 and D3, for a total dose of 1 mg of each plasmid.
Intervention: CELLECTRA™ 2000 with Side Port needle, OpBlock 0070 Electroporation device
Cohort G - 4x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, D3, D28 and D31, for a total dose of 2 mg of each plasmid.
Intervention: dMAb AZD5396
Cohort G - 4x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, D3, D28 and D31, for a total dose of 2 mg of each plasmid.
Intervention: dMAb AZD8076
Cohort G - 4x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, D3, D28 and D31, for a total dose of 2 mg of each plasmid.
Intervention: CELLECTRA™ 2000 with Side Port needle, OpBlock 0078 Electroporation device
Cohort G - 4x 0.5 mg
Participants (n=5) will be administered 0.5 mg of dMAb AZD5396 and 0.5 mg of dMAb AZD8076 with Hylenex® delivered intramuscularly using the side port needle followed by electroporation (EP) with OpBlock 0078 parameter on D0, D3, D28 and D31, for a total dose of 2 mg of each plasmid.
Intervention: Hylenex
Outcomes
Primary Outcomes
Evaluation of the pain experienced by the participant
Time Frame: Immediately after EP, 5 minutes after EP and 10 minutes after EP
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.
Serum concentration of dMAb AZD5396 nm/mL.
Time Frame: Up to 72 Weeks after administration of the investigational products
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.
Frequency and nature of injection site reaction
Time Frame: 7 days after administration of the investigational products
Injection site reactions occurring up to 7 days after administration of the investigational product
Serum concentration of dMAb AZD8076 nm/mL.
Time Frame: Up to 72 Weeks after administration of the investigational products
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.
Frequency and nature of Serious Adverse Events
Time Frame: 72 Weeks after administration of the investigational products
SAE will be classified using the CTCAE v5 throughout the study
Evaluation of laboratory related adverse events
Time Frame: Up to 7 days after administration of the investigational product
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.
Frequency and nature of systemic reactions
Time Frame: 7 days after administration of the investigational products
Systemic reactions occurring up to 7 days after administration of the investigational product.