A Phase 1 Dose-escalation Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of the Monoclonal Antibody PGT121.414.LS Administered Alone and in Combination With VRC07-523LS Via Intravenous or Subcutaneous Infusions in Healthy, HIV-uninfected Adult Participants
Overview
- Phase
- Phase 1
- Intervention
- PGT121.414.LS
- Conditions
- HIV Infections
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 33
- Locations
- 5
- Primary Endpoint
- Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS via intravenous or subcutaneous infusions in healthy, HIV-uninfected adult participants.
Detailed Description
This study will evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS via intravenous (IV) or subcutaneous (SC) infusions in healthy, HIV-uninfected adult participants. The study will be conducted in two parts (Part A and B). Part A will include four groups (Groups 1, 2, 3, and 4) and Part B will include two groups (Groups 5 and 6). In Part A of the study, PGT121.414.LS will be administered via IV infusion at 3, 10, or 30 mg/kg (Groups 1-3) or via SC infusion at 5 mg/kg (Group 4). Participants in Part B will receive consecutive administration of PGT121.414.LS followed by VRC07-523LS, at 20 mg/kg IV each per dose (Group 5) or 5 mg/kg SC each per dose (Group 6). Participants will be followed for 32 weeks after the last study product administration via IV infusion and 24 weeks after the last study product administration via SC infusion. Participants in Groups 1, 2, and 3 will attend 8 months of study visits. Participants in Group 4 will attend 6 months of study visits. Part B participants will attend 16 months of study visits. Study visits may include physical examinations, blood and urine collection, and questionnaires.
Investigators
Eligibility Criteria
Inclusion Criteria
- •General and Demographic Criteria
- •Age of 18 to 50 years
- •Access to a participating Clinical Research Site (CRS) and willingness to be followed for the planned duration of the study
- •Ability and willingness to provide informed consent
- •Assessment of understanding: volunteer demonstrates understanding of this study and completes a questionnaire prior to first study product administration with verbal demonstration of understanding of all questionnaire items answered incorrectly
- •Agrees not to enroll in another study of an investigational research agent until completion of the last required protocol clinic visit
- •Good general health as shown by medical history, physical exam, and screening laboratory tests
- •HIV-Related Criteria:
- •Willingness to receive HIV test results
- •Willingness to discuss HIV infection risks and amenable to HIV risk reduction counseling.
Exclusion Criteria
- •Weight \>115 kg
- •Blood products received within 120 days before first study product administration, unless eligibility for earlier enrollment is determined by the HVTN 136/HPTN 092 PSRT
- •Investigational research agents received within 30 days before first study product administration
- •Intent to participate in another study of an investigational research agent or any other study that requires non-Network HIV antibody testing during the planned duration of the study
- •Pregnant or breastfeeding
- •Vaccines and other Injections
- •HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received control/placebo in an HIV vaccine trial, the HVTN 136/HPTN 092 PSRT will determine eligibility on a case-by-case basis.
- •Previous receipt of humanized or human mAbs, whether licensed or investigational; the HVTN 136/HPTN 092 PSRT will determine eligibility on a case-by-case basis.
- •Previous receipt of monoclonal antibodies VRC01, VRC01LS, VRC07-523LS, or PGT121
- •Immune System
Arms & Interventions
Part A (Group 1): PGT121.414.LS (3 mg/kg)
Participants will receive 3 mg/kg of PGT121.414.LS by intravenous (IV) infusion at Month 0.
Intervention: PGT121.414.LS
Part A (Group 2): PGT121.414.LS (10 mg/kg)
Participants will receive 10 mg/kg of PGT121.414.LS by IV infusion at Month 0.
Intervention: PGT121.414.LS
Part A (Group 3): PGT121.414.LS (30 mg/kg)
Participants will receive 30 mg/kg of PGT121.414.LS by IV infusion at Month 0.
Intervention: PGT121.414.LS
Part A (Group 4): PGT121.414.LS (5 mg/kg)
Participants will receive 5 mg/kg of PGT121.414.LS by subcutaneous (SC) infusion at Month 0.
Intervention: PGT121.414.LS
Part B (Group 5): PGT121.414.LS + VRC07-523LS (20 mg/kg)
Participants will receive 20 mg/kg of PGT121.414.LS and 20 mg/kg of VRC07-523LS by IV infusion sequentially in this order at Months 0, 4, and 8.
Intervention: PGT121.414.LS
Part B (Group 5): PGT121.414.LS + VRC07-523LS (20 mg/kg)
Participants will receive 20 mg/kg of PGT121.414.LS and 20 mg/kg of VRC07-523LS by IV infusion sequentially in this order at Months 0, 4, and 8.
Intervention: VRC07-523LS
Part B (Group 6): PGT121.414.LS + VRC07-523LS (5 mg/kg)
Participants will receive 5 mg/kg of PGT121.414.LS and 5 mg/kg of VRC07-523LS by SC infusion sequentially in this order at Months 0, 4, and 8.
Intervention: PGT121.414.LS
Part B (Group 6): PGT121.414.LS + VRC07-523LS (5 mg/kg)
Participants will receive 5 mg/kg of PGT121.414.LS and 5 mg/kg of VRC07-523LS by SC infusion sequentially in this order at Months 0, 4, and 8.
Intervention: VRC07-523LS
Outcomes
Primary Outcomes
Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness
Time Frame: Measured through 3 days after each vaccine dose at T1-T4: Day 0; T5-T6: Days 0, 112, 224
Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]. The maximum grade observed for each symptom over the time frame is presented
Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Erythema and/or Induration
Time Frame: Measured through 3 days after each vaccine dose at T1-T4: Day 0; T5-T6: Days 0, 112, 224
Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]. The maximum grade observed for each symptom over the time frame is presented
Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms
Time Frame: Measured through 3 days after each vaccine dose at T1-T4: Day 0; T5-T6: Days 0, 112, 224
Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]. The following symptoms are considered as systemic reactogenicity if the onset date was within the periods of assessment specified in the protocol: malaise and/or fatigue, myalgia, headache, nausea, vomiting, chills, arthralgia, and body temperature. The item Max. Systemic Symptoms is the maximum of the individual systemic reactogenicities excluding body temperature for a participant
Chemistry and Hematology Laboratory Measures - Alkaline Phosphatase, AST, ALT in U/L
Time Frame: Measured during Screening, Days 0, 112, 168
For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population
Number of Participants Reporting Unsolicited Adverse Events (AEs)
Time Frame: Measured through Month 24
The number (percentage) of Participants Reporting Unsolicited Adverse Events (AEs) was summarized by arm
Number of Participants With Early Discontinuation of Vaccinations and Reason for Discontinuation
Time Frame: Measured through Month 8
The number (percentage) of participants with early discontinuation of vaccinations and reason for discontinuation was summarized by arm
Chemistry and Hematology Laboratory Measures - Creatinine in mg/dL
Time Frame: Measured during Screening, Days 0, 112, 168
For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population
Chemistry and Hematology Laboratory Measures - Lymphocyte Count, Neutrophil Count in 1000 Cells/Cubic mm
Time Frame: Measured during Screening, Days 0, 112, 168
For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population
Chemistry and Hematology Laboratory Measures - Hemoglobin in g/dL
Time Frame: Measured during Screening, Days 0, 112, 168
For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population
Chemistry and Hematology Laboratory Measures - Platelets, WBC in 1000 Cells/Cubic mm
Time Frame: Measured during Screening, Days 0, 112, 168
For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population
Number of Participants With Early Study Termination and Reason for Early Study Termination
Time Frame: Measured through Month 16
The number (percentage) of participants with early study termination and reason for early study termination was summarized by arm
PGT121.414.LS and VRC07523LS Serum Concentrations
Time Frame: Days 0, 0.0417, 1, 2, 3, 6, 14, 28, 56, 84, 112, 112.0417, 140, 168, 196, 224, 224.0417, 252, 280, 336, 392, 448
Serum concentrations of PGT121.414.LS and VRC07-523LS at prespecified timepoints among participants who received all scheduled product administrations
Magnitude of Serum Neutralizing Activity Measured With mAb-specific Env-pseudotyped Viruses in TZM-bl Cells
Time Frame: Day 3, Months 1, 2, 4, 6, 8, 10, 12
Level of ID50 and ID80 titer data from the TZMbl neutralizing antibody assays against 1 bnAb-specific virus (CH505TF.N334S.N160A.N280D.1, sensitive to PGT121, resistant to VRC07) for all Part A participants (IV or SC administration of PGT121.414.LS alone), and 1 bnAb-specific virus (CNE55.N160K, sensitive to VRC07, resistant to PGT121) for all Part B participants (IV or SC administration of PGT121.414.LS in combination with VRC07523LS) at all expected timepoints.
Secondary Outcomes
- Occurrence of Antidrug Antibodies (ADA)(Day 0, 112, 196, 224, 336, 392, 448)
- Magnitude and Breadth of Neutralizing Antibody Responses Against Autologous Viral Isolates as Assessed by Area Under the Magnitude-breadth Curves at Months 1, 4, and 9(Months 1, 4, and 9)