A Clinical Trial of PGDM1400 and PGT121 and VRC07-523LS Monoclonal Antibodies in HIV-infected and HIV-uninfected Adults
Study Details
Study Description
Brief Summary
This is a Phase 1 study to evaluate the safety, tolerability, pharmacokinetics and anti-viral efficacy of the PGDM1400 and PGT121 and VRC07-523LS mAbs for HIV prevention and therapy.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This is a Phase 1 study to evaluate the safety, tolerability, pharmacokinetics and anti-viral efficacy of the PGDM1400, PGT121 and VRC07-523LS mAbs for HIV prevention and therapy. PGDM1400, PGT121 and VRC07-523LS mAbs are recombinant human IgG1 monoclonal antibodies that target V1V2 (PGDM1400), a V3 glycan-dependent epitope (PGT121) and the CD4 binding site (VRC07-523LS) epitope region of the HIV envelope protein. PGT121, PGDM1400 and VRC07-523LS mAb were chosen for this study because of their potency, their ability to neutralize a wide array of cross-clade HIV viruses in a complementary pattern and their proven antiviral activity in animal studies e.g., their capacity to robustly prevent and treat simian-human immunodeficiency virus (SHIV) in rhesus monkeys.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Group 1A HIV-Uninfected PGDM1400 low dose |
Biological: PGDM1400/Placebo (3mg/kg IV)
3/1 (6/2 if DLT)
|
| Experimental: Group 1B HIV-Uninfected PGDM1400 mid dose |
Biological: PGDM1400/Placebo (10mg/kg IV)
3/1 (6/2 if DLT)
|
| Experimental: Group 1C HIV-Uninfected PGDM1400 high dose |
Biological: PGDM1400/Placebo (30mg/kg IV)
3/1 (6/2 if DLT)
|
| Experimental: Group 2A HIV-Uninfected PGDM1400 + PGT121 low dose |
Biological: PGDM1400 + PGT121/Placebo (3mg/kg + 3mg/kg IV)
3/1 (6/2 if DLT)
|
| Experimental: Group 2B HIV-Uninfected PGDM1400 + PGT121 mid dose |
Biological: PGDM1400 + PGT121/Placebo (10mg/kg + 10mg/kg IV)
3/1 (6/2 if DLT);
|
| Experimental: Group 2C HIV-Uninfected PGDM1400 + PGT121 high dose |
Biological: PGDM1400 + PGT121/Placebo (30mg/kg + 30mg/kg IV)
3/1 (6/2 if DLT)
|
| Experimental: Group 3A HIV-infected off ART PGDM1400 + PGT121 + VRC07-523LS at 20mg/kg; HIV+ without ART |
Biological: PGDM1400 + PGT121 + VRC07-523LS (20mg/kg + 20mg/kg + 20 mg/kg IV)
3 (max 9)
|
| Experimental: Group 3B HIV-infected off ART PGDM1400 + PGT121 at high dose; HIV + without ART |
Biological: PGDM1400 + PGT121 (MTD IV)
3 (max 9)
|
Outcome Measures
Primary Outcome Measures
- Safety and tolerability [6 Months post infusion]
Proportion of participants with moderate or greater reactogenicity (e.g., solicited adverse events) for 3 days following IV infusion of PGDM1400 mAb alone, and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb Proportion of participants with adverse events (AEs), including safety laboratory (biochemical, hematological) parameters, during the first 56 days following IV infusion of PGDM1400 mAb alone and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb, that are moderate or greater, and/or related to PGDM1400 mAb or PGT121 mAb or VRC07-523LS mAb Proportion of participants with SAEs throughout the study period following IV infusion of PGDM1400 mAb alone and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb, that are related to PGDM1400 mAb or PGT121 mAb or VRC07-523LS mAb
- Elimination half-life (t1/2) [6 Months post infusion]
Elimination half-life following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults
- Clearance (CL/F) [6 months post infusion]
Clearance following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults.
- Volume of distribution (Vz/F) [6 months post infusion]
Volume of distribution following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults
- Area under the concentration decay curve (AUC) [6 months post infusion]
AUC following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults
- Impact of viral load and/or ART [6 months post infusion]
Impact of viral load and/or ART on PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb disposition
- Antiviral activity of PGDM1400 in combination with PGT121 or PGDM1400 in combination with PGT121 and VRC07-523LS mAbs [6 Months post infusion]
Antiviral activity following IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb, in viremic HIV-infected adults not on ART: Change in plasma HIV-1 RNA levels from baseline (mean of pre-entry and entry values)
Secondary Outcome Measures
- Serum antibody titers against bNAbs [6 Months post infusion]
Serum anti-PGDM1400 antibody titers, Serum anti-PGT121 antibody titers and Serum anti-VRC07-523LS antibody titers
- CD4+ T cell count [6 Months post infusion]
Determine if IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb, has any impact on CD4+ T cell counts in HIV-infected adults. Change in CD4+ T cell count compared to baseline as measured by single platform flow cytometry
- HIV genotyping of circulating virus [6 Months post infusion]
Compare plasma virus genotype activity before and after IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb to determine if PGDM1400 mAb and PGT121 mAb and/or PGT121VRC07-523LS mAb induced viral escape mutations have developed in viremic HIV-infected adults not on ART Genotypic analysis: Development of sequence variations in epitopes known to result in reduced PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization susceptibility or known to cause resistance to antiretroviral drugs
- HIV phenotyping of circulating virus [6 months post infusion]
Compare plasma virus phenotypic activity before and after IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb to determine if PGDM1400 mAb and PGT121 mAb and/or PGT121VRC07-523LS mAb induced viral escape mutations have developed in viremic HIV-infected adults not on ART. Phenotypic analysis: Changes in viral susceptibility to PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization Phenotypic analysis: Changes in viral susceptibility to PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization.
Eligibility Criteria
Criteria
Groups 1 and 2 Inclusion Criteria:
-
HIV-uninfected males or females age 18-50 years old
-
Willing to maintain low risk behavior for HIV infection
Groups 1 and 2 Exclusion Criteria:
• Confirmed HIV-infection, pregnancy or lactation, significant acute or chronic disease and clinically significant laboratory abnormalities
Group 3 Inclusion Criteria:
-
HIV-infected males or females age 18-65 years old
-
Not on antiretroviral therapy with HIV-1 RNA plasma level between 1,000 and 100,000 copies/ml, CD4 cell count ≥ 300 cells/uL
Group 3 Exclusion Criteria:
• Significant acute or chronic medical condition other than HIV infection, and clinically significant laboratory abnormalities
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Beth Israel Deaconess Medical Center | Boston | Massachusetts | United States | 02215 |
Sponsors and Collaborators
- International AIDS Vaccine Initiative
- Beth Israel Deaconess Medical Center
- Ragon Institute of MGH, MIT and Harvard
- University of Texas Health, Houston AIDS Research Team (HART)
- Orlando Immunology Clinic
Investigators
- Principal Investigator: Boris Juelg, MD, PhD, Beth Israel Deaconess Medical Center, Center for Virology and Vaccine Research, Ragon Institute of MGH, MIT and Harvard
- Study Chair: Kathryn Stephenson, MD, MPH, Beth Israel Deaconess Medical Center, Center for Virology and Vaccine Research
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- IAVI T002