A Clinical Trial of PGDM1400 and PGT121 and VRC07-523LS Monoclonal Antibodies in HIV-infected and HIV-uninfected Adults

• ClinicalTrials.gov Identifier: NCT03205917
• Recruitment Status: Completed
• First Posted: July 2, 2017
• Last Update Posted: September 14, 2020
• Sponsor: International AIDS Vaccine Initiative
• Collaborators: Beth Israel Deaconess Medical Center; Ragon Institute of MGH, MIT and Harvard; University of Texas Health, Houston AIDS Research Team (HART); Orlando Immunology Clinic
• Information provided by (Responsible Party): International AIDS Vaccine Initiative

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
HIV Infections	Biological: PGDM1400/Placebo (3mg/kg IV); Biological: PGDM1400/Placebo (10mg/kg IV); Biological: PGDM1400/Placebo (30mg/kg IV); Biological: PGDM1400 + PGT121/Placebo (3mg/kg + 3mg/kg IV); Biological: PGDM1400 + PGT121/Placebo (10mg/kg + 10mg/kg IV); Biological: PGDM1400 + PGT121/Placebo (30mg/kg + 30mg/kg IV); Biological: PGDM1400 + PGT121 + VRC07-523LS (20mg/kg + 20mg/kg + 20 mg/kg IV); Biological: PGDM1400 + PGT121 (MTD IV)	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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: A Phase 1 Randomized Placebo-controlled Clinical Trial of the Safety, Pharmacokinetics and Antiviral Activity of PGDM1400 and PGT121 and VRC07-523LS Monoclonal Antibodies in HIV-uninfected and HIV-infected Adults
• Actual Study Start Date: October 23, 2017
• Actual Primary Completion Date: April 20, 2020
• Actual Study Completion Date: April 20, 2020

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 :

1. Safety and tolerability [ Time Frame: 6 Months post infusion ]
   1. 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
   2. 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
   3. 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
2. Elimination half-life (t1/2) [ Time Frame: 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
3. Clearance (CL/F) [ Time Frame: 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.
4. Volume of distribution (Vz/F) [ Time Frame: 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
5. Area under the concentration decay curve (AUC) [ Time Frame: 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
6. Impact of viral load and/or ART [ Time Frame: 6 months post infusion ]
   Impact of viral load and/or ART on PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb disposition
7. Antiviral activity of PGDM1400 in combination with PGT121 or PGDM1400 in combination with PGT121 and VRC07-523LS mAbs [ Time Frame: 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 :

1. Serum antibody titers against bNAbs [ Time Frame: 6 Months post infusion ]
   Serum anti-PGDM1400 antibody titers, Serum anti-PGT121 antibody titers and Serum anti-VRC07-523LS antibody titers
2. CD4+ T cell count [ Time Frame: 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
3. HIV genotyping of circulating virus [ Time Frame: 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

4. HIV phenotyping of circulating virus [ Time Frame: 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

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

United States, Massachusetts

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

More Information

Additional Information:

IAVI Website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Julg B, Stephenson KE, Wagh K, Tan SC, Zash R, Walsh S, Ansel J, Kanjilal D, Nkolola J, Walker-Sperling VEK, Ophel J, Yanosick K, Borducchi EN, Maxfield L, Abbink P, Peter L, Yates NL, Wesley MS, Hassell T, Gelderblom HC, deCamp A, Mayer BT, Sato A, Gerber MW, Giorgi EE, Gama L, Koup RA, Mascola JR, Monczor A, Lupo S, Rolle CP, Arduino R, DeJesus E, Tomaras GD, Seaman MS, Korber B, Barouch DH. Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial. Nat Med. 2022 Jun;28(6):1288-1296. doi: 10.1038/s41591-022-01815-1. Epub 2022 May 12.

• Responsible Party: International AIDS Vaccine Initiative
• ClinicalTrials.gov Identifier: NCT03205917
• Other Study ID Numbers: IAVI T002
• First Posted: July 2, 2017
• Last Update Posted: September 14, 2020
• Last Verified: September 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases