A Study to Evaluate the Safety and Effects of Repeated Doses of 3BNC117-LS and 10-1074-LS on Persistent Viral Reservoirs in People Living With HIV and on Suppressive Antiretroviral Therapy

HIV-1 Clinical Trial

Official title: A Randomized Placebo-controlled Study to Evaluate the Safety and Effects of Repeated Doses of 3BNC117-LS and 10-1074-LS on Persistent Viral Reservoirs in People Living With HIV and on Suppressive Antiretroviral Therapy

Status Recruiting

Clinical Trial Summary

Background:

Antiretroviral therapy (ART) can suppress HIV to undetectable levels in people, but the virus rebounds quickly if the drug treatment is stopped; this is because HIV can remain dormant in a pool of blood cells called the persistent viral reservoir (PVR). Yet lifelong ART is expensive and can lead to serious side effects over the long term. Some drugs may be more effective at reducing the PVR.

Objective:

To see if 2 study drugs (3BNC117-LS and 10-1074-LS) are safe and if they can lower the number of HIV-infected blood cells in people with HIV who are on ART.

Eligibility:

People aged 18 to 70 years with HIV who are on ART.

Design:

Participants will be screened. They will have a physical exam and blood and urine tests. They will undergo leukapheresis. Leukapheresis is a procedure where blood is drawn from a needle in one arm. The blood will pass through a machine that separates out the white blood cells. The remaining blood will be given back through a second needle in the other arm.

The study drugs or placebo (normal saline) will be administered 3 times at 20-week intervals. The drugs will be given through a tube attached to a needle inserted into a vein in the arm. This will take 1 hour. Some participants will receive only a saline solution. They will not know if they are getting the drugs or the placebo.

Participants will undergo leukapheresis up to 4 more times during the study.

Participants will have follow-up visits every 10 weeks until the study ends.

Clinical Trial Description

Study Description:

This is randomized placebo-controlled study of the safety and virologic activity of the 3BNC117-LS plus 10-1074-LS broadly neutralizing antibody (bNAb) combination during standard antiretroviral therapy (ART).

Participants will be enrolled sequentially and randomized to receive 3BNC117-LS plus 10-1074-LS or placebo (sterile saline) at a 1:1 ratio. Participants will receive two intravenous infusions of 3BNC117-LS (dosed at 30 mg/kg) and 10-1074-LS (dosed at 10 mg/kg) or placebo at weeks 0 and 20. Participants will remain on ART during the study.

Objectives:

Primary Objectives:

-To evaluate the safety and tolerability of repeated doses of 3BNC117-LS and 10-1074-LS in adults living with human immunodeficiency virus (HIV) during suppressive ART.

Secondary Objectives:

• To evaluate the impact of 3BNC117-LS and 10-1074-LS on intact human immunodeficiency type 1 (HIV-1) proviruses over time in adults living with HIV during suppressive ART.

• To determine the effects of repeated doses of 3BNC117-LS and 10- 1074-LS during suppressive ART on HIV-1 specific cellular immune responses by enzyme-linked immunosorbent spot (ELISpot).

• To describe the pharmacokinetic parameters of the repeated doses of 3BNC117-LS and 10-1074-LS in adults living with HIV during suppressive ART.

Exploratory Objectives:

• To characterize the HIV-1 reservoir in peripheral blood during and following repeated doses of 3BNC117-LS and 10-1074-LS during suppressive ART.

• To evaluate effects on HIV-1 transcriptional activity during and following repeated doses of 3BNC117-LS and 10-1074-LS during suppressive ART.

• To characterize host HIV-1 specific humoral, cellular and innate immune responses during and following repeated doses of 3BNC117-LS and 10-1074-LS during suppressive ART.

• To correlate HIV-1 specific immune responses and effects on intact proviruses.

• To correlate virologic outcomes with bNAb sensitivity of reservoir proviruses.

Endpoints:<TAB>

Primary Endpoints:

-The occurrence of solicited and unsolicited grade 3 or higher adverse events (AE) (including confirmed laboratory abnormalities) that are possibly, probably, or definitely related to 3BNC117-LS and/or 10- 1074-LS, or premature study treatment discontinuation due to an AE (regardless of grade).

Secondary Endpoints:

• The occurrence of serious adverse events, regardless of relationship to 3BNC117-LS and/or 10-1074-LS.

• Change in the intact proviral reservoir size, measured by quadruplex polymerase chain reaction (Q4PCR) and/or intact proviral deoxyribonucleic acid assay (IPDA), from baseline to weeks 40 and

80 after dosing with 3BNC117-LS and 10-1074-LS during suppressive ART.

• Changes in HIV-1 specific T cell immune responses in peripheral blood, measured by ELISpot, before, during and after dosing with 3BNC117-LS and 10-1074-LS during suppressive ART.

• Pharmacokinetic parameters (including: peak concentrations, half- life, area under curve and clearance rate) of repeated doses of 3BNC117-LS and 10-1074-LS during suppressive ART.

Exploratory Endpoints:

• Size of the latent HIV-1 reservoir, measured by quantitative viral outgrowth assay (QVOA) and/or other appropriate assays, before, during and after dosing with 3BNC117-LS and 10-1074-LS during suppressive ART.

• Composition of the intact proviral reservoir before and after immunotherapy with 3BNC117-LS and 10-1074-LS during suppressive ART by Q4PCR or other appropriate assays that may become available.

• The half-life of the HIV-1 intact proviral reservoir during 3BNC117- LS and 10-1074-LS therapy and ART suppression.

• HIV-1 transcriptional activity as determined by spliced and unspliced HIV-1 ribonucleic acid (RNA) in circulating total CD4+ T cells and/or other appropriate assays, before, during and after dosing with 3BNC117-LS and 10-1074-LS during suppressive ART.

• Changes in HIV-1 specific T cell immune responses in peripheral blood, measured by assays such as polyfunctional intracellular cytokine staining (ICS) and viral inhibition assay before, during and after immunotherapy with 3BNC117-LS and 10-1074-LS during suppressive ART.

• Changes in antibody dependent cell-mediated cytotoxicity (ADCC) against HIV-1-infected CD4+ T-cells by ex vivo autologous natural killer cells before and after immunotherapy with 3BNC117-LS and 10-1074-LS during suppressive ART.

• Correlation between magnitude, breadth and functionality of HIV-1 specific T cell immune responses and effects on intact proviruses.

• Correlation between changes in intact proviruses and bNAb sensitivity of reservoir proviruses determined by Env sequencing.

• Correlation between HIV-1 transcriptional activity and changes in the composition of the intact proviral reservoir. ;

Related Conditions & MeSH terms

• HIV-1

• NCT number: NCT05612178
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Catherine A Seamon, R.N.
• Phone: (301) 402-3481
• Email: cseamon@cc.nih.gov
• Status: Recruiting
• Phase: Phase 1
• Start date: July 26, 2023
• Completion date: December 31, 2025