3BNC117-LS and 10-1074-LS Plus N-803 (bNAb+N-803)

Study Overview
=================
Brief Summary
-----------------
The proposed study is a phase 1, open label, single arm study to evaluate the safety and antiretroviral activity of the combination of two long-acting broadly neutralizing antibodies, 3BNC117-LS dosed once at 30 mg/kg and 10-1074-LS dosed once at 10 mg/kg, both intravenously (IV) at week 0, plus an IL-15 superagonist complex, N-803, dosed at 6 mcg/kg, subcutaneously (SC) at week 1 and then every 3 weeks for a total of 8 doses, in ART-treated adults living with HIV during analytical treatment interruption.

Detailed Description
-----------------
The proposed study is a phase 1, open label study of the safety and antiretroviral activity of the 3BNC117-LS plus 10-1074-LS broadly neutralizing antibody (bNAb) combination plus N-803, an IL-15 superagonist complex, in ART-treated individuals living with HIV during interruption of ART. Thirty-six eligible participants will be enrolled sequentially and will be assigned to Group A or Group B after Monogram PhenoSense Assay results become available: Group A (n=18) - participants with 3BNC117 and 10-1074 IC90 less or equal to 1 mcg/mL and MPI greater or equal to 98% by the Monogram PhenoSense assay using PBMCs; Group B (n=18) - all other participants, including participants from whom the PhenoSense Assay (PBMC) does not yield a result. Participants will discontinue ART on day 2 (2 days after the first antibody infusions) and will be followed for up to 72 weeks while off ART and for 24 weeks after ART is resumed.

Official Title
-----------------
An Open Label, Single Arm Study of the Safety and Antiretroviral Activity of Two Long-acting Broadly Neutralizing Antibodies Plus an IL-15 Superagonist in ART-treated Adults Living With HIV During Analytical Treatment Interruption

Conditions
-----------------
Human Immunodeficiency Virus

Intervention / Treatment
-----------------
* Drug: 3BNC117-LS
* Drug: 10-1074-LS
* Drug: N803


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and females, age 18 to 70. Confirmed HIV-1 infection. On antiretroviral therapy with plasma HIV-1 RNA levels of < 50 copies/ml and no reported interruption of ART for 7 consecutive days or longer for at least 48 weeks, and < 20 copies/ml at screening. NOTE: At least two Viral Load (VL) measurements within 48 weeks prior to the Step 0 screening visit must be available for review. A single plasma HIV-1 RNA > 50 copies/mL but < 200 copies/mL that is followed by an HIV-1 RNA <50 copies/mL is permitted. Current CD4+ T cell counts > 450 cells/mcL, CD4+ T cell % ≥ 15%, and CD4+ T cell count nadir of ≥ 200 cells/mcL. If on an NNRTI-based regimen, willing to switch to an integrase inhibitor-based regimen for at least 4 weeks prior to discontinuing ART. For participants who can become pregnant (i.e., participants who have not been post-menopausal for at least 24 consecutive months, who have had menses within the preceding 24 months, or who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy), negative pregnancy test at screening (Step 0) and within 48 hours prior to day 0 (Step 1 entry). Participants who can become pregnant must agree to use two methods of contraception, one of which must be from the highly effective methods for contraception listed below. Barrier methods of contraception are permitted for the second method of contraception. Contraception must be used from 10 days prior to the first of the investigational products (IP), while receiving the IPs, for 12 months after the last IP dose and until ART is reinitiated and viral suppression is achieved. Participants who can impregnate a partner and who are engaging in sexual activity that could lead to pregnancy must agree to use condoms from 10 days prior to the first dose of the investigational products (IP), while receiving the IPs, and for 12 months after the last IP dose to avoid impregnating a partner who can get pregnant. Willingness to use barrier protection (male or female) during sexual activity during analytical treatment interruption (ATI) and until viral re-suppression for those who re-start ART. Exclusion Criteria: History of AIDS-defining illness within 3 years prior to enrollment. History of systemic corticosteroids (e.g. an equivalent dose of prednisone of > 20 mg daily for > 14 days), immunosuppressive anti-cancer, interleukins, systemic interferons, systemic chemotherapy or other medications considered significant by the trial physician within the last 6 months. Any clinically significant acute or chronic medical condition (e.g. such as autoimmune diseases, cirrhosis), other than HIV infection, that in the opinion of the investigator would preclude participation. History of or current clinical atherosclerotic cardiovascular disease (ASCVD), as defined by 2013 ACC/AHA guidelines. QTcF interval ≥ 440 ms at screening. Any history of an HIV-associated malignancy, including Kaposi's sarcoma, or any type of lymphoma or virus-associated cancers. History of Progressive Multifocal Leukoencephalopathy (PML). Active or recent non-HIV-associated malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months; Hepatitis B or C infection as indicated by the presence of Hepatitis B surface antigen (HBsAg) or hepatitis C virus RNA (HCV-RNA) in blood. Participants with known hypersensitivity to any constituent of the investigational products. Pregnancy or lactation. ART initiated during acute infection (defined as p24, HIV NAAT, or HIV RNA PCR positive, and negative or indeterminate HIV antibody testing). Receipt of cabotegravir-LA IM or rilpivirine-LA IM within 24 months prior to Step 1 study entry. Known resistance to all drugs within two or more ARV drug classes. Laboratory abnormalities in the parameters listed below: Absolute neutrophil count < 1,000 cells/microlitre; Hemoglobin < 10 gm/dL; Platelet count < 100,000 cells/microlitre; ALT > 1.5 x ULN; AST > 1.5 x ULN; Total bilirubin > 1.5 x ULN; eGFR < 60 mL/min/1.73m2; Any history of receipt of therapeutic HIV vaccine or HIV monoclonal antibody therapy. Participation in any clinical study of an investigational product within 12 weeks prior to study entry (day 0) or expected participation in such a study during this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3BNC117-LS + 10-1074-LS + N-803<br>3BNC117-LS dosed at 30 mg/kg IV, day 0 10-1074-LS dosed at 10 mg/kg IV, day 0 N-803 dosed at 6 mcg/kg, SC, 8 doses every 3 weeks (week 1 through week 22) | Drug: 3BNC117-LS<br>* Intravenous infusion of 3BNC117-LS at 30 mg/kg<br>* Other names: monoclonal antibody;Drug: 10-1074-LS<br>* Intravenous infusion of 10-1074-LS at 10 mg/kg<br>* Other names: monoclonal antibody;Drug: N803<br>* Subcutaneous injections of N803 at 6 mcg/kg<br>* Other names: IL-15 superagonist complex;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related Grade 3 adverse events and serious adverse events | The number of participants with treatment-related solicited and unsolicited grade 3 and serious adverse events (including confirmed laboratory abnormalities), or premature study treatment discontinuation due to an adverse event (regardless of grade). | 72 weeks | 
| Any serious adverse events | The number of participants with serious adverse events, regardless of relationship to 3BNC117-LS, 10-1074-LS and N-803. | 72 weeks | 
| Dosing completion | The proportion of participants who complete dosing with 3BNC117-LS, 10-1074-LS and N-803. | 24 weeks | 
| Viral rebound before or at week 24 post withdrawing ART | The number of participants experiencing viral rebound, defined as confirmed HIV-1 RNA >200 copies/mL at or prior to week 24 of ART discontinuation. | 24 weeks | 
| ART not restarted by weeks 60 and 72 | The proportion of participants who do not meet ART restart criteria by weeks 60 and 72. | 72 weeks | 
| ART not restarted when bNABs below threshold | The proportion of participants who do not meet ART restart criteria for 12 or more weeks after bNAbs are below a threshold of 10 mcg/ml. | 72 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related Grade 2 adverse events | The number of participants with treatment-related solicited and unsolicited grade 2 adverse events. | 72 weeks | 
| Viral rebound through Step 2 | The number of participants experiencing viral rebound, defined as confirmed HIV-1 RNA >200 copies/mL, through Step 2 of the study. | 72 weeks | 
| Time from ART withdrawal to re-initiating ART | Time from ART withdrawal to virologic or immunologic criteria (i.e. viral load, CD4 cell count, or development of severe acute retroviral syndrome) to reinitiate ART. | 72 weeks | 
| Viral rebound determined by Monogram assay | Time to viral rebound (confirmed HIV-1 RNA >200 copies/mL) across different 3BNC117-LS and 10-1074-LS IC90s cut points determined by the Monogram PhenoSense assay. | 72 weeks | 
| Size of latent HIV-1 reservoir | Size of the latent HIV-1 reservoir, measured by IPDA and/or other appropriate assay, before, during (Step 1) and after dosing with 3BNC117-LS, 10-1074-LS and N-803 (Step 2), and after antibody concentrations have declined below a therapeutic threshold. | 72 weeks | 
| Changes in HIV-1 specific T Cell immune responses | Changes in HIV-1 specific T cell immune responses in peripheral blood, measured by ELISPOT, before, during (Step 1) and after dosing with 3BNC117-LS, 10-1074-LS and N-803 (Step 2), and after antibody concentrations have declined below a therapeutic threshold. | 72 weeks | 
| Half-life of 3BNC117-LS and 10-1074-LS | Half-life of 3BNC117-LS and 10-1074-LS, when administered in combination with N-803 to individuals with HIV during ART interruption. | 72 weeks | 
| Anti-drug antibodies (ADA) | The proportion of individuals with treatment-induced ADA against each bNAb or N-803 and magnitude of the response. | 72 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
3BNC117-LS, 10-1074-LS, Broadly Neutralizing Antibody, N-803, IL-15 superagonist complex