Safety, Tolerability, and Efficacy of IL-15 Superagonist (N-803) With and Without Combination Broadly Neutralizing Antibodies to Induce HIV-1 Control During Analytic Treatment Interruption

HIV Infection Clinical Trial

Official title:

A Phase I Clinical Trial of the Safety, Tolerability, and Efficacy of IL-15 Superagonist (N-803) With and Without Combination Broadly Neutralizing Antibodies to Induce HIV-1 Control During Analytic Treatment Interruption

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04340596
• Other study ID #: ACTG A5386
• Secondary ID: 38639
• Status: Recruiting
• Phase: Phase 1
• Start date: May 21, 2021
• Est. completion date: April 30, 2026

Study information

• Verified date: April 2024
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the safety, tolerability, and efficacy of N-803, an IL-15 superagonist, with or without combination broadly neutralizing antibodies (bNAbs), to induce HIV-1 control during analytic treatment interruption (ATI).

Description:

This study will evaluate the safety, tolerability, and efficacy of N-803, an IL-15 superagonist, with or without combination broadly neutralizing antibodies (bNAbs), to induce HIV-1 control during analytic treatment interruption (ATI).

Participants will be screened for eligibility and undergo leukapheresis, and a subset will also undergo optional rectal biopsy and/or lymph node fine needle aspirations (FNAs) (Step 1).

After pre-entry and determination of eligibility in Step 1, participants will be randomized before Step 2 entry to either the N-803 only arm (Arm A) or the N-803 with combination bNAbs arm (Arm B):

• Arm A will receive a dose of N-803, 6 mcg/kg, subcutaneously 1 week after Step 2 entry and then every 3 weeks for a total of eight doses (during the first 22 weeks).

• Arm B will receive the following (during the first 22 weeks):

• Combination bNAb at Step 2 entry with VRC07-523LS dosed at 20 mg/kg and 10-1074 dosed at 30 mg/kg, intravenously;

• A dose of N-803, 6 mcg/kg, subcutaneously 1 week after Step 2 entry and then every 3 weeks for a total of eight doses;

• A second dose of 10-1074 at week 9 of Step 2 dosed at 30 mg/kg, intravenously

After completing randomized treatment (Step 2), participants will interrupt antiretroviral therapy (ART) (Step 3) and will be followed closely to monitor for indications for reinitiation of ART (Step 4).

After Step 2 entry, most participants will be followed for approximately 100 weeks across the remaining three study steps (i.e., Steps 2, 3, and 4).

Step 1 will last up to 90 days, Step 2 will last approximately 52 weeks (study intervention), Step 3 will last up to 24 weeks (ATI), and Step 4 will last 24 weeks (ART restart).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 46
• Est. completion date: April 30, 2026
• Est. primary completion date: October 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria

• HIV-1 infection

• On ART for at least 96 weeks prior to randomization

• On ART regimen containing an integrase inhibitor and two nucleoside reverse transcriptase inhibitors (NRTIs) or dolutegravir/lamivudine for at least 6 weeks prior to randomization.

• CD4 cell count >450 cells/mm^3 within 90 days prior to randomization

• CD4 cell count nadir =200 cells/mm^3.

• Plasma HIV-1 RNA levels of <50 copies/mL for at least 96 weeks prior to randomization

• Select laboratory results within 90 days of randomization

• IC90 to 10-1074 of =1.5 mcg/mL, 10-1074 maximum percent inhibition (MPI) =98%, and IC80 to VRC07-523LS of =1 mcg/mL on the Monogram PhenoSense assay.

• QTcF interval =440 msec within 90 days prior to randomization.

• For cisgender women and transgender men of reproductive potential, negative urine or serum pregnancy test within 30 days prior to randomization

• Cisgender women and transgender men of reproductive potential must agree to use two methods of contraception, if participating in sexual activity that could lead to pregnancy.

• Cisgender men and transgender women participants engaging in sexual activity that could lead to pregnancy and who are of reproductive potential must agree to use a barrier method of contraception

• Willingness to abstain from sexual intercourse or use a barrier method of contraception consistently

• Willingness to participate in an ATI.

• Weight >50 kg and <115 kg.

• Completion of pre-entry leukapheresis

Exclusion Criteria

• History of AIDS-defining illness, with the exception of recurrent pneumonia.

• History of or current clinical cardiovascular disease

• Current clinically significant acute or chronic medical condition

• History of HIV-associated neurocognitive disease

• History of an HIV-associated malignancy

• ART initiated during acute HIV infection

• Current receipt of ART other than NRTI and integrase inhibitor.

• Resistance to one or more drugs in two or more ARV drug classes.

• Receipt of any therapeutic HIV vaccine or monoclonal antibody therapy (anti-HIV or otherwise) at any time in the past.

• History of prior immunoglobulin (IgG) therapy.

• History of use of any immunomodulatory medications within 6 months prior to randomization

• Participation in another clinical study of an investigational product currently or within past 12 weeks

• Breastfeeding or pregnancy

Related Conditions & MeSH terms

• HIV Infection
• HIV Infections

Intervention

Biological:
• N-803 (IL-15 Superagonist)
Administered by subcutaneous (SQ) injection
• VRC07-523LS
Administered by intravenous (IV) infusion
• 10-1074
Administered by intravenous (IV) infusion

Locations

Country	Name	City	State
United States	Alabama CRS (Site ID# 31788)	Birmingham	Alabama
United States	Massachusetts General Hospital CRS (MGH CRS) (Site ID: 101)	Boston	Massachusetts
United States	Chapel Hill CRS (Site ID: 3201)	Chapel Hill	North Carolina
United States	Northwestern University CRS	Chicago	Illinois
United States	Case Clinical Research Site	Cleveland	Ohio
United States	UCLA CARE Center CRS	Los Angeles	California
United States	Columbia P&S CRS	New York	New York
United States	Weill Cornell Uptown CRS (Site ID: 7803)	New York	New York
United States	New Jersey Medical School Clinical Research Center CRS [Site ID: 31786]	Newark	New Jersey
United States	Penn Therapeutics, CRS (Site ID: 6201)	Philadelphia	Pennsylvania
United States	University of Pittsburgh CRS (Site ID# 1001)	Pittsburgh	Pennsylvania
United States	Washington University Therapeutics (WT) CRS	Saint Louis	Missouri
United States	UCSD Antiviral Research Center CRS (Site ID: 701)	San Diego	California
United States	Ucsf Hiv/Aids Crs	San Francisco	California
United States	Whitman-Walker Institute, Inc. CRS (Site ID: 31791)	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	ImmunityBio, Inc., Rockefeller University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurrence of a Grade =3 adverse event (AE) that is at least possibly related to N-803, as judged by the Clinical Management Committee (CMC)		Step 2 week 1 to week 52
Primary	Number of N-803 doses completed	Eight doses of N-803 are scheduled at the distinct time points listed in Time Frame. At each timepoint, dose completion status is recorded. Number of N-803 doses completed is the total number completed doses across all 8 timepoints.	From step 2 week 1 to step 2 week 22
Primary	Proportion of participants requiring dose reduction	Eight doses of N-803 are scheduled at distinct time points (Step 2 weeks 1, 4, 7, 10, 13, 16, 19 and 22). Proportion of participants requiring dose reduction is calculated as the number of participants who receive a reduced dose of N-803 at any of the 7 scheduled doses occurring after the first dose, divided by the total number of participants receiving N-803.	From step 2 week 4 to step 2 week 22
Primary	Proportion of participants with plasma HIV-1 RNA <200 copies/mL 8 weeks after interruption of ART		At step 3 week 8
Secondary	Occurrence of a Grade =2 AE without regard to relationship to study treatment		Study entry to participant's last study visit, at approx. study week 100
Secondary	Occurrence of a Grade =2 AE that is at least possibly related to N-803, as judged by the CMC		Step 2 week 1 to week 52
Secondary	Occurrence of a Grade =2 AE that is at least possibly related to VRC07-523LS or 10-1074		Step 2 week 0 to week 52
Secondary	Cell-associated HIV-1 RNA		At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32
Secondary	Measurement of HIV-1 reservoir (dQVOA)		At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32
Secondary	Measurement of plasma viremia by HIV-1 single copy assay		At step 1 pre-entry evaluation and step 2 weeks 0, 1, 7, 13, 22 and 32
Secondary	Measurement of intact proviral DNA		At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32
Secondary	Total HIV-1 DNA		At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32
Secondary	Proportion of participants with plasma HIV-1 RNA <200 copies/mL at 4, 12 and 24 weeks after interruption of ART in Step 3		At step 3 weeks 4, 12, and 24
Secondary	PK parameters: AUC0-t of 10-1074		At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46
Secondary	PK parameters: AUC0-t of VRC07-523LS		At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46
Secondary	Proportion of participants with antidrug antibodies	Presence of anti-N803, anti-10-1074, and anti-VRC07-523LS antibodies	At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46