Clinical trial NCT04340596: 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
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: HIV Infection
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Rockefeller University
name: ImmunityBio, Inc.
First posted: 2020-04-09
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

Detailed 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).

Eligibility criteria: 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

Primary outcomes:
measure: 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)
timeFrame: Step 2 week 1 to week 52
measure: Number of N-803 doses completed
timeFrame: From step 2 week 1 to step 2 week 22
measure: Proportion of participants requiring dose reduction
timeFrame: From step 2 week 4 to step 2 week 22
measure: Proportion of participants with plasma HIV-1 RNA <200 copies/mL 8 weeks after interruption of ART
timeFrame: At step 3 week 8
Secondary outcomes:
measure: Occurrence of a Grade ≥2 AE without regard to relationship to study treatment
timeFrame: Study entry to participant's last study visit, at approx. study week 100
measure: Occurrence of a Grade ≥2 AE that is at least possibly related to N-803, as judged by the CMC
timeFrame: Step 2 week 1 to week 52
measure: Occurrence of a Grade ≥2 AE that is at least possibly related to VRC07-523LS or 10-1074
timeFrame: Step 2 week 0 to week 52
measure: Cell-associated HIV-1 RNA
timeFrame: At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32
measure: Measurement of HIV-1 reservoir (dQVOA)
timeFrame: At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32
measure: Measurement of plasma viremia by HIV-1 single copy assay
timeFrame: At step 1 pre-entry evaluation and step 2 weeks 0, 1, 7, 13, 22 and 32
measure: Measurement of intact proviral DNA
timeFrame: At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32
measure: Total HIV-1 DNA
timeFrame: At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32
measure: Proportion of participants with plasma HIV-1 RNA <200 copies/mL at 4, 12 and 24 weeks after interruption of ART in Step 3
timeFrame: At step 3 weeks 4, 12, and 24
measure: PK parameters: AUC0-τ of 10-1074
timeFrame: At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46
measure: PK parameters: AUC0-τ of VRC07-523LS
timeFrame: At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46
measure: Proportion of participants with antidrug antibodies
timeFrame: At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama CRS (Site ID# 31788)
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS (Site ID: 701)
state: California
city: San Francisco
country: United States
facility: University of California, San Fransisco HIV/AIDS CRS
state: California
city: Washington
country: United States
facility: Whitman-Walker Institute, Inc. CRS (Site ID: 31791)
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital CRS (MGH CRS) (Site ID: 101)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) CRS
state: Missouri
city: Newark
country: United States
facility: New Jersey Medical School Clinical Research Center CRS [Site ID: 31786]
state: New Jersey
city: New York
country: United States
facility: Columbia P&S CRS
state: New York
city: New York
country: United States
facility: Weill Cornell Uptown CRS (Site ID: 7803)
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS (Site ID: 3201)
state: North Carolina
city: Cleveland
country: United States
facility: Case Clinical Research Site
state: Ohio
city: Philadelphia
country: United States
facility: Penn Therapeutics, CRS (Site ID: 6201)
state: Pennsylvania
Study officials:
affiliation: Weill Medical College of Cornell University
name: Timothy Wilkin, MD, MPH
role: STUDY_CHAIR
References: