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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

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ClinicalTrials.gov Identifier: NCT04340596
Recruitment Status : Not yet recruiting
First Posted : April 9, 2020
Last Update Posted : April 9, 2020
Sponsor:
Collaborators:
The Rockefeller University
Vaccine Research Center
BELIEVE Collaboratory
ImmunityBio, Inc.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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).

Condition or disease Intervention/treatment Phase
HIV Infection Biological: N-803 (IL-15 Superagonist) Biological: VRC07-523LS Biological: 10-1074 Phase 1

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : July 1, 2020
Estimated Primary Completion Date : September 1, 2022
Estimated Study Completion Date : June 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Arm A: N-803 only
Participants will receive N-803 6 mcg/kg 1 week after Step 2 entry and then every 3 weeks for a total of eight doses.
Biological: N-803 (IL-15 Superagonist)
Administered by subcutaneous (SQ) injection

Experimental: Arm B: N-803 in combination with 10-1074 and VRC07-523LS

Participants will receive N-803 in combination with 10-1074 and VRC07-523LS as follows:

  • At Step 2 entry:

    • VRC07-523LS 20 mg/kg
    • 10-1074 30 mg/kg
  • At Step 2, week 1: N-803 6 mcg/kg every 3 weeks for eight doses
  • At Step 2, week 9: 10-1074 30 mg/kg
Biological: N-803 (IL-15 Superagonist)
Administered by subcutaneous (SQ) injection

Biological: VRC07-523LS
Administered by intravenous (IV) infusion

Biological: 10-1074
Administered by intravenous (IV) infusion




Primary Outcome Measures :
  1. 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) [ Time Frame: Step 2 week 1 to week 52 ]
  2. Number of N-803 doses completed [ Time Frame: From step 2 week 1 to step 2 week 22 ]
    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.

  3. Proportion of participants requiring dose reduction [ Time Frame: From step 2 week 4 to step 2 week 22 ]
    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.

  4. Proportion of participants with plasma HIV-1 RNA <200 copies/mL 8 weeks after interruption of ART [ Time Frame: At step 3 week 8 ]

Secondary Outcome Measures :
  1. Occurrence of a Grade ≥2 AE without regard to relationship to study treatment [ Time Frame: Study entry to participant's last study visit, at approx. study week 100 ]
  2. Occurrence of a Grade ≥2 AE that is at least possibly related to N-803, as judged by the CMC [ Time Frame: Step 2 week 1 to week 52 ]
  3. Occurrence of a Grade ≥2 AE that is at least possibly related to VRC07-523LS or 10-1074 [ Time Frame: Step 2 week 0 to week 52 ]
  4. Cell-associated HIV-1 RNA [ Time Frame: At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32 ]
  5. Measurement of HIV-1 reservoir (dQVOA) [ Time Frame: At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32 ]
  6. Measurement of plasma viremia by HIV-1 single copy assay [ Time Frame: At step 1 pre-entry evaluation and step 2 weeks 0, 1, 7, 13, 22 and 32 ]
  7. Measurement of intact proviral DNA [ Time Frame: At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32 ]
  8. Total HIV-1 DNA [ Time Frame: At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32 ]
  9. Proportion of participants with plasma HIV-1 RNA <200 copies/mL at 4, 12 and 24 weeks after interruption of ART in Step 3 [ Time Frame: At step 3 weeks 4, 12, and 24 ]
  10. PK parameters: AUC0-τ of 10-1074 [ Time Frame: At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46 ]
  11. PK parameters: AUC0-τ of VRC07-523LS [ Time Frame: At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46 ]
  12. Proportion of participants with antidrug antibodies [ Time Frame: At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46 ]
    Presence of anti-N803, anti-10-1074, and anti-VRC07-523LS antibodies



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04340596


Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
The Rockefeller University
Vaccine Research Center
BELIEVE Collaboratory
ImmunityBio, Inc.
Investigators
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Study Chair: Timothy Wilkin, MD, MPH Weill Cornell Medicine
Additional Information:
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT04340596    
Other Study ID Numbers: ACTG A5386
38639 ( Registry Identifier: DAIDS-ES Registry Number )
First Posted: April 9, 2020    Key Record Dates
Last Update Posted: April 9, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie results in the publication, after deidentification.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
Access Criteria:
  • With whom?

    • Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.
  • For what types of analyses?

    • To achieve aims in the proposal approved by the AIDS Clinical Trials Group.
  • By what mechanism will data be made available?

    • Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/about-actg/templates-and-forms. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases