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

Primary Purpose

Human Immunodeficiency Virus

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
3BNC117-LS
10-1074-LS
N803
Sponsored by
Rockefeller University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Human Immunodeficiency Virus focused on measuring 3BNC117-LS, 10-1074-LS, Broadly Neutralizing Antibody, N-803, IL-15 superagonist complex

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male and females, age 18 to 70.
  2. Confirmed HIV-1 infection.
  3. 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.

  4. Current CD4+ T cell counts > 450 cells/mcL, CD4+ T cell % ≥ 15%, and CD4+ T cell count nadir of ≥ 200 cells/mcL.
  5. If on an NNRTI-based regimen, willing to switch to an integrase inhibitor-based regimen for at least 4 weeks prior to discontinuing ART.
  6. 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).
  7. 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.
  8. 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.
  9. 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:

  1. History of AIDS-defining illness within 3 years prior to enrollment.
  2. 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.
  3. 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.
  4. History of or current clinical atherosclerotic cardiovascular disease (ASCVD), as defined by 2013 ACC/AHA guidelines.
  5. QTcF interval ≥ 440 ms at screening.
  6. Any history of an HIV-associated malignancy, including Kaposi's sarcoma, or any type of lymphoma or virus-associated cancers.
  7. History of Progressive Multifocal Leukoencephalopathy (PML).
  8. 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;
  9. 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.
  10. Participants with known hypersensitivity to any constituent of the investigational products.
  11. Pregnancy or lactation.
  12. ART initiated during acute infection (defined as p24, HIV NAAT, or HIV RNA PCR positive, and negative or indeterminate HIV antibody testing).
  13. Receipt of cabotegravir-LA IM or rilpivirine-LA IM within 24 months prior to Step 1 study entry.
  14. Known resistance to all drugs within two or more ARV drug classes.
  15. 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;
  16. Any history of receipt of therapeutic HIV vaccine or HIV monoclonal antibody therapy.
  17. 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.

Sites / Locations

  • Weill Cornell Medicine, Cornell Clinical Trials UnitRecruiting
  • The Rockefeller UniversityRecruiting
  • Perelman School of Medicine University of PennsylvaniaRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

3BNC117-LS + 10-1074-LS + N-803

Arm Description

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)

Outcomes

Primary Outcome Measures

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).
Any serious adverse events
The number of participants with serious adverse events, regardless of relationship to 3BNC117-LS, 10-1074-LS and N-803.
Dosing completion
The proportion of participants who complete dosing with 3BNC117-LS, 10-1074-LS and N-803.
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.
ART not restarted by weeks 60 and 72
The proportion of participants who do not meet ART restart criteria by weeks 60 and 72.
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.

Secondary Outcome Measures

Treatment-related Grade 2 adverse events
The number of participants with treatment-related solicited and unsolicited grade 2 adverse events.
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.
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.
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.
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.
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.
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.
Anti-drug antibodies (ADA)
The proportion of individuals with treatment-induced ADA against each bNAb or N-803 and magnitude of the response.

Full Information

First Posted
February 8, 2022
Last Updated
October 23, 2023
Sponsor
Rockefeller University
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID), Weill Medical College of Cornell University, University of Pennsylvania
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1. Study Identification

Unique Protocol Identification Number
NCT05245292
Brief Title
3BNC117-LS and 10-1074-LS Plus N-803 (bNAb+N-803)
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 7, 2022 (Actual)
Primary Completion Date
December 31, 2025 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Rockefeller University
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID), Weill Medical College of Cornell University, University of Pennsylvania

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Human Immunodeficiency Virus
Keywords
3BNC117-LS, 10-1074-LS, Broadly Neutralizing Antibody, N-803, IL-15 superagonist complex

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
3BNC117-LS + 10-1074-LS + N-803
Arm Type
Experimental
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
3BNC117-LS
Other Intervention Name(s)
broadly neutralizing antibody, monoclonal antibody
Intervention Description
Intravenous infusion of 3BNC117-LS at 30 mg/kg
Intervention Type
Drug
Intervention Name(s)
10-1074-LS
Other Intervention Name(s)
broadly neutralizing antibody, monoclonal antibody
Intervention Description
Intravenous infusion of 10-1074-LS at 10 mg/kg
Intervention Type
Drug
Intervention Name(s)
N803
Other Intervention Name(s)
IL-15 superagonist complex
Intervention Description
Subcutaneous injections of N803 at 6 mcg/kg
Primary Outcome Measure Information:
Title
Treatment-related Grade 3 adverse events and serious adverse events
Description
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).
Time Frame
72 weeks
Title
Any serious adverse events
Description
The number of participants with serious adverse events, regardless of relationship to 3BNC117-LS, 10-1074-LS and N-803.
Time Frame
72 weeks
Title
Dosing completion
Description
The proportion of participants who complete dosing with 3BNC117-LS, 10-1074-LS and N-803.
Time Frame
24 weeks
Title
Viral rebound before or at week 24 post withdrawing ART
Description
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.
Time Frame
24 weeks
Title
ART not restarted by weeks 60 and 72
Description
The proportion of participants who do not meet ART restart criteria by weeks 60 and 72.
Time Frame
72 weeks
Title
ART not restarted when bNABs below threshold
Description
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.
Time Frame
72 weeks
Secondary Outcome Measure Information:
Title
Treatment-related Grade 2 adverse events
Description
The number of participants with treatment-related solicited and unsolicited grade 2 adverse events.
Time Frame
72 weeks
Title
Viral rebound through Step 2
Description
The number of participants experiencing viral rebound, defined as confirmed HIV-1 RNA >200 copies/mL, through Step 2 of the study.
Time Frame
72 weeks
Title
Time from ART withdrawal to re-initiating ART
Description
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.
Time Frame
72 weeks
Title
Viral rebound determined by Monogram assay
Description
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.
Time Frame
72 weeks
Title
Size of latent HIV-1 reservoir
Description
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.
Time Frame
72 weeks
Title
Changes in HIV-1 specific T Cell immune responses
Description
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.
Time Frame
72 weeks
Title
Half-life of 3BNC117-LS and 10-1074-LS
Description
Half-life of 3BNC117-LS and 10-1074-LS, when administered in combination with N-803 to individuals with HIV during ART interruption.
Time Frame
72 weeks
Title
Anti-drug antibodies (ADA)
Description
The proportion of individuals with treatment-induced ADA against each bNAb or N-803 and magnitude of the response.
Time Frame
72 weeks
Other Pre-specified Outcome Measures:
Title
Plasma rebound virus sensitivity
Description
The relationship between plasma rebound virus sensitivity to 3BNC117-LS and 10-1074-LS and serum levels of 3BNC117-LS and 10-1074-LS at the time of viral rebound.
Time Frame
48 weeks
Title
HIV-1 specific T cell immune response changes
Description
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 in combination with N-803.
Time Frame
72 weeks
Title
Latent HIV-1 reservoir composition
Description
Composition of the latent HIV-1 reservoir before and after immunotherapy with 3BNC117-LS and 10-1074-LS in combination with N-803 evaluated by Q4PCR or other appropriate assays that may become available.
Time Frame
72 weeks
Title
Neutralization sensitivity
Description
Neutralization sensitivity by TZM/bl assay (IC50, IC80 and IC90) of representative viruses during ART and antibody suppression, and of plasma rebound viruses to 3BNC117 and 10-1074.
Time Frame
72 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Recruitment Specialist
Phone
800-782-2737
Email
rucares@rockefeller.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Marina Caskey, MD
Email
mcaskey@rockefeller.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marina Caskey, MD
Organizational Affiliation
The Rockefeller University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Weill Cornell Medicine, Cornell Clinical Trials Unit
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Timothy Wilkin, MD
Phone
212-746-4177
Email
tiw2001@med.cornell.edu
Facility Name
The Rockefeller University
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Recruitment Specialist
Phone
800-782-2737
Email
rucares@rockefeller.edu
First Name & Middle Initial & Last Name & Degree
Katrina Millard, ANP
Phone
212-327-7546
Email
kmillard@rockefeller.edu
Facility Name
Perelman School of Medicine University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kendra Poirier
Phone
267-328-7016
Email
poirierk@sas.upenn.edu

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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