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3BNC117 and 10-1074 in HIV-infected Individuals

Primary Purpose

Human Immunodeficiency Virus (HIV)

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
3BNC117
10-1074
Analytical treatment interruption
Placebo
Sponsored by
Rockefeller University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Human Immunodeficiency Virus (HIV) focused on measuring Broadly neutralizing antibody, 3BNC117, 10-1074

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

All groups:

  • Age 18 to 65.
  • HIV-1 infection confirmed by two independent laboratory assays.
  • If sexually active male or female, and participating in sexual activity that could lead to pregnancy, agrees to use two effective methods of contraception (i.e. condom with spermicide, diaphragm with spermicide, hormone-eluting intrauterine device (IUD), hormone-based contraceptive with condom) for the study duration.

Groups 1A and 1B:

  • HIV-infected volunteers on ART with HIV-1 plasma RNA levels < 20 copies/ml.
  • Current CD4 cell count > 300 cells/μl.

Groups 1C and 3:

  • HIV-infected volunteers off ART with detectable HIV-1 plasma RNA levels < 100,000 copies/ml by standard assays.
  • Current CD4 cell count > 300 cells/μl.

Group 2:

  • On antiretroviral therapy for a minimum of 24 months, with plasma HIV-1 RNA levels of < 50 copies/ml for at least 18 months, and < 20 copies/ml at screening. Note: a single viral load measurement > 50 but < 500 copies/ml during this time period is allowed.
  • Current CD4+ T cell counts > 500 cells/μl. CD4 cell count nadir > 200 cells/μl.
  • If on an NNRTI-based regimen willing to switch to a dolutegravir-based regimen for 4 weeks prior to discontinuing ART.

Exclusion Criteria:

  • Have a history of AIDS-defining illness within 3 year prior to enrollment.
  • History of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the trial physician within the last 6 months.
  • Any clinically significant acute or chronic medical condition (such as autoimmune diseases or coronary artery disease), other than HIV infection, that in the opinion of the investigator would preclude participation.
  • 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.
  • History of resistance to 2 or more classes of antiretroviral medication or known resistance to dolutegravir in participants on non-nucleoside reverse-transcriptase inhibitors (NNRTI), who would switch regimen prior to ATI (Group 2).
  • Laboratory abnormalities in the parameters listed below:
  • Absolute neutrophil count ≤ 1,000 cells/l
  • Hemoglobin ≤ 10 gm/dL
  • Platelet count ≤ 100,000 cells/l
  • Alanine Aminotransferase (AST) ≥ 1.5 x ULN
  • Aspartate Aminotransferase (AST) ≥ 1.5 x ULN
  • Alkaline phosphatase ≥ 1.5 x ULN
  • Total bilirubin > 1.0 ULN
  • eGFR < 60 mL/min/1.73m2
  • Pregnancy or lactation;
  • Any vaccination within 14 days prior to 3BNC117 and 10-1074 administration;
  • Subjects with known hypersensitivity to any constituent of the investigational products;
  • Receipt of any therapeutic HIV vaccine or monoclonal antibody therapy of any kind in the past;
  • Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.

Sites / Locations

  • The Rockefeller University
  • University Hospital of Cologne

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Group 1A

Group 1B

Group 1C

Group 2

Group 3

Arm Description

HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one intravenous infusion of 10-1074), each dosed at 10 mg/kg OR placebo (sterile saline), on day 0.

HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one intravenous infusion 10-1074, each dosed at 30 mg/kg, OR placebo (sterile saline), on day 0.

HIV-infected individuals, off ART will be administered one infusion of 3BNC117 and one infusion 10-1074, each dosed at 30 mg/kg, on day 0.

HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be administered three infusions of 3BNC117 and three infusions of 10-1074, each dosed at 30 mg/kg, on days 0, 21 and 42. Participants enrolled in Group 2 will undergo an analytical treatment interruption and they will discontinue their antiretroviral (ART) regimen on day 2.

HIV-infected individuals, off ART who will be administered three infusions of 3BNC117 and three infusions of 10-1074, each dosed at 30 mg/kg on days 0, 14 and 28.

Outcomes

Primary Outcome Measures

The number of participants with adverse events 1 week after 3BNC117 and 10-1074 infusions in all study groups.
Adverse events include: signs, symptoms and laboratory abnormalities, in addition to local and systemic reactogenicity
The decline in plasma HIV-1 RNA levels by a standard clinical assay in participants off ART enrolled in groups 1C and 3.
The percentage of participants who meet ART re-initiation criteria (plasma HIV-1 RNA ≥ 200 copies/ml and/or CD4 count < 350 cells/μl on two consecutive measurements) prior to 8 weeks after ART interruption in group 2.
Time to meeting ART re-initiation criteria (plasma HIV-1 RNA level ≥ 200 copies/ml, CD4+ T cell count < 350 cells/l in 2 consecutive measurements) following ART interruption in group 2.

Secondary Outcome Measures

The number of participants with adverse events that occur during study follow up after 3BNC117 and 10-1074 infusions in all study groups.
Adverse events include signs, symptoms and laboratory abnormalities.
The serum level of 3BNC117 and 10-1074 at the time of viral rebound in all study groups.
Number of participants with induced anti-3BNC117 and anti-10-1074 antibodies.
Level of induced anti-3BNC117 and anti-10-1074 antibodies.
Change in number of CD4+ T cells/uL

Full Information

First Posted
June 28, 2016
Last Updated
August 20, 2018
Sponsor
Rockefeller University
Collaborators
University Hospital of Cologne
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1. Study Identification

Unique Protocol Identification Number
NCT02825797
Brief Title
3BNC117 and 10-1074 in HIV-infected Individuals
Official Title
An Phase 1b Study of the Safety, Pharmacokinetics and Antiretroviral Activity of the Combination of 3BNC117 and 10-1074 in HIV-infected Individuals
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
June 2016 (undefined)
Primary Completion Date
August 1, 2018 (Actual)
Study Completion Date
August 15, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Rockefeller University
Collaborators
University Hospital of Cologne

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a phase 1b clinical trial to evaluate the safety, pharmacokinetics and the antiretroviral effects of the combination of two anti-human immunodeficiency virus (HIV) broadly neutralizing antibodies, 3BNC117 and 10-1074, administered intravenously in HIV-infected individuals. This study is intended to support the development of the combination of 3BNC117 and 10-1074 mAbs for use in the treatment of HIV-1 infection.
Detailed Description
The proposed study is a Phase 1b clinical trial to evaluate the safety, pharmacokinetics and the antiretroviral effects of the combination of two anti-HIV broadly neutralizing antibodies, 3BNC117 and 10-1074, administered intravenously in HIV-infected individuals. The study includes 5 study groups. Study participants will be administered one or three intravenous infusions of 3BNC117 and 10-1074, each mAb dosed at 10 or 30 mg/kg: Single dose groups: Group 1A (n=6) - HIV-infected individuals, on antiretroviral therapy (ART) with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one infusion of 10-1074, each dosed at 10 mg/kg (n=4), OR placebo (sterile saline; n=2), on day 0. Group 1B (n=6) - HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one infusion 10-1074, each dosed at 30 mg/kg (n=4), OR placebo (sterile saline; n=2), on day 0. Participants and investigators will be blinded to study assignment in groups 1A and 1B. Group 1C (n=4) - HIV-infected individuals, off ART will be administered one infusion of 3BNC117 and one infusion 10-1074, each dosed at 30 mg/kg, on day 0. Three doses groups: Group 2 (n=15) - HIV-infected individuals, on ART who will be administered three infusions of 3BNC117 and three infusions of 10-1074, each dosed at 30 mg/kg, on days 0, 21 (week 3) and 42 (week 6). Participants enrolled in Group 2 will discontinue their antiretroviral (ART) regimen on day 2. Group 3 (n=6) - HIV-infected individuals, off ART who will be administered three infusions of 3BNC117 and three infusions of 10-1074, each dosed at 30 mg/kg on days 0, 14 (week 2) and 28 (week 4). Following 3BNC117 and 10-1074 infusions, study participants will return for safety assessments at multiple time points. Blood samples will be collected for safety testing at weeks 1, 2, and 4 following each mAb infusion, then bi-monthly or monthly until the end of study follow up. Serum samples for PK (pharmacokinetic) measurements will be collected before the start of the first mAb infusion. Peak PK sampling for 3BNC117 will occur following the completion of the 3BNC117 infusion and prior to the start of the 10-1074 infusion. Peak PK sampling for 10-1074 will occur following the completion of the 10-1074 infusion. Additional samples for PK assessments will be collected at multiple time points during study follow up. Samples will also be collected for measurement of HIV-1 plasma RNA levels before 3BNC117 and 10-1074 infusions (screen, pre-infusion and day 0), at all follow up visits in Groups 1A, 1B and 2, and weekly during the ATI period and at later time points in Group 2. All participants will be followed for 24 weeks after the last 3BNC117 and 10-1074 infusions.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Human Immunodeficiency Virus (HIV)
Keywords
Broadly neutralizing antibody, 3BNC117, 10-1074

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
34 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1A
Arm Type
Experimental
Arm Description
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one intravenous infusion of 10-1074), each dosed at 10 mg/kg OR placebo (sterile saline), on day 0.
Arm Title
Group 1B
Arm Type
Experimental
Arm Description
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one intravenous infusion 10-1074, each dosed at 30 mg/kg, OR placebo (sterile saline), on day 0.
Arm Title
Group 1C
Arm Type
Experimental
Arm Description
HIV-infected individuals, off ART will be administered one infusion of 3BNC117 and one infusion 10-1074, each dosed at 30 mg/kg, on day 0.
Arm Title
Group 2
Arm Type
Experimental
Arm Description
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be administered three infusions of 3BNC117 and three infusions of 10-1074, each dosed at 30 mg/kg, on days 0, 21 and 42. Participants enrolled in Group 2 will undergo an analytical treatment interruption and they will discontinue their antiretroviral (ART) regimen on day 2.
Arm Title
Group 3
Arm Type
Experimental
Arm Description
HIV-infected individuals, off ART who will be administered three infusions of 3BNC117 and three infusions of 10-1074, each dosed at 30 mg/kg on days 0, 14 and 28.
Intervention Type
Drug
Intervention Name(s)
3BNC117
Other Intervention Name(s)
Monoclonal Antibody
Intervention Description
Intravenous infusion of 3BNC117
Intervention Type
Drug
Intervention Name(s)
10-1074
Other Intervention Name(s)
Monoclonal Antibody
Intervention Description
Intravenous infusion of 10-1074
Intervention Type
Other
Intervention Name(s)
Analytical treatment interruption
Other Intervention Name(s)
ART interruption
Intervention Description
Analytical treatment interruption
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Sterile Saline
Intervention Description
Intravenous infusion of placebo (sterile saline)
Primary Outcome Measure Information:
Title
The number of participants with adverse events 1 week after 3BNC117 and 10-1074 infusions in all study groups.
Description
Adverse events include: signs, symptoms and laboratory abnormalities, in addition to local and systemic reactogenicity
Time Frame
1 week following each combination of 3BNC117 and 10-1074 infusion
Title
The decline in plasma HIV-1 RNA levels by a standard clinical assay in participants off ART enrolled in groups 1C and 3.
Time Frame
20-24 weeks
Title
The percentage of participants who meet ART re-initiation criteria (plasma HIV-1 RNA ≥ 200 copies/ml and/or CD4 count < 350 cells/μl on two consecutive measurements) prior to 8 weeks after ART interruption in group 2.
Time Frame
30 weeks
Title
Time to meeting ART re-initiation criteria (plasma HIV-1 RNA level ≥ 200 copies/ml, CD4+ T cell count < 350 cells/l in 2 consecutive measurements) following ART interruption in group 2.
Time Frame
30 weeks
Secondary Outcome Measure Information:
Title
The number of participants with adverse events that occur during study follow up after 3BNC117 and 10-1074 infusions in all study groups.
Description
Adverse events include signs, symptoms and laboratory abnormalities.
Time Frame
20-30 weeks
Title
The serum level of 3BNC117 and 10-1074 at the time of viral rebound in all study groups.
Time Frame
20-30 weeks
Title
Number of participants with induced anti-3BNC117 and anti-10-1074 antibodies.
Time Frame
20-30 weeks
Title
Level of induced anti-3BNC117 and anti-10-1074 antibodies.
Time Frame
20-30 weeks
Title
Change in number of CD4+ T cells/uL
Time Frame
20-30 weeks
Other Pre-specified Outcome Measures:
Title
Changes in viral envelope sequences following 3BNC117 and 10-1074 infusions (groups 1C, 2-3)
Time Frame
20-30 weeks
Title
Phylogenetic comparison of viruses grown from PBMCs collected from subjects while on ART to rebound viruses collected after treatment interruption (group 2).
Time Frame
20-30 weeks
Title
Levels of cell-associated HIV-1 RNA and DNA before and after 3BNC117 and 10-1074 infusions in HIV-infected individuals.
Time Frame
20-30 weeks
Title
Analysis of HIV-1 integration sites before and after 3BNC117 and 10-1074 infusions in HIV-infected individuals.
Time Frame
20-30 weeks
Title
HIV-1 specific T and B immune responses following 3BNC117 and 10-1074 infusions (groups 1-3).
Description
These will be measured by intracellular cytokine staining and by TZM.bl assays against a panel of viruses from multiple HIV clades.
Time Frame
20-30 weeks
Title
Elimination half-life (t1/2) of 3BNC117 and 10-1074
Time Frame
20-30 weeks
Title
Clearance (CL/F) of 3BNC117 and 10-1074
Time Frame
20-30 weeks
Title
Volume of distribution (Vz/F) of 3BNC117 and 10-1074
Time Frame
20-30 weeks
Title
Area under the plasma concentration versus time curve (AUC) of 3BNC117 and 10-1074
Time Frame
20-30 weeks
Title
Decay Curves of 3BNC117 and 10-1074
Time Frame
20-30 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: All groups: Age 18 to 65. HIV-1 infection confirmed by two independent laboratory assays. If sexually active male or female, and participating in sexual activity that could lead to pregnancy, agrees to use two effective methods of contraception (i.e. condom with spermicide, diaphragm with spermicide, hormone-eluting intrauterine device (IUD), hormone-based contraceptive with condom) for the study duration. Groups 1A and 1B: HIV-infected volunteers on ART with HIV-1 plasma RNA levels < 20 copies/ml. Current CD4 cell count > 300 cells/μl. Groups 1C and 3: HIV-infected volunteers off ART with detectable HIV-1 plasma RNA levels < 100,000 copies/ml by standard assays. Current CD4 cell count > 300 cells/μl. Group 2: On antiretroviral therapy for a minimum of 24 months, with plasma HIV-1 RNA levels of < 50 copies/ml for at least 18 months, and < 20 copies/ml at screening. Note: a single viral load measurement > 50 but < 500 copies/ml during this time period is allowed. Current CD4+ T cell counts > 500 cells/μl. CD4 cell count nadir > 200 cells/μl. If on an NNRTI-based regimen willing to switch to a dolutegravir-based regimen for 4 weeks prior to discontinuing ART. Exclusion Criteria: Have a history of AIDS-defining illness within 3 year prior to enrollment. History of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the trial physician within the last 6 months. Any clinically significant acute or chronic medical condition (such as autoimmune diseases or coronary artery disease), other than HIV infection, that in the opinion of the investigator would preclude participation. 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. History of resistance to 2 or more classes of antiretroviral medication or known resistance to dolutegravir in participants on non-nucleoside reverse-transcriptase inhibitors (NNRTI), who would switch regimen prior to ATI (Group 2). Laboratory abnormalities in the parameters listed below: Absolute neutrophil count ≤ 1,000 cells/l Hemoglobin ≤ 10 gm/dL Platelet count ≤ 100,000 cells/l Alanine Aminotransferase (AST) ≥ 1.5 x ULN Aspartate Aminotransferase (AST) ≥ 1.5 x ULN Alkaline phosphatase ≥ 1.5 x ULN Total bilirubin > 1.0 ULN eGFR < 60 mL/min/1.73m2 Pregnancy or lactation; Any vaccination within 14 days prior to 3BNC117 and 10-1074 administration; Subjects with known hypersensitivity to any constituent of the investigational products; Receipt of any therapeutic HIV vaccine or monoclonal antibody therapy of any kind in the past; Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marina Caskey, MD
Organizational Affiliation
Rockefeller University
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Rockefeller University
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
University Hospital of Cologne
City
Cologne
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

3BNC117 and 10-1074 in HIV-infected Individuals

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