3BNC117 Monoclonal Antibody in HIV-infected Subjects During Treatment Interruption

Study Overview
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Brief Summary
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This study evaluates the effects of two infusions of 3BNC117 in preventing or delaying rebound of viral load during a brief treatment interruption of standard ART and its safety during a brief analytical interruption of antiretroviral therapy.

Detailed Description
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The proposed study is a Phase II, open label study to evaluate the safety and antiretroviral activity of two and four infusions of 3BNC117 in HIV-infected subjects on combination ART during a brief analytical treatment interruption. After meeting enrollment criteria sixteen subjects with 3BNC117 sensitive virus (<2μg/ml IC50) will receive two (Group A) or four (Group B) intravenous infusions of 3BNC117, administered at 30 mg/kg. In both dosing groups, antiretroviral therapy will be discontinued 2 days after the first 3BNC117 infusion (day 2) until week 12. Combination ART will be resumed at week 12. ART will be resumed sooner if plasma HIV-1 RNA level is ≥ 200 copies/ml or if CD4+ count drops < 350 cells/μl and either result is confirmed upon repeat measurement. Participants will be followed weekly until week 12 for safety assessments and for monitoring plasma HIV-1 RNA levels (viral load). CD4+ T cell counts will be monitored every 2 weeks until week 12. Participants may remain off antiretroviral therapy after week 12, with weekly viral load monitoring, if viral rebound does not occur by week 12. Participants will be followed for a total of 36 weeks.

Official Title
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A Phase 2, Open Label Study of the Safety, Antiretroviral Activity and Pharmacokinetics of 3BNC117 During a Short Analytical Treatment Interruption in HIV-infected Subjects

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: 3BNC117
* Other: ART Interruption


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 to 65 HIV-1 infection confirmed by ELISA and immunoblot. Plasma HIV-1 RNA < 50 copies/ml for at least 12 months while on combination ART and < 20 copies/ml at the screening visit. [Note: One or two viral blips of < 200 copies/mL prior to enrollment are permitted if preceded and followed by test results showing VL less than or equal to 50 copies/mL on the same ARV regimen.] 3BNC117 sensitivity (IC50 < 2 μg/ml) of subject derived HIV-1 virus isolates. These are isolated under protocol MCA-823 by co-culture of subject PBMCs with HIV-uninfected donor PBMCs followed by in vitro neutralization assays as previously described Current CD4 cell count > 500 cells/μl and no prior CD4 cell count < 200 cells/μl. Willing to interrupt antiretroviral treatment for 12 weeks, or until viral rebound occurs. If sexually active male or female, and participating in sexual activity that could lead to pregnancy using an effective method of contraception throughout the study period. Subjects should also agree to use a male or female condom during the time of pausing their HIV medication. If on an NNRTI-based regimen willing to a switch for 4 weeks to dolutegravir. Exclusion Criteria: Have a history of AIDS-defining illness within 1 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; Chronic hepatitis B or hepatitis C; Patient report, or chart history, of significant coronary artery disease, myocardial infarction, percutaneous coronary intervention with placement of cardiac stents; Patient report, or chart history, of diabetes type 1 or 2 and/or current use of insulin or oral hypoglycemic medications; Uncontrolled hypertension, as defined by a systolic blood pressure > 180 and/or diastolic blood pressure > 120, in the presence or absence of anti-hypertensive medications; Any other clinically significant acute or chronic medical condition, such as autoimmune diseases, that in the opinion of the investigator would preclude participation; Current cigarette use in excess of 1 pack per day; Laboratory abnormalities in the parameters listed below: Absolute neutrophil count ≤1,000 Hemoglobin ≤ 10 gm/dL Platelet count ≤125,000 ALT ≥ 2.0 x ULN AST ≥ 2.0 x ULN Total bilirubin ≥ 1.5 ULN Creatinine ≥ 1.1 x ULN Coagulation parameters ≥ 1.5 x ULN; Current antiretroviral regimen includes either maraviroc or enfuvirtide; Pregnancy or lactation; Any vaccination within 14 days prior to 3BNC117 administration; Receipt of any 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. History of resistance to two or more antiretroviral drug classes

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: 3BNC117 IV + ART Interruption<br>Two intravenous infusions of 3BNC117 (30 mg/kg) at day 0 and day 21, with interruption of antiretroviral treatment (ART) at day 2. | Drug: 3BNC117<br>* 3BNC117 infusions<br>* Other names: 3BNC117 antibody;Other: ART Interruption<br>* Antiretroviral therapy will be discontinued 2 days after the first 3BNC117 infusion (day 2) and resumed at week 12.<br>* Other names: Treatment Interruption;|
| Experimental: Group B: 3BNC117 IV + ART interruption<br>Four intravenous infusions of 3BNC117 (30 mg/kg) at day 0, day 14, day 28, and day 42 with interruption of antiretroviral treatment (ART) at day 2. | Drug: 3BNC117<br>* 3BNC117 infusions<br>* Other names: 3BNC117 antibody;Other: ART Interruption<br>* Antiretroviral therapy will be discontinued 2 days after the first 3BNC117 infusion (day 2) and resumed at week 12.<br>* Other names: Treatment Interruption;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Virologic Rebound at 8 Weeks After Interruption of Antiretroviral Therapy | Virologic rebound is defined as confirmed plasma HIV-1 RNA level > 200 copies/ml in two separate occasions | 8 weeks | 
| The Rate of Signs, Symptoms and Laboratory Abnormalities After 3BNC117 Infusions | The percentage of participants who experienced adverse events (e.g. signs, symptoms and laboratory abnormalities) following 3BNC117 infusions. | 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Plasma Level of 3BNC117 at the Time of Viral Rebound. | The plasma concentrations of 3BNC117 at the time of viral rebound (i.e. confirmed plasma HIV-1 RNA levels > 200 copies/ml). | 36 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, 3BNC117, Broadly neutralizing antibody