A Phase 1, Open Label, Dose-escalation Study of the Safety, Pharmacokinetics and Antiretroviral Activity of 3BNC117

Study Overview
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Brief Summary
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The proposed study is a first-in-man phase I study that aims to evaluate the safety, tolerability and pharmacokinetics of 3BNC117 in HIV-infected and HIV-uninfected subjects, and its antiretroviral activity in HIV-infected subjects.

Detailed Description
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In preclinical studies carried out in humanized mice and non-human primates, 3BNC117 alone or in combination with other neutralizing antibodies led to protection from HIV-1 or SHIV infection and also to sustained suppression of HIV-1 plasma viremia. The aims of this protocol are to evaluate the safety, tolerability and pharmacokinetics profile of 3BNC117 in both HIV-infected and HIV-uninfected subjects,and its antiretroviral activity in HIV-infected subjects.

Official Title
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A Phase 1, Open Label, Dose-escalation Study of the Safety, Pharmacokinetics and Antiretroviral Activity of 3BNC117 Monoclonal Antibody in HIV-infected and HIV-uninfected Volunteers

Conditions
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Healthy, HIV

Intervention / Treatment
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* Biological: 1 mg/kg, single dose IV administration of 3BNC117
* Biological: 3 mg/kg, single dose IV administration of 3BNC117
* Biological: 10 mg/kg, single dose IV administration of 3BNC117
* Biological: 30 mg/kg, single dose IV administration of 3BNC117
* Biological: 10 mg/kg, two doses IV of 3BNC117
* Biological: 30 mg/kg, two doses IV of 3BNC117


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Group 1 (HIV-uninfected): Adult males and females, age 18 to 65 Amenable to HIV risk reduction counseling and agrees to maintaining behavior consistent with low risk of HIV exposure; If a sexually active male or female, participating in sexual activity that could lead to pregnancy, agrees to use an effective method of contraception throughout the study. Groups 2-5 (HIV-infected): Age 18 to 65 HIV infection confirmed by ELISA and immunoblot Groups 2A-D - on ART with HIV-1 plasma RNA levels below 100,000 copies/ml, or off ART for at least 8 weeks with HIV-1 plasma RNA level between 2,000-100,000 copies/ml by standard assays on 2 occasions at least 1 week apart; Group 2E - Untreated HIV-infected (not on ART for at least 8 weeks): HIV-1 RNA plasma levels between 2,000 - 100,000 copies/ml; Group 3 - Untreated HIV controllers (not on ART for at least 8 weeks): HIV-1 RNA plasma level of < 2,000 copies/ml by standard assays, on 2 occasions, at least 1 week apart, and ART-naive. Group 4 - ART treated with HIV-1 RNA plasma level of > 20 copies/ml by standard assays on 2 occasions, at least 1 week apart, while on combination antiretroviral therapy; Groups 5A and 5B - ART treated with HIV-1 RNA plasma level of < 20 copies/ml by standard assays on 2 occasions, at least 1 week apart, while on combination antiretroviral therapy; Current CD4 cell count > 300 cells/µl If sexually active male and female, participating in sexual activity that could lead to pregnancy, agrees to use an effective method of contraception throughout the study. Exclusion criteria: Group 1 (HIV-uninfected): Confirmed HIV-1 or HIV-2 infection; History of immunodeficiency or autoimmune disease; use 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 that in the opinion of the investigator would preclude participation; Within the 12 months prior to enrollment, the volunteer has a history of sexually transmitted disease; Hepatitis B (surface antigen, HbsAg) or hepatitis C (HCV antibodies); Laboratory abnormalities in the parameters listed below: Absolute neutrophil count ≤ 2,000 Hemoglobin ≤ 12 gm/dL if female; ≤ 13.5 gm/dL if male Platelet count ≤ 140,000 ALT ≥ 1.25 x ULN AST ≥ 1.25 x ULN Total bilirubin ≥ 1.1 ULN Creatinine ≥ 1.1 x ULN Coagulation parameters (PT, PTT, INR) ≥ 1.1 x ULN Pregnancy or breastfeeding; Any vaccination within 14 days prior to 3BNC117 administration; Receipt of any experimental HIV vaccine in the past 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. Groups 2-5 (HIV-infected): History of AIDS-defining illness 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, other than HIV infection, that in the opinion of the investigator would preclude participation; Hepatitis B (surface antigen, HbsAg) or hepatitis C (HCV antibodies); Laboratory abnormalities in the parameters listed below: Absolute neutrophil count ≤ 1,300 Hemoglobin ≤ 10 gm/dL Platelet count ≤ 125,000 ALT ≥ 2.0 x ULN AST ≥ 2.0 x ULN Total bilirubin ≥ 1.1 ULN Creatinine ≥ 1.1 x ULN Coagulation parameters ≥ 1.1 x ULN; Current antiretroviral regimen includes either maraviroc or enfuvirtide; Pregnancy or breastfeeding; Any vaccination within 14 days prior to 3BNC117 administration; Receipt of any experimental 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.

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1A<br>HIV-uninfected individuals 1 mg/kg, single dose IV administration of 3BNC117 | Biological: 1 mg/kg, single dose IV administration of 3BNC117<br>* 1 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Groups 1B<br>HIV-uninfected individuals 3 mg/kg, single dose IV administration of 3BNC117 | Biological: 3 mg/kg, single dose IV administration of 3BNC117<br>* 3 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Group 1C<br>HIV-uninfected individuals 10 mg/kg, single dose IV administration of 3BNC117 | Biological: 10 mg/kg, single dose IV administration of 3BNC117<br>* 10 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Group 1D<br>HIV-uninfected individuals 10 mg/kg, two doses IV of 3BNC117 | Biological: 10 mg/kg, two doses IV of 3BNC117<br>* 10 mg/kg, two IV administrations of 3BNC117 at weeks 0 and 12<br>|
| Experimental: Group 1E<br>HIV-uninfected individuals 30 mg/kg, single dose IV administration of 3BNC117 | Biological: 30 mg/kg, single dose IV administration of 3BNC117<br>* 30 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Group 1F<br>HIV-uninfected individuals 30 mg/kg, two doses IV of 3BNC117 | Biological: 30 mg/kg, two doses IV of 3BNC117<br>* 30 mg/kg, two IV administrations of 3BNC117 at weeks 0 and 12<br>|
| Experimental: Group 2A<br>HIV-infected individuals on or off ART 1 mg/kg, single dose IV administration of 3BNC117 | Biological: 1 mg/kg, single dose IV administration of 3BNC117<br>* 1 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Group 2B<br>HIV-infected individuals on or off ART 3 mg/kg, single dose IV administration of 3BNC117 | Biological: 3 mg/kg, single dose IV administration of 3BNC117<br>* 3 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Group 2C<br>HIV-infected individuals on or off ART 10 mg/kg, single dose IV administration of 3BNC117 | Biological: 10 mg/kg, single dose IV administration of 3BNC117<br>* 10 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Group 2D<br>HIV-infected individuals on or off ART 30 mg/kg, single dose IV administration of 3BNC117 | Biological: 30 mg/kg, single dose IV administration of 3BNC117<br>* 30 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Group 2E<br>HIV-infected individuals off ART, VL 2,000-100,000 copies/ml 30 mg/kg, single dose IV administration of 3BNC117 | Biological: 30 mg/kg, single dose IV administration of 3BNC117<br>* 30 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Group 3<br>HIV-infected individuals off ART, VL < 2,000 copies/ml 30 mg/kg, single dose IV administration of 3BNC117 | Biological: 30 mg/kg, single dose IV administration of 3BNC117<br>* 30 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Group 4<br>HIV-infected individuals on ART, VL < 100,000 copies/ml 30 mg/kg, single dose IV administration of 3BNC117 | Biological: 30 mg/kg, single dose IV administration of 3BNC117<br>* 30 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Group 5A<br>HIV-infected individuals on ART, VL < 20 copies/ml 10 mg/kg, single dose IV administration of 3BNC117 | Biological: 10 mg/kg, single dose IV administration of 3BNC117<br>* 10 mg/kg, single dose IV administration of 3BNC117<br>|
| Experimental: Group 5B<br>HIV-infected individuals on ART, VL < 20 copies/ml 30 mg/kg, single dose IV administration of 3BNC117 | Biological: 30 mg/kg, single dose IV administration of 3BNC117<br>* 30 mg/kg, single dose IV administration of 3BNC117<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | To evaluate the safety and tolerability profile of one or two intravenous infusions of 3BNC117 at 3 increasing dose levels in HIV-infected and HIV-uninfected individuals. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profile | To determine the pharmacokinetic profile of one or two intravenous infusions of 3BNC117 in HIV-uninfected and HIV-infected subjects. | 24 hours post infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Healthy Volunteers