3BNC117-LS and 10-1074-LS in Viremic HIV-infected Individuals

Study Overview
=================
Brief Summary
-----------------
The proposed study is a phase 1, open label, single arm study to evaluate the safety, pharmacokinetics and antiviral activity of single intravenous infusions of 3BNC117-LS and 10-1074-LS, each monoclonal antibody (mAb) dosed at 30 mg/kg in viremic human immunodeficiency virus (HIV)-infected individuals.

Detailed Description
-----------------
The proposed study is a phase 1, open label, single arm study to evaluate the safety, pharmacokinetics and antiviral activity of single intravenous infusions of 3BNC117-LS and 10-1074-LS in viremic HIV-infected individuals. Ten eligible participants will be enrolled sequentially in the study and will receive each mAb, dosed at 30 mg/kg intravenously and in sequence on study day 0. Following mAb administration, study participants will return for safety assessments on days 1 and 3, and weeks 1, 2, 3 and 4 following dosing, then bi-weekly or monthly until the end of study follow up. All participants will be followed for 24 weeks after 3BNC117-LS and 10-1074-LS administration. Safety assessments will be performed at multiple time points following 3BNC117-LS and 10-1074-LS infusions. Serum samples for pharmacokinetic (PK) measurements will be collected before and at the end each mAb infusion administration and at multiple subsequent time points during study follow up. Samples will also be collected for measurement of HIV-1 plasma RNA levels before 3BNC117-LS and 10-1074-LS infusions (screen and day 0) and at every follow up visit. T cell subsets will also be monitored during study follow up. Assessments will also include measurement of anti-drug antibody responses and sequencing of plasma envelope before infusions and after viral rebound (first time point after viremia nadir is reached and viral load (VL) is > 1,000 copies/ml). Participants will be advised and encouraged to start antiretroviral therapy (ART) within 4 weeks of receiving 3BNC117-LS and 10-1074-LS infusions or sooner if: VL fails to decrease by > 0.5 log10 copies/ml within 2 weeks of antibody infusions, VL increases > 0.5 log10 copies/ml between weekly measurements or significant T-cell decline (confirmed CD4+ T cells < 200 cells/μl) is noted.

Official Title
-----------------
An Open Label, Single Arm Study of the Safety, Pharmacokinetics and Antiretroviral Activity of the Combination of 3BNC117-LS and 10-1074-LS in Viremic HIV-infected Individuals.

Conditions
-----------------
Human Immunodeficiency Virus

Intervention / Treatment
-----------------
* Drug: 3BNC117-LS
* Drug: 10-1074-LS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females, >18 years of age. Confirmed HIV-1 infection. Off ART for at least 4 weeks with a HIV-1 plasma RNA level between 500 and 100,000 copies/mL (ART-naïve or off ART due to intolerance or by choice). Current CD4+ T cell count > 300 cells/μl. If sexually active male or female, and participating in sexual activity that could lead to pregnancy or transmission of HIV, agrees to use two effective methods of contraception (i.e. condom with spermicide, diaphragm with spermicide, hormone-eluting IUD, hormone-based contraceptive with condom) from 10 days prior to and six months after 3BNC117-LS and 10-1074-LS administration. Exclusion Criteria: Have a history of AIDS-defining illness within 3 years 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), 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. Laboratory abnormalities in the parameters listed below: Absolute neutrophil count ≤ 1,000 cells/μl; Hemoglobin ≤ 10 gm/dL; Platelet count ≤ 100,000 cells/μl; ALT ≥ 1.5 x ULN; AST ≥ 1.5 x ULN; Alkaline phosphatase ≥ 1.5 x ULN; Total bilirubin > 1.25 x ULN; eGFR < 60 mL/min/1.73m2. Pregnancy or lactation. Any vaccination within 14 days prior to mAb infusions, except for influenza vaccine. Receipt of another investigational product currently or within the past 12 weeks, or expected concurrent participation in another study in which investigational products will be administered. Receipt of any experimental HIV vaccine or anti-HIV monoclonal antibody therapy in the past. History of severe reaction to a vaccine or drug infusion or history of severe allergic reactions. Individuals with known hypersensitivity to any constituent of the investigational products.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Participants<br>HIV-infected individuals, off ART, and with plasma HIV-1 RNA levels between 500 and 100,000 copies/ml by standard assays. Study participants will receive a single intravenous infusion of 3BNC117-LS and a single infusion of 10-1074-LS. The antibodies will be administered sequentially and dosed at 30 mg/kg. | Drug: 3BNC117-LS<br>* Intravenous infusion of 3BNC117-LS at 30mg/kg<br>* Other names: Monoclonal Antibody;Drug: 10-1074-LS<br>* Intravenous infusion of 10-1074-LS at 30mg/kg<br>* Other names: Monoclonal Antibody;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3 and Serious Adverse Events | The number of participants with treatment-related solicited and unsolicited grade 3 and serious adverse events (including confirmed laboratory abnormalities). | 24 weeks | 
| Peak Concentration | Peak concentration of 3BNC117-LS and 10-1074-LS when administered intravenously and in combination to viremic HIV-infected individuals. | 24 weeks | 
| Half-life | Half-life of 3BNC117-LS and 10-1074-LS when administered intravenously and in combination to viremic HIV-infected individuals. | 24 weeks | 
| Area Under Curve | Area under curve of 3BNC117-LS and 10-1074-LS when administered intravenously and in combination to viremic HIV-infected individuals. | 24 weeks | 
| Maximum Decline in Plasma HIV-1 RNA Level | Maximum decline in plasma HIV-1 RNA level after 3BNC117-LS plus 10-1074-LS intravenous infusions in viremic HIV-infected individuals through week 4 after infusions. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-drug Antibodies | Number of individuals with treatment-induced anti-drug antibodies against each mAb and magnitude of the response. | 24 weeks | 
| Adverse Events | The number of adverse events that occur during the study follow up period after 3BNC117-LS and 10-1074-LS administration. | 24 weeks | 
| Laboratory Abnormalities | The number of confirmed laboratory abnormalities that occur during the study follow up period after 3BNC117-LS and 10-1074-LS administration. | 24 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
3BNC117-LS, 10-1074-LS, Broadly Neutralizing Antibody