Human Immunodeficiency Virus
Conditions
Keywords
3BNC117-LS, 10-1074-LS, Broadly Neutralizing Antibody
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.
Interventions
DRUG3BNC117-LS
Intravenous infusion of 3BNC117-LS at 30mg/kg
DRUG10-1074-LS
Intravenous infusion of 10-1074-LS at 30mg/kg
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Weill Medical College of Cornell University
University of Pennsylvania
Rockefeller University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females, \>18 years of age. 2. Confirmed HIV-1 infection. 3. 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). 4. Current CD4+ T cell count \> 300 cells/μl. 5. 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
1. Have a history of AIDS-defining illness within 3 years prior to enrollment. 2. History of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the trial physician within the last 6 months. 3. 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. 4. 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. 5. 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. 6. Pregnancy or lactation. 7. Any vaccination within 14 days prior to mAb infusions, except for influenza vaccine. 8. 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. 9. Receipt of any experimental HIV vaccine or anti-HIV monoclonal antibody therapy in the past. 10. History of severe reaction to a vaccine or drug infusion or history of severe allergic reactions. 11. Individuals with known hypersensitivity to any constituent of the investigational products.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Decline in Plasma HIV-1 RNA Level | 4 weeks | 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. |
| Peak Concentration | 24 weeks | Peak concentration of 3BNC117-LS and 10-1074-LS when administered intravenously and in combination to viremic HIV-infected individuals. |
| Half-life | 24 weeks | Half-life of 3BNC117-LS and 10-1074-LS when administered intravenously and in combination to viremic HIV-infected individuals. |
| Area Under Curve | 24 weeks | Area under curve of 3BNC117-LS and 10-1074-LS when administered intravenously and in combination to viremic HIV-infected individuals. |
| Grade 3 and Serious Adverse Events | 24 weeks | The number of participants with treatment-related solicited and unsolicited grade 3 and serious adverse events (including confirmed laboratory abnormalities). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | 24 weeks | The number of adverse events that occur during the study follow up period after 3BNC117-LS and 10-1074-LS administration. |
| Laboratory Abnormalities | 24 weeks | The number of confirmed laboratory abnormalities that occur during the study follow up period after 3BNC117-LS and 10-1074-LS administration. |
| Anti-drug Antibodies | 24 weeks | Number of individuals with treatment-induced anti-drug antibodies against each mAb and magnitude of the response. |
Countries
United States
Participant flow
Pre-assignment details
Open-label, sequential enrollment
Participants by arm
| Arm | Count |
|---|---|
| Study Participants 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. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 2 |
Baseline characteristics
| Characteristic | Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 35.8 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 1 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
Area Under Curve
Area under curve of 3BNC117-LS and 10-1074-LS when administered intravenously and in combination to viremic HIV-infected individuals.
Time frame: 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Study Participants | Area Under Curve | 3BNC117-LS | 13965.98 (mcg x day)/mL | Standard Deviation 2922.99 |
| Study Participants | Area Under Curve | 10-1074-LS | 34539.92 (mcg x day)/mL | Standard Deviation 34539.92 |
Primary
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).
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Participants | Grade 3 and Serious Adverse Events | 0 Participants |
Primary
Half-life
Half-life of 3BNC117-LS and 10-1074-LS when administered intravenously and in combination to viremic HIV-infected individuals.
Time frame: 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Study Participants | Half-life | 3BNC117-LS | 41.63 days | Standard Deviation 11.71 |
| Study Participants | Half-life | 10-1074-LS | 47.62 days | Standard Deviation 15.38 |
Primary
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.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Participants | Maximum Decline in Plasma HIV-1 RNA Level | 1.79 log 10 HIV-1-RNA copies/ml |
Primary
Peak Concentration
Peak concentration of 3BNC117-LS and 10-1074-LS when administered intravenously and in combination to viremic HIV-infected individuals.
Time frame: 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Study Participants | Peak Concentration | 3BNC117-LS | 719.83 mcg/ml | Standard Deviation 77.62 |
| Study Participants | Peak Concentration | 10-1074-LS | 915.15 mcg/ml | Standard Deviation 207.18 |
Secondary
Adverse Events
The number of adverse events that occur during the study follow up period after 3BNC117-LS and 10-1074-LS administration.
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Participants | Adverse Events | 5 adverse events |
Secondary
Anti-drug Antibodies
Number of individuals with treatment-induced anti-drug antibodies against each mAb and magnitude of the response.
Time frame: 24 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Study Participants | Anti-drug Antibodies | Anti-3BNC117-LS | 0 Participants |
| Study Participants | Anti-drug Antibodies | Anti-10-1074-LS | 1 Participants |
Secondary
Laboratory Abnormalities
The number of confirmed laboratory abnormalities that occur during the study follow up period after 3BNC117-LS and 10-1074-LS administration.
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Participants | Laboratory Abnormalities | 20 graded laboratory abnormalities |