VRC 605: Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB075-00-AB (VRC07-523LS), Administered Intravenously or Subcutaneously to Healthy Adults

Study Overview
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Brief Summary
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Background: Human immunodeficiency virus (HIV) is a global health threat. The body uses antibodies to fight infection. VRC07-523LS is an antibody directed against HIV. It may be used to prevent mother-to-child transmission of HIV. It may also prevent sexual transmission of HIV and treat HIV-1 infected people. Objective: To test the safety, tolerability, dose, and pharmacokinetics of VRC07-523LS in healthy adults. Eligibility: Healthy people ages 18-50 Design: Participants will be screened with: Medical history Physical exam Blood and urine tests Participants will be assigned to 1 of 7 groups: Groups 1-5 will get the drug at 1 visit and then be observed for 24 weeks. Groups 6 and 7 will get the drug at 1 visit every 12 weeks, for a total of 3 doses over 48 weeks. Participants will get the drug in 1 of 2 ways: Infusion into a vein over at least 30 minutes. Participants will have blood tests 1, 3, and 6 hours after the infusion. They will have 1-3 visits during that week. Those in Group 7 will have 4-5 visits in the week after their second and third doses. Injection into the fatty tissue under the skin. Participants will have blood tests before the injection. They will have 1-3 visits during that week. Those in Group 6 will have 4-5 visits after the second and third doses. Visits include: Physical exam Blood and urine tests Optional oral swabs to collect saliva Participants will keep a diary of their temperature and symptoms for 3 days after each dose.

Detailed Description
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This is the first study of the VRC-HIVMAB075-00-AB (VRC07-523LS) monoclonal antibody (MAb) in healthy adults. It is a phase 1, dose-escalation study to examine safety, tolerability, dose, and pharmacokinetics of VRC07-523LS. The hypothesis is that VRC07-523LS will be safe for administration to healthy adults by the intravenous (IV) and subcutaneous (SC) routes. Healthy adults 18-50 years of age will be enrolled. There are 4 open-label, dose escalations of VRC07-523LS from 1 mg/kg IV to 40 mg/kg IV, 1 route escalation from IV to SC, and 2 open-label groups to assess repeat dosing. Groups 1-5 are expected to include 3 subjects and Groups 6-7 are expected to enroll 5 subjects. Subjects will be followed for 24 weeks after the last study product administration.

Official Title
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VRC 605: A Phase 1 Dose-Escalation Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB075-00-AB (VRC07-523LS), Administered Intravenously or Subcutaneously to Healthy Adults

Conditions
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HIV Prevention

Intervention / Treatment
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* Biological: VRC-HIVMAB075-00-AB


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: A volunteer must meet all of the following criteria: Able and willing to complete the informed consent process. 18 to 50 years of age. Based on history and examination, must be in good general health and without history of any of the conditions listed in the exclusion criteria. Willing to have blood samples collected, stored indefinitely, and used for research purposes. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process. Willing to adhere to reduced risk sexual behavior during study participation. Screening laboratory values within 84 days prior to enrollment must meet the following criteria: White Blood Cell (WBC) 2,500-12,000/mm^3. WBC differential either within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval. Platelets = 125,000 - 400,000/mm^3. Hemoglobin within institutional normal range. Creatinine less than or equal to 1.1 x upper limit of normal (ULN). Alanine aminotransferase (ALT) less than or equal to 1.25 x ULN. Negative for HIV infection by the FDA approved method of detection. Female-Specific Criteria: If a woman is of reproductive potential and sexually active with a male partner, then she agrees to use an effective means of birth control from the time of study enrollment until the last study visit, or to be monogamous with a partner who has had a vasectomy. Negative Beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment for women presumed to be of reproductive potential. EXCLUSION CRITERIA: A volunteer will be excluded if one or more of the following conditions apply: Previous receipt of licensed or investigational monoclonal antibody. Weight >115 kg. Any history of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis prior to enrollment that has a reasonable risk of recurrence during the study. Hypertension that is not well controlled. Woman who is breast-feeding, or planning to become pregnant during the study participation. Receipt of any investigational study agent within 28 days prior to enrollment. Any other chronic or clinically significant medical condition that in the opinion of the investigator would jeopardize the safety or rights of the volunteer, including but not limited to: diabetes mellitus type I, chronic hepatitis; OR clinically significant forms of: drug or alcohol abuse, asthma, autoimmune disease, psychiatric disorders, heart disease, or cancer.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Prevention
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 1 mg/kg IV Single Dose<br>Group 1 subjects received a single IV infusion of VRC07-523LS (VRC-HIVMAB075-00-AB) on Day 0 at a dose of 1 mg/kg. | Biological: VRC-HIVMAB075-00-AB<br>* VRC07-523LS is an Investigational Monoclonal Antibody targeted to the CD4 binding site of HIV-1.<br>* Other names: VRC07-523LS;|
| Experimental: Group 2: 5 mg/kg IV Single Dose<br>Group 2 subjects received a single IV infusion of VRC07-523LS (VRC-HIVMAB075-00-AB) on Day 0 at a dose of 5 mg/kg. | Biological: VRC-HIVMAB075-00-AB<br>* VRC07-523LS is an Investigational Monoclonal Antibody targeted to the CD4 binding site of HIV-1.<br>* Other names: VRC07-523LS;|
| Experimental: Group 3: 5 mg/kg SC Single Dose<br>Group 3 subjects received a single SC injection of VRC07-523LS (VRC-HIVMAB075-00-AB) on Day 0 at a dose of 5 mg/kg. | Biological: VRC-HIVMAB075-00-AB<br>* VRC07-523LS is an Investigational Monoclonal Antibody targeted to the CD4 binding site of HIV-1.<br>* Other names: VRC07-523LS;|
| Experimental: Group 4: 20 mg/kg IV Single Dose<br>Group 4 subjects received a single IV infusion of VRC07-523LS (VRC-HIVMAB075-00-AB) on Day 0 at a dose of 20 mg/kg. | Biological: VRC-HIVMAB075-00-AB<br>* VRC07-523LS is an Investigational Monoclonal Antibody targeted to the CD4 binding site of HIV-1.<br>* Other names: VRC07-523LS;|
| Experimental: Group 5: 40 mg/kg IV Single Dose<br>Group 5 subjects received a single IV infusion of VRC07-523LS (VRC-HIVMAB075-00-AB) on Day 0 at a dose of 40 mg/kg. | Biological: VRC-HIVMAB075-00-AB<br>* VRC07-523LS is an Investigational Monoclonal Antibody targeted to the CD4 binding site of HIV-1.<br>* Other names: VRC07-523LS;|
| Experimental: Group 6: 5 mg/kg SC Multiple Doses<br>Group 6 subjects received a SC injection of VRC07-523LS (VRC-HIVMAB075-00-AB) on Day 0, Week 12 and Week 24 at a dose of 5 mg/kg. | Biological: VRC-HIVMAB075-00-AB<br>* VRC07-523LS is an Investigational Monoclonal Antibody targeted to the CD4 binding site of HIV-1.<br>* Other names: VRC07-523LS;|
| Experimental: Group 7: 20 mg/kg IV Multiple Doses<br>Group 7 subjects received an IV infusion of VRC07-523LS (VRC-HIVMAB075-00-AB) on Day 0, Week 12 and Week 24 at a dose of 20 mg/kg. | Biological: VRC-HIVMAB075-00-AB<br>* VRC07-523LS is an Investigational Monoclonal Antibody targeted to the CD4 binding site of HIV-1.<br>* Other names: VRC07-523LS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting Systemic Reactogenicity Signs and Symptoms Within 3 Days of Any Product Administration | Subjects recorded 3-day systemic symptoms in a diary after each study product administration. Solicited systemic symptoms include: unusually tired/feeling unwell, muscles aches, headache, chills, nausea, temperature and joint pain. Subjects recorded highest measured temperature daily. Clinicians reviewed the diary with the subject and collected resolution information for any symptoms that were not resolved within 3 days. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom at any severity during the reporting period. The number reported for Any Systemic Symptom is the number of subjects reporting any systemic symptom at the worst severity. Solicited reactogenicity was recorded without an attribution assessment. Grading was done by Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Version 2.0. | 3 days after each product administration | 
| Number of Subjects Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of Any Product Administration | Local symptoms assessed and recorded by the clinicians. Solicited local symptoms include pain/tenderness, swelling, redness, bruising, and pruritus (itchiness) at the product administration site. Clinicians assessed the study product administration site for local symptoms on the day of product administration after completion of the administration and on Days 1, 2 and 7 post administration. Subjects were counted once for each symptom at the worst severity if they experienced the symptom at any severity during the reporting period. If symptoms were experienced, clinicians collected resolution information for any symptom that was not resolved within 7 days. The number reported for Any Local Symptom is the number of subjects reporting any local symptom at the worst severity. Solicited reactogenicity recorded without an attribution assessment. If symptoms were reported, grading was done by Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Version 2.0. | 7 days after each product administration | 
| Number of Subjects Reporting 1 or More Unsolicited Non-Serious Adverse Events | Unsolicited adverse events (AEs) collected during the period from study product administration at Day 0 through 56 days after the last product administration. After the indicated time period through the last expected study visit at 24 weeks after the last product administration, only new chronic medical conditions collected as unsolicited AEs. The number reported is the number of subjects who experienced at least one AE in the reporting period. A subject with multiple experiences of the same event is counted once using the event of worst severity. | Through 24 weeks after the last product administration | 
| Number of Subjects Reporting Serious Adverse Events | Serious adverse events (SAEs) collected during the period from study product administration at Day 0 through 24 weeks after the last product administration. | Through 24 weeks after the last product administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) of VRC07-523LS: Single Dose Groups | Cmax is the peak serum concentration that VRC07-523LS achieves after it has been administered; it is determined as a maximum value on the summary pharmacokinetic (PK) curve for each study group. Serum was collected at the following time points: Groups 1, 2, 4, and 5: Pre-infusion (baseline), end of infusion (0h) and 1, 3, 6, 24 and 48 hours post infusion, followed by Weeks 1-4, 8, 12, 16, 20, and 24 post infusion; Group 3: Pre-injection (baseline) and 24, 48, 72 hours post injection, and Weeks 1-4, 8, 12, 16, 20, and 24 post injection | Up to 24 weeks post product administration | 
| Maximum Observed Serum Concentration (Cmax) of VRC07-523LS: Multiple Dose Groups | Cmax is the peak serum concentration that VRC07-523LS achieves after it has been administered; it is determined as a maximum value on the summary pharmacokinetic (PK) curve for each study group. Serum was collected at the following time points for Groups 6 and 7 after Dose 1 and Dose 3: Group 6, Dose 1: Pre-injection (baseline) and 24, 48, and 72 hours post injection, followed by Weeks 1, 2, 4 and 8 post injection; Group 6, Dose 3: Pre-injection (Week 24) and 72 hours post injection, followed by Weeks 25-28 and every 4 weeks up to 48 weeks post injection; Group 7, Dose 1: Pre-infusion (baseline), end of infusion (0h) and 1, 3, 6, 24 and 48 hrs post infusion, followed by Weeks 1, 2, 4 and 8 post infusion; Group 7, Dose 3: Pre-infusion (Week 24), end of infusion and 1 hour post infusion followed by Weeks 25-28 and every 4 weeks up to 48 weeks post infusion | Through 24 weeks after the last product administration | 
| Time to Reach Maximum Observed Serum Concentration (Tmax) of VRC07-523LS | Tmax is the time it takes to reach Cmax of VRC07-523LS after it has been administered; it is determined based on the summary PK curve for each study group Serum was collected at the following time points: Groups 1, 2, 4, and 5: Pre-infusion (baseline), end of infusion (0h) and 1, 3, 6, 24 and 48 hours post infusion, followed by Weeks 1-4, 8, 12, 16, 20, and 24 post infusion; Group 3: Pre-injection (baseline) and 24, 48, 72 hours post injection, and Weeks 1-4, 8, 12, 16, 20, and 24 post injection; Group 6, Dose 1: Pre-injection (baseline) and 24, 48, and 72 hours post injection, followed by Weeks 1, 2, 4 and 8 post injection; Group 7, Dose 1: Pre-infusion (baseline), end of infusion (0h) and 1, 3, 6, 24 and 48 hours post infusion, followed by Weeks 1, 2, 4 and 8 post infusion | Through 24 weeks after the last product administration for Groups 1-5 and through 8 weeks after the last product administration for Groups 6 and 7 | 
| 4 Week Mean Serum Concentration of VRC07-523LS | The mean of individual subject VRC07-523LS serum concentrations by administered dose group | Week 4 post product administration | 
| 12 Week Mean Serum Concentration of VRC07-523LS: Single Dose Groups | The mean of individual subject VRC07-523LS serum concentrations by administered dose group | Week 12 post product administration | 
| 12 Week Mean Serum Concentration of VRC07-523LS: Multiple Dose Groups | The mean of individual subject VRC07-523LS serum concentrations by administered dose group | Up to 12 weeks after each product administration | 
| Area Under the Curve (AUC(0-inf)): Single Dose Groups | The total area under the curve (AUC(inf)) was taken as the sum of the observed AUC up to the final concentration (AUC(obs)) plus the AUC after the final concentration (AUC(Clast-inf)) where AUC(Clast-inf) was estimated as Clast/lz. Serum was collected at the following time points: Groups 1, 2, 4, and 5: Pre-infusion (baseline), end of infusion (0h) and 1, 3, 6, 24 and 48 hours post infusion, followed by Weeks 1-4, 8, 12, 16, 20, and 24 post infusion; Group 3: Pre-injection (baseline) and 24, 48, 72 hours post injection, and Weeks 1-4, 8, 12, 16, 20, and 24 post injection | Administration (0h) to 24 weeks post product administration | 
| Area Under the Curve (AUC0-84D): Multiple Dose Groups | The AUC0-84D represents the total drug exposure in 84 days after VRC07-523LS administration; it is determined based on the summary PK curve for each group. Serum was collected at the following time points for Groups 6 and 7 after Dose 1 and Dose 3: Group 6, Dose 1: Pre-injection (baseline) and 24, 48, and 72 hours post injection, followed by Weeks 1, 2, 4 and 8 post injection; Group 6, Dose 3: Pre-injection (Week 24) and 72 hours post injection, followed by Weeks 25-28 and every 4 weeks up to 48 weeks post injection; Group 7, Dose 1: Pre-infusion (baseline), end of infusion (0h) and 1, 3, 6, 24 and 48 hrs post infusion, followed by Weeks 1, 2, 4 and 8 post infusion; Group 7, Dose 3: Pre-infusion (Week 24), end of infusion and 1 hour post infusion followed by Weeks 25-28 and every 4 weeks up to 48 weeks post infusion | Administration (0h) up to 84 days after each product administration | 
| VRC07-523LS Clearance Rate | Rate of VRC07-523LS elimination divided by the plasma VRC07-523LS concentration; determined based on the summary PK curve for each study group. Serum was collected at the following time points: Groups 1, 2, 4, and 5: Pre-infusion (baseline), end of infusion (0h) and 1, 3, 6, 24 and 48 hours post infusion, followed by Weeks 1-4 post infusion; Group 3: Pre-injection (baseline) and 24, 48, 72 hours post injection, and Weeks 1-4 post injection; Group 6, Dose 1: Pre-injection (baseline) and 24, 48, and 72 hours post injection, followed by Weeks 1, 2 and 4 post injection; Group 7, Dose 1: Pre-infusion (baseline), end of infusion (0h) and 1, 3, 6, 24 and 48 hours post infusion, followed by Weeks 1, 2 and 4 post infusion | Administration (0h) to 28 days post product administration | 
| Overall IV Half-life (T1/2) of VRC07-523LS | Half-life (T1/2) is the time required for half of the drug to be eliminated from the serum. Serum was collected at the following time points: Groups 1, 2, 4, and 5: Pre-infusion (baseline), end of infusion (0h) and 1, 3, 6, 24 and 48 hours post infusion, followed by Weeks 1-4 and 8 post infusion; Group 3: Pre-injection (baseline) and 24, 48, 72 hours post injection, and Weeks 1-4 and 8 post injection; Group 6, Dose 1: Pre-injection (baseline) and 24, 48, and 72 hours post injection, followed by Weeks 1, 2, 4 and 8 post injection; Group 7, Dose 1: Pre-infusion (baseline), end of infusion (0h) and 1, 3, 6, 24 and 48 hours post infusion, followed by Weeks 1, 2, 4 and 8 post infusion | Administration (0h) to 56 days post product administration | 
| Number of Single Dose Subjects Who Produced Anti-Drug Antibodies to VRC07-523LS | Serum samples collected 4 weeks and 8 weeks after VRC07-523LS administration | Weeks 4 and 8 post product administration | 
| Number of Multiple Dose Subjects Who Produced Anti-Drug Antibodies to VRC07-523LS | Serum samples collected 4 weeks, 28 weeks and 32 weeks after VRC07-523LS administration | Weeks 4, 28 and 32 after the first product administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Broadly Neutralizing, HIV Prevention, Anti-Drug Antibody, HIV-1, Immune Response