Evaluating the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of the Monoclonal Antibody PGT121.414.LS Administered Alone and in Combination With VRC07-523LS Via Intravenous or Subcutaneous Infusions in Healthy, HIV-uninfected Adult Participants

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS via intravenous or subcutaneous infusions in healthy, HIV-uninfected adult participants.

Detailed Description
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This study will evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS via intravenous (IV) or subcutaneous (SC) infusions in healthy, HIV-uninfected adult participants. The study will be conducted in two parts (Part A and B). Part A will include four groups (Groups 1, 2, 3, and 4) and Part B will include two groups (Groups 5 and 6). In Part A of the study, PGT121.414.LS will be administered via IV infusion at 3, 10, or 30 mg/kg (Groups 1-3) or via SC infusion at 5 mg/kg (Group 4). Participants in Part B will receive consecutive administration of PGT121.414.LS followed by VRC07-523LS, at 20 mg/kg IV each per dose (Group 5) or 5 mg/kg SC each per dose (Group 6). Participants will be followed for 32 weeks after the last study product administration via IV infusion and 24 weeks after the last study product administration via SC infusion. Participants in Groups 1, 2, and 3 will attend 8 months of study visits. Participants in Group 4 will attend 6 months of study visits. Part B participants will attend 16 months of study visits. Study visits may include physical examinations, blood and urine collection, and questionnaires.

Official Title
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A Phase 1 Dose-escalation Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of the Monoclonal Antibody PGT121.414.LS Administered Alone and in Combination With VRC07-523LS Via Intravenous or Subcutaneous Infusions in Healthy, HIV-uninfected Adult Participants

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: PGT121.414.LS
* Biological: VRC07-523LS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General and Demographic Criteria Age of 18 to 50 years Access to a participating Clinical Research Site (CRS) and willingness to be followed for the planned duration of the study Ability and willingness to provide informed consent Assessment of understanding: volunteer demonstrates understanding of this study and completes a questionnaire prior to first study product administration with verbal demonstration of understanding of all questionnaire items answered incorrectly Agrees not to enroll in another study of an investigational research agent until completion of the last required protocol clinic visit Good general health as shown by medical history, physical exam, and screening laboratory tests HIV-Related Criteria: Willingness to receive HIV test results Willingness to discuss HIV infection risks and amenable to HIV risk reduction counseling. Assessed by the clinic staff as being at low risk for HIV infection and committed to maintaining behavior consistent with low risk of HIV exposure through the last required protocol clinic visit (see study protocol). Laboratory Inclusion Values: Hemogram/Complete Blood Count Hemoglobin ≥11.0 g/dL for participants who were assigned female sex at birth, ≥13.0 g/dL for participants who were assigned male sex at birth. For transgender participants who have been on feminizing hormone therapy for more than 6 consecutive months, determine hemoglobin eligibility based on the gender with which they identify (ie, a transgender female who has been on hormone therapy for more than 6 consecutive months should be assessed for eligibility using the hemoglobin parameters for persons assigned female sex at birth). White blood cell (WBC) count = 2,500 to 12,000 cells/mm^3 WBC differential either within institutional normal range or with site clinician approval Platelets = 125,000 to 550,000 cells/mm^3 Chemistry Chemistry panel: alanine aminotransferase (ALT) <1.25 times the institutional upper limit of normal; creatinine ≤ institutional upper limit of normal Virology Negative HIV-1 and -2 blood test: US volunteers must have a negative Food and Drug Administration (FDA)-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA). Negative Hepatitis B surface antigen (HBsAg) Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase chain reaction (PCR) if the anti-HCV is positive Urine Negative or trace urine protein Reproductive Status Volunteers who were assigned female sex at birth: negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test performed prior to study product administration on the day of initial study product administration. Persons who are NOT of reproductive potential due to having undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing Reproductive status: A volunteer who was assigned female sex at birth must: Agree to use effective contraception for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment through the last required protocol clinic visit. Effective contraception is defined as using the following methods: Condoms (male or female) with or without a spermicide, Diaphragm or cervical cap with spermicide, Intrauterine device (IUD), Hormonal contraception, Tubal ligation, or Any other contraceptive method approved by the HIV Vaccine Trials Network (HVTN) 136/HIV Prevention Trials Network (HPTN) 092 Protocol Safety Review Team (PSRT) Successful vasectomy in any partner assigned male sex at birth (considered successful if a volunteer reports that a male partner has [1] documentation of azoospermia by microscopy, or [2] a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity postvasectomy); Or not be of reproductive potential, such as having reached menopause (no menses for 1 year) or having undergone hysterectomy, bilateral oophorectomy; Or be sexually abstinent. Volunteers who were assigned female sex at birth must also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization until after the last required protocol clinic visit Exclusion Criteria: General Weight >115 kg Blood products received within 120 days before first study product administration, unless eligibility for earlier enrollment is determined by the HVTN 136/HPTN 092 PSRT Investigational research agents received within 30 days before first study product administration Intent to participate in another study of an investigational research agent or any other study that requires non-Network HIV antibody testing during the planned duration of the study Pregnant or breastfeeding Vaccines and other Injections HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received control/placebo in an HIV vaccine trial, the HVTN 136/HPTN 092 PSRT will determine eligibility on a case-by-case basis. Previous receipt of humanized or human mAbs, whether licensed or investigational; the HVTN 136/HPTN 092 PSRT will determine eligibility on a case-by-case basis. Previous receipt of monoclonal antibodies VRC01, VRC01LS, VRC07-523LS, or PGT121 Immune System Immunosuppressive medications received within 30 days before first study product administration (Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatological condition; or [4] a single course of oral/parenteral prednisone or equivalent at doses <20 mg/day and length of therapy <14 days.) Serious adverse reactions to VRC07-523LS or PGT121.414.LS formulation components (acetate, sucrose, polysorbate 80, histidine, and sorbitol; see study protocol), including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain Immunoglobulin received within 90 days before first study product administration, unless eligibility for earlier enrollment is determined by the HVTN 136/HPTN 092 PSRT (for mAb see criterion above) Autoimmune disease (Not excluded from participation: Participant with mild, stable and uncomplicated autoimmune disease that does not require immunosuppressive medication and that, in the judgment of the site investigator, is likely not subject to exacerbation and likely not to complicate Solicited and Unsolicited AE assessments) Immunodeficiency Clinically significant medical conditions Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. A clinically significant condition or process includes but is not limited to: A process that would affect the immune response, A process that would require medication that affects the immune response, Any contraindication to repeated infusions, or blood draws, including inability to establish venous or subcutaneous access, A condition that requires active medical intervention or monitoring to avert grave danger to the volunteer's health or well-being during the study period, A condition or process (eg, chronic urticaria or recent injection or infusion with evidence of residual inflammation) for which signs or symptoms could be confused with reactions to the study product, or Any condition specifically listed among the exclusion criteria. Any medical, psychiatric, occupational, or skin condition (eg, tattoos) that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety, Solicited AEs, or a participant's ability to give informed consent Psychiatric condition that precludes compliance with the protocol. Specifically excluded are persons with psychoses within the past 3 years, ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years. Current anti-tuberculosis (TB) therapy Asthma other than mild, well-controlled asthma. (Symptoms of asthma severity as defined in the most recent National Asthma Education and Prevention Program (NAEPP) Expert Panel report). Exclude a volunteer who: Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or Uses moderate/high-dose, inhaled corticosteroids, or In the past year has either of the following: Greater than 1 exacerbation of symptoms treated with oral/parenteral corticosteroids; Needed emergency care, urgent care, hospitalization, or intubation for asthma. Diabetes mellitus type 1 or type 2 (Not excluded: type 2 cases controlled with diet alone or a history of isolated gestational diabetes.) Hypertension: If a person has been found to have elevated blood pressure or hypertension during screening or previously, exclude for blood pressure that is not well controlled. Well-controlled blood pressure is defined as consistently ≤140 mm Hg systolic and ≤90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be ≤150 mm Hg systolic and ≤100 mm Hg diastolic. For these volunteers, blood pressure must be ≤140 mm Hg systolic and ≤90 mm Hg diastolic at enrollment. If a person has NOT been found to have elevated blood pressure or hypertension during screening or previously, exclude for systolic blood pressure ≥150 mm Hg at enrollment or diastolic blood pressure ≥100 mm Hg at enrollment. Bleeding disorder diagnosed by a clinician (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions) Malignancy (Not excluded from participation: Volunteer who has had malignancy excised surgically and who, in the investigator's estimation, has a reasonable assurance of sustained cure, or who is unlikely to experience recurrence of malignancy during the period of the study) Seizure disorder: History of seizure(s) within past 3 years. Also exclude if volunteer has used medications in order to prevent or treat seizure(s) at any time within the past 3 years. Asplenia: any condition resulting in the absence of a functional spleen History of generalized urticaria, angioedema, or anaphylaxis.

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A (Group 1): PGT121.414.LS (3 mg/kg)<br>Participants will receive 3 mg/kg of PGT121.414.LS by intravenous (IV) infusion at Month 0. | Biological: PGT121.414.LS<br>* Administered via IV infusion or SC infusion, depending on the arm<br>|
| Experimental: Part A (Group 2): PGT121.414.LS (10 mg/kg)<br>Participants will receive 10 mg/kg of PGT121.414.LS by IV infusion at Month 0. | Biological: PGT121.414.LS<br>* Administered via IV infusion or SC infusion, depending on the arm<br>|
| Experimental: Part A (Group 3): PGT121.414.LS (30 mg/kg)<br>Participants will receive 30 mg/kg of PGT121.414.LS by IV infusion at Month 0. | Biological: PGT121.414.LS<br>* Administered via IV infusion or SC infusion, depending on the arm<br>|
| Experimental: Part A (Group 4): PGT121.414.LS (5 mg/kg)<br>Participants will receive 5 mg/kg of PGT121.414.LS by subcutaneous (SC) infusion at Month 0. | Biological: PGT121.414.LS<br>* Administered via IV infusion or SC infusion, depending on the arm<br>|
| Experimental: Part B (Group 5): PGT121.414.LS + VRC07-523LS (20 mg/kg)<br>Participants will receive 20 mg/kg of PGT121.414.LS and 20 mg/kg of VRC07-523LS by IV infusion sequentially in this order at Months 0, 4, and 8. | Biological: PGT121.414.LS<br>* Administered via IV infusion or SC infusion, depending on the arm<br>Biological: VRC07-523LS<br>* Administered via IV infusion or SC infusion, depending on the arm<br>|
| Experimental: Part B (Group 6): PGT121.414.LS + VRC07-523LS (5 mg/kg)<br>Participants will receive 5 mg/kg of PGT121.414.LS and 5 mg/kg of VRC07-523LS by SC infusion sequentially in this order at Months 0, 4, and 8. | Biological: PGT121.414.LS<br>* Administered via IV infusion or SC infusion, depending on the arm<br>Biological: VRC07-523LS<br>* Administered via IV infusion or SC infusion, depending on the arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants who experience local solicited adverse events (AEs) | Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol. | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 
| Percentage of participants who experience systemic solicited AEs | Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol. | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 
| Percentage of participants who experience unsolicited AEs | Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol. | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 
| Percentage of participants who experience unsolicited severe adverse events (SAEs) | Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol. | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 
| Percentage of participants who discontinue study product administration early |  | Measured through Month 8 | 
| Percentage of participants who terminate the study early |  | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 
| Serum concentrations of PGT121.414.LS | Measured at prespecified timepoints among participants who received all scheduled product administrations | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 
| Serum concentrations of VRC07-523LS | Measured at prespecified timepoints among participants who received all scheduled product administrations | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 
| Magnitude of serum neutralizing activity measured with monoclonal antibody (mAb)-specific Env-pseudotyped viruses in TZM-bl cells | Measured from samples obtained at prespecified timepoints among participants who received all scheduled product administrations | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum concentrations of PGT121.414.LS | Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 
| Serum concentrations of VRC07-523LS | Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 
| Magnitude of neutralizing activity against a panel of Env-pseudotyped reference viruses in TZM-bl cells | Measured at selected timepoints for all participants in all groups regardless of how many product administrations and how much product they received | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 
| Magnitude of neutralizing activity against a panel of Env pseudotyped reference viruses in TZM-bl cells | Measured at selected timepoints for all participants in all groups regardless of how many product administrations and how much product they received, and for the clinical product assayed at the same time. | Measured through participant's last study visit at Month 6-16, depending on which arm they are in | 
| Anti-drug antibodies (ADA) titers | Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received | Measured through participant's last study visit at Month 6-16, depending on which arm they are in |