A Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of PGDM1400LS Alone and in Combination With VRC07-523LS and PGT121.414.LS in Healthy, HIV-uninfected Adult Participants

Study Overview
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Brief Summary
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Part A: The purpose of this part of the study is to understand how the body's immune system responds to a new lab-made antibody against HIV. The study is looking to see if the way the antibody is given affects the immune response. The study will also look at whether the antibody is safe to give to people and does not make them too uncomfortable. Part B: The purpose of this part of the study is to understand how the body's immune system responds to lab-made antibodies against HIV when they are given in combination at different doses. The study also wants to see if the way the antibodies are given affects the immune response.

Detailed Description
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The HIV Vaccine Trials Network (HVTN) and the HIV Prevention Trials Network (HPTN) are conducting this study to test a combination of different antibodies against HIV. HIV is the virus that causes AIDS. Antibodies are made by the body as one way to respond to or fight infection. Researchers can also make antibodies in laboratories and give them to people by infusions into a vein or under the skin. There are 2 parts of this study, Part A and Part B. About 15 people will take part in Part A of this study to test one study antibody. After early safety results from Part A are obtained, a decision will be made as to whether or not to do Part B of the study. Part B of the study would test a combination of 3 antibodies. If it is decided to move forward with Part B, 80 more people will join.

Official Title
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A Phase 1 Dose-escalation Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of PGDM1400LS Alone and in Combination With VRC07-523LS and PGT121.414.LS in Healthy, HIV-uninfected Adult Participants

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: PGDM1400LS (5mg/kg, IV)
* Drug: PGDM1400LS (20mg/kg, IV)
* Drug: PGDM1400LS (20mg/kg, SC)
* Drug: PGDM1400LS (40mg/kg, IV)
* Drug: PGDM1400LS (40mg/kg, SC)
* Drug: PGDM1400LS (1.4g, IV)
* Drug: PGDM1400LS (1.4g, SC)
* Drug: VRC07-523LS (20mg/kg, IV)
* Drug: VRC07-523LS (20mg/kg, SC)
* Drug: VRC07-523LS (1.4g, IV)
* Drug: VRC07-523LS (1.4g, SC)
* Drug: VRC07-523LS (40mg/kg, IV)
* Drug: PGT121.414.LS (20mg/kg, IV)
* Drug: PGT121.414.LS (20mg/kg, SC)
* Drug: PGT121.414.LS (1.4g, IV)
* Drug: PGT121.414.LS (1.4g, SC)
* Drug: PGT121.414.LS (40mg/kg, IV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 18 through 50 years Access to a participating 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 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 Appendix J and Appendix K). Hemoglobin ≥ 11.0 g/dL for volunteers who were assigned female sex at birth ≥ 13.0 g/dL for volunteers who were assigned male sex at birth and transgender males who have been on hormone therapy for more than 6 consecutive months ≥ 12.0 g/dL for transgender females who have been on hormone therapy for more than 6 consecutive months For transgender volunteers who have been on hormone therapy for less than 6 consecutive months, determine hemoglobin eligibility based on the sex assigned at birth White blood cell count = 2,500 to 12,000 cells/mm3 WBC differential either within institutional normal range or with site clinician approval Platelets = 125,000 to 550,000 cells/mm3 Chemistry panel: alanine aminotransferase (ALT) < 1.25 times the institutional upper limit of normal (ie, < 1.25 times the reference range upper limit) and creatinine < 1.1 times the institutional upper limit of normal (ie, <1.1 times the reference range upper limit) Negative HIV-1 and -2 blood test: US volunteers must have a negative FDA-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA). Non-US sites may use locally available assays that have been approved by HVTN and HPTN Laboratory Operations 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 Negative or trace urine protein Volunteers who were assigned female sex at birth: negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test(s) performed within 48 hours prior to 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. 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 visit. Effective contraception is defined as using one of the following methods: Condoms (internal and external) 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 HVTN 140/HPTN 101 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 or 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: Weight < 35kg or > 115 kg Blood products received within 120 days before first study product administration, unless eligibility for earlier enrollment is determined by the HVTN 140/HPTN 101 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 HVTN 140/HPTN 101 study Pregnant or breastfeeding HIV vaccine(s) received in a prior HIV vaccine trial. Volunteers who have received control/placebo in an HIV vaccine trial are not excluded. SARS-CoV-2 vaccine(s) received within 7 days prior to HVTN 140/HPTN 101 enrollment or planned within 7 days after enrollment. Receipt of humanized or human mAbs, whether licensed or investigational. Previous receipt of mAbs VRC01, VRC01LS, VRC07-523LS, PGDM1400, PGT121, PGT121.414.LS. 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 PGDM1400LS, VRC07-523LS, or PGT121.414.LS formulation components (see Section 8.2) including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain. Immunoglobulin received within 60 days before first study product administration (for mAb see criterion 8 above) Autoimmune disease (Not excluded from participation: Volunteer with mild, stable and uncomplicated autoimmune disease that does not require immunosuppressive medication and that, in the judgment of the CRS investigator, is likely not subject to exacerbation and likely not to complicate Solicited and Unsolicited AE assessments.) Immunodeficiency 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: Symptoms consistent with COVID-19 or known SARS-CoV-2 infection, 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, or skin condition (eg, tattoos), or occupational responsibility that, in the judgment of the investigator, would interfere with or serve as a contraindication to protocol adherence, assessment of safety or 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 had either of the following: Greater than 1 exacerbation of symptoms treated with oral/parenteral corticosteroids; 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 in this protocol 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 (Not exclusionary: angioedema or anaphylaxis to a known trigger with at least 5 years since last reaction to demonstrate satisfactory avoidance of trigger).

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: PGDM1400LS 5 mg/kg IV<br>Participants will receive PGDM1400LS 5 mg/kg by intravenous (IV) infusion at Month 0 | Drug: PGDM1400LS (5mg/kg, IV)<br>* 5 mg/kg to be administered via IV infusion<br>|
| Experimental: PGDM1400LS 20 mg/kg IV<br>Participants will receive PGDM1400LS 20 mg/kg by IV infusion at Month 0 | Drug: PGDM1400LS (20mg/kg, IV)<br>* 20 mg/kg to be administered via IV infusion<br>|
| Experimental: PGDM1400LS 20 mg/kg SC<br>Participants will receive PGDM1400LS 20 mg/kg by subcutaneous (SC) infusion at Month 0 | Drug: PGDM1400LS (20mg/kg, SC)<br>* 20 mg/kg to be administered via SC infusion<br>|
| Experimental: PGDM1400LS 40 mg/kg IV<br>Participants will receive PGDM1400LS 40 mg/kg by IV infusion at Month 0 | Drug: PGDM1400LS (40mg/kg, IV)<br>* 40 mg/kg to be administered via IV infusion<br>|
| Experimental: PGDM1400LS 40 mg/kg SC<br>Participants will receive PGDM1400LS 40 mg/kg by SC infusion at Month 0 | Drug: PGDM1400LS (40mg/kg, SC)<br>* 40 mg/kg to be administered via SC infusion<br>|
| Experimental: PGDM1400LS 20mg/kg + VRC07-523LS 20mg/kg + PGT121.414.LS 20 mg/kg IV<br>Participants will receive PGDM1400LS 20mg/kg + VRC07-523LS 20mg/kg + PGT121.414.LS 20 mg/kg by IV infusion sequentially in this order at Month 0 and Month 4 | Drug: PGDM1400LS (20mg/kg, IV)<br>* 20 mg/kg to be administered via IV infusion<br>Drug: VRC07-523LS (20mg/kg, IV)<br>* VRC07-523LS 20mg/kg administered via IV infusion<br>Drug: PGT121.414.LS (20mg/kg, IV)<br>* PGT121.414.LS 20mg/kg administered via IV infusion<br>|
| Experimental: PGDM1400LS 20mg/kg + VRC07-523LS 20mg/kg + PGT121.414.LS 20 mg/kg SC<br>Participants will receive PGDM1400LS 20mg/kg + VRC07-523LS 20mg/kg + PGT121.414.LS 20 mg/kg by SC infusion sequentially in this order at Month 0 and Month 4 | Drug: PGDM1400LS (20mg/kg, SC)<br>* 20 mg/kg to be administered via SC infusion<br>Drug: VRC07-523LS (20mg/kg, SC)<br>* VRC07-523LS 20mg/kg administered via SC infusion<br>Drug: PGT121.414.LS (20mg/kg, SC)<br>* PGT121.414.LS 20mg/kg administered via SC infusion<br>|
| Experimental: PGDM1400LS 1.4gram + VRC07-523LS 1.4gram + PGT121.414.LS 1.4gram IV<br>Participants will receive PGDM1400LS 1.4gram + VRC07-523LS 1.4gram + PGT121.414.LS 1.4gram by IV infusion sequentially in this order at Month 0 and Month 4 | Drug: PGDM1400LS (1.4g, IV)<br>* 1.4gram to be administered via IV infusion<br>Drug: VRC07-523LS (1.4g, IV)<br>* VRC07-523LS 1.4g administered via IV infusion<br>Drug: PGT121.414.LS (1.4g, IV)<br>* PGT121.414.LS 1.4g administered via IV infusion<br>|
| Experimental: PGDM1400LS 1.4gram + VRC07-523LS 1.4gram + PGT121.414.LS 1.4gram SC<br>Participants will receive PGDM1400LS 1.4gram + VRC07-523LS 1.4gram + PGT121.414.LS 1.4gram by SC infusion sequentially in this order at Month 0 and Month 4 | Drug: PGDM1400LS (1.4g, SC)<br>* 1.4gram to be administered via SC infusion<br>Drug: VRC07-523LS (1.4g, SC)<br>* VRC07-523LS 1.4g administered via SC infusion<br>Drug: PGT121.414.LS (1.4g, SC)<br>* PGT121.414.LS 1.4g administered via SC infusion<br>|
| Experimental: PGDM1400LS 40mg/kg + VRC07-523LS 40mg/kg + PGT121.414.LS 40 mg/kg IV<br>Participants will receive PGDM1400LS 40mg/kg + VRC07-523LS 40mg/kg + PGT121.414.LS 40 mg/kg by IV infusion sequentially in this order at Month 0 and Month 4 | Drug: PGDM1400LS (40mg/kg, IV)<br>* 40 mg/kg to be administered via IV infusion<br>Drug: VRC07-523LS (40mg/kg, IV)<br>* VRC07-523LS 40mg/kg administered via IV infusion<br>Drug: PGT121.414.LS (40mg/kg, IV)<br>* PGT121.414.LS 40mg/kg administered via IV infusion<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) in Part A | 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. | Day 3 | 
| Percentage of participants who experience local solicited adverse events (AEs) in Part B | 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. | Week 24 | 
| Percentage of participants who experience systemic solicited AEs in Part A | 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. | Day 3 | 
| Percentage of participants who experience systemic solicited AEs in Part B | 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. | Day 24 | 
| Percentage of participants who experience unsolicited AEs in Part A | 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. | Week 24 | 
| Percentage of participants who experience unsolicited AEs in Part B | 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. | Week 40 | 
| Percentage of participants who experience unsolicited severe adverse events (SAEs) Part A | 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. The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used for this study. | Week 24 | 
| Percentage of participants who experience unsolicited severe adverse events (SAEs) Part B | 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. The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used for this study. | Week 40 | 
| Percentage of participants who discontinue study product administration early in Part A |  | Day 0 | 
| Percentage of participants who discontinue study product administration early in Part B |  | Week 16 | 
| Percentage of participants who terminate the study early in Part A |  | Week 24 | 
| Percentage of participants who terminate the study early in Part B | Measured at prespecified timepoints among participants who received all scheduled product administrations | Week 40 | 
| Serum concentrations of PGDM1400LS in Part A | Measured at prespecified timepoints among participants who received all scheduled product administrations | Week 24 | 
| Serum concentrations of PGDM1400LS in Part B |  | Week 40 | 
| Serum concentrations of PGT121.414.LS for participants in Part B | Measured at prespecified timepoints among participants who received all scheduled product administrations | Week 40 | 
| Serum concentrations of VRC07-523LS for participants in Part B | Measured at prespecified timepoints among participants who received all scheduled product administrations | Week 40 | 
| Magnitude of serum neutralizing activity (ie, neutralizing antibody titers, including ID50, ID80) measured with monoclonal antibody mAb-specific Env-pseudotyped viruses in TZM-bl cells (in the validated TZM-bl pseudovirus neutralization assay) for Part A | Measured from samples obtained at prespecified timepoints among participants who received all scheduled product administrations for participants in Part A | Week 24 | 
| Magnitude of serum neutralizing activity (ie, neutralizing antibody titers, including ID50, ID80) measured with monoclonal antibody mAb-specific Env-pseudotyped viruses in TZM-bl cells (in the validated TZM-bl pseudovirus neutralization assay) for Part B | Measured from samples obtained at prespecified timepoints among participants who received all scheduled product administrations for participants in Part B | Week 40 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum concentrations of PGDM1400LS for participants in Part A | Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received | Week 24 | 
| Serum concentrations of PGDM1400LS for participants in Part B | Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received | Week 40 | 
| Serum concentrations of PGT121.414.LS for participants in Part B | Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received | Week 40 | 
| Serum concentrations of VRC07-523LS for participants in Part B | Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received | Week 40 | 
| Magnitude of neutralizing activity (ie, neutralizing antibody titers, including ID50, ID80) against Env-pseudotyped viruses in TZM-bl cells (in the validated TZM-bl pseudovirus neutralization assay) for Part A and clinical product assayed at same time. | Measured at selected timepoints for all participants in all groups regardless of how many product administrations and how much product they received | Week 24 | 
| Magnitude of neutralizing activity (i.e., neutralizing antibody titers, including ID50 and ID80) against a panel of Env-pseudotyped reference viruses in TZM-bl cells (in the validated TZM-bl pseudovirus neutralization assay) for participants in Part B | 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. | Week 40 | 
| Anti-drug antibodies (ADA) titers for participants in Part A | Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received | Week 24 | 
| Anti-drug antibodies (ADA) titers for participants in Part B | Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received | Week 40 |