A Phase 1/2a Study of PGT121, VRC07-523LS and PGDM1400 Monoclonal Antibodies in HIV-uninfected and HIV-infected Adults

NCT ID: NCT03721510

Last Updated: 2022-05-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 19 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-12-03
• Study Completion Date: 2022-05-02

Brief Summary

This is a Phase 1/2a open label study to evaluate the safety, tolerability, pharmacokinetics and anti-viral activity of PGT121, VRC07-523LS and PGDM1400 for HIV prevention and therapy.

Detailed Description

This is a Phase 1/2a open label study to evaluate the safety, tolerability, pharmacokinetics and anti-viral efficacy of PGT121, VRC07-523LS and PGDM1400 antibodies for HIV prevention and therapy. PGT121, VRC07-523LS and PGDM1400 are recombinant human IgG1 monoclonal antibodies that target a V3 glycan-dependent epitope region of the HIV envelope protein and the CD4 binding site (CD4bs) of the HIV envelope protein. PGT121, VRC07-523LS and PGDM1400 mAbs were chosen for this study because of their potency, their ability to neutralize a wide array of cross-clade HIV viruses in a complementary pattern, and their proven antiviral activity in animal studies, e.g., their capacity to robustly prevent and treat simian-human immunodeficiency virus (SHIV) in rhesus monkeys.

The potency and breadth of PGT121, VRC07-523LS and PGDM1400 raise the possibility that monoclonal antibodies may be effective for HIV prophylaxis at low doses and against global viruses. Neutralization sensitivity profiles are complementary; and the combination of these mAbs with unique epitope specificities will provide experience assessing the potential additive, synergistic, or antagonistic properties of two bNAbs given sequentially.

Conditions

HIV/AIDS

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Group 1A

HIV-uninfected volunteers receiving one IV infusion

Group Type: ACTIVE_COMPARATOR

PGT121 + VRC07-523LS

Intervention Type: BIOLOGICAL

PGT121 + VRC07-523LS, dose 30 mg/kg each, given intravenously

Group 1B

HIV-uninfected volunteers receiving one IV infusion

Group Type: ACTIVE_COMPARATOR

PGT121 + VRC07-523LS + PGDM1400

Intervention Type: BIOLOGICAL

PGT121 + VRC07-523LS + PGDM1400, dose 20 mg/kg each, given intravenously

Group 2

HIV-infected volunteers on ART receiving three or six IV infusions

Group Type: ACTIVE_COMPARATOR

PGT121 + VRC07-523LS + PGDM1400

Intervention Type: BIOLOGICAL

PGT121 + VRC07-523LS + PGDM1400, dose 20 mg/kg each, given intravenously

Interventions

PGT121 + VRC07-523LS

PGT121 + VRC07-523LS, dose 30 mg/kg each, given intravenously

Intervention Type: BIOLOGICAL

PGT121 + VRC07-523LS + PGDM1400

PGT121 + VRC07-523LS + PGDM1400, dose 20 mg/kg each, given intravenously

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

1. Healthy male or female, including transgender, volunteers, as assessed by a medical history, physical exam, and laboratory test

2. At least 18 years of age on the day of screening and has not reached his or her 51st birthday on the day of signing the Informed Consent Document

3. Willing to undergo HIV testing, risk reduction counseling and receive HIV test results

4. Low risk for HIV infection for 12 months prior to study participation and willing to maintain low-risk behavior for the duration of the trial

1. At least 18 years of age on the day of screening and has not reached his or her 66th birthday on the day of signing the Informed Consent Document

2. Confirmed HIV-1 infection (HIV Ab+ or HIV RNA+) by documentation in the medical records or in-clinic HIV testing

3. CD4 ≥ 400 cells/µl

4. On antiretroviral therapy for a minimum of 24 months, with plasma HIV-1 RNA levels of < 50 copies/ml for at least 12 months as documented in the medical records, and with a viral load < 50 copies / ml at time of screening (within 56 days prior to IP administration). ART must not have been initiated during the acute phase of the infection as suggested by the available medical history and laboratory data from the time of the diagnosis. Note: ART is defined as a regimen including > 2 compounds, e.g., 2x nucleoside reverse transcriptase inhibitors plus either non-nucleoside reverse transcriptase inhibitor or protease inhibitor or integrase inhibitor.

5. If on an NNRTI-based regimen, willing to switch to an integrase inhibitor containing regimen for 4 weeks prior to discontinuing ART

6. No history of AIDS-defining illness within the past 5 years

7. No history of CD4 nadir <200 cells/ul

Exclusion Criteria

1. Any clinically significant acute or chronic medical condition, other than HIV infection, that is considered progressive or in the opinion of the investigator makes the volunteer unsuitable for participation in the study.

2. Any clinically relevant abnormality on history or examination including history of immunodeficiency (other then HIV infection) or autoimmune disease; use of systemic corticosteroids, immunosuppressive, anticancer, or other medications considered significant by the investigator within the previous 6 months. The following exceptions are permitted and will not exclude study participation: use of corticosteroid nasal spray for rhinitis, topical corticosteroids for an acute uncomplicated dermatitis; or a short course (duration of 10 days or less, or a single injection) of corticosteroid for a non-chronic condition (based on investigator clinical judgment) at least 6 weeks prior to enrollment in this study.

3. If born female, pregnant, lactating or planning a pregnancy during the period of screening through completion of the study.

4. In the past 6 months a history of alcohol or substance use, including marijuana, judged by the Investigator to potentially interfere with volunteer study compliance.

5. Bleeding disorder that was diagnosed by a physician. Note: A volunteer who states that he or she has easy bruising or bleeding, but does not have a formal diagnosis and has intramuscular injections and blood draws without any adverse experience, is eligible.

6. History of a splenectomy.

7. Receipt of live attenuated vaccine within the previous 30 days or planned receipt within 30 days after administration of investigational product; or receipt of other vaccine within the previous 14 days or planned receipt within 14 days after infusion with investigational product (exception is live attenuated influenza vaccine within 14 days).

8. Receipt of blood transfusion or blood-derived products within the previous 3 months.

9. Participation in another clinical trial of an investigational product currently, within the previous 3 months or expected participation during this study. Note: receipt of placebo in a clinical trial in the previous 3 months will not exclude a volunteer from participation if documentation is available and the Medical Monitor gives approval.

10. Prior receipt of an investigational HIV vaccine candidate, monoclonal antibody or polyclonal immunoglobulin. Note: receipt of placebo in a previous HIV vaccine or monoclonal antibody trial will not exclude a volunteer from participation if documentation is available and the Medical Monitor gives approval.

11. History of severe local or systemic reactogenicity to injections or IV infusion (e.g., anaphylaxis, respiratory difficulties, angioedema).

12. Psychiatric condition that compromises safety of the volunteer and 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.

13. If, in the opinion of the Principal Investigator, it is not in the best interest of the volunteer to participate in the trial.

14. Seizure disorder: a volunteer who has had a seizure in the last 3 years is excluded.

15. Body mass index ≥ 35 or ≤ 18.5.

16. Infectious disease: chronic hepatitis B infection (HbsAg), current hepatitis C infection (HCV Ab positive and HCV RNA positive) or interferon-alfa treatment for chronic hepatitis C infection in the past year, chlamydia, gonorrhea, or active syphilis.

17. A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, which is considered cured with minimal risk of recurrence)

18. Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic, antiviral or antifungal therapy within 30 days prior to enrollment.

19. Any of the following abnormal laboratory parameters listed below:

Hematology

• Hemoglobin < 10.5 g/dL in females; hemoglobin <11.0 g/dL in males
• Absolute Neutrophil Count (ANC): ≤ 1000/mm3
• Platelets: < 100,000 mm3 or ≥ 550,000/mm3 Chemistry
• AST ≥ 1.5 x ULN
• ALT ≥ 1.5 x ULN
• Total bilirubin ≥ 1.1 x ULN
• Alkaline phosphatase ≥ 1.5 x ULN
• Albumin ≤ 3.0 g/dL (equivalent to ≤ 30 g/L)
• Estimated Glomerular filtration rate (GFR) < 60 ml/min according to the Cockcroft Gault formula for creatinine clearance

• Male: (140 - age in years) x (wt in kg) = CLcr (ml/min) / 72 x (serum creatinine in mg/dL)
• Female: (140 - age in years) x (wt in kg) x 0.85 = CLcr (mL/min) / 72 x (serum creatinine in mg/dL)

Urinalysis: Any of the following abnormal findings if consistent with clinically significant disease:

• Protein = 2+ or more
• Blood = 2+ or more (not due to menses)

1. Confirmed HIV-1 infection

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Beth Israel Deaconess Medical Center

OTHER

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Orlando Immunology Center

OTHER

Sponsor Role: collaborator

Houston AIDS Research Team

UNKNOWN

Sponsor Role: collaborator

International AIDS Vaccine Initiative

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Orlando Immunology Center

Orlando, Florida, United States

Center for Virology and Vaccine Research/ Clinical Trials Unit/ BIDMC

Boston, Massachusetts, United States

Houston AIDS Research Team (HART)

Houston, Texas, United States

Countries

United States

References

Julg B, Walker-Sperling VEK, Wagh K, Aid M, Stephenson KE, Zash R, Liu J, Nkolola JP, Hoyt A, Castro M, Serebryannyy L, Yanosick K, Speidel T, Borducchi EN, Murzda T, Maxfield L, Arduino R, McDermott AB, Gama L, Giorgi EE, Koup RA, Seaman MS, Rolle CP, DeJesus E, Li W, Korber B, Barouch DH. Safety and antiviral effect of a triple combination of HIV-1 broadly neutralizing antibodies: a phase 1/2a trial. Nat Med. 2024 Dec;30(12):3534-3543. doi: 10.1038/s41591-024-03247-5. Epub 2024 Sep 12.

Reference Type: DERIVED

PMID: 39266747 (View on PubMed)

Related Links

http://iavi.org

Related Info

Other Identifiers

IAVI T003

Identifier Type: -

Identifier Source: org_study_id