A Single Dose of Pembrolizumab in HIV-Infected People

A Randomized, Double-Blind, Placebo-Controlled Study of a Single Dose of Pembrolizumab in HIV-Infected Patients

Background:

Human immunodeficiency virus (HIV) attacks the immune system. Some people with HIV have a low CD4+ T-cell count despite taking antiviral medicines that control HIV replication. These cells fight disease, so a low count makes it easier for people to become sick. Researchers want to see if a new drug can improve the immune system, including T cells. The drug is called pembrolizumab

Objective:

To see if pembrolizumab is safe to use in people with HIV who have a low CD4+ T cell count despite taking medcines that control HIV replication, and to see if it strengthens the immune system.

Eligibility:

People age 18 years or older with HIV who are taking antiretroviral drugs as treatment, have blood HIV levels below detection limits of commercial assays, and have a low CD4+ T-cell count (below 350 cells/mm3).

Design:

Participants will be screened with:

Medical history

Physical exam

Heart, blood, and urine tests

Sexually active participants must use 2 kinds of birth control.

Participants will have leukapheresis. Blood will be removed through a needle in one arm. A machine will remove white blood cells. The rest of the blood will be returned into the other arm.

Participants will have a baseline visit. They will have blood tests. They may have a pregnancy test.

A needle will insert a thin plastic tube (IV) into an arm vein. The participants will get the study drug or a placebo through the IV for 30 minutes. They will be watched for a couple hours after.

Participants will have 11 follow-up visits over the next 48 weeks. They will have a physical exam, vital signs, medical review, and blood tests.

Participants may have another leukapheresis.

Participants will be called every 12 weeks after their last follow-up visit to talk about how they feel and their health. Participation ends after the week 96 phone call.

...

Study Overview

• Status: Recruiting
• Conditions: Human Immunodeficiency Virus
• Intervention / Treatment: Other: Placebo; Drug: Pembrolizumab

Detailed Description

A subset of HIV-infected patients, those with poor immunologic response to combined antiretroviral therapy (CD4+ T-cell count of less than 300-350 cells/mm^3) despite control of viremia, are at increased risk for both HIV-related and non-HIV-related complications compared to immunologic responders. Thus, novel approaches for treating HIV infection are needed to facilitate management of this patient population.

One potential drug target for HIV treatment is the T-cell receptor PD-1. Binding of PD-1 to its ligands, PD-L1 and PD-L2, inhibits proliferation of T cells and production of cytokines. This naturally serves to dampen potentially harmful excessive immune responses. Upregulation of PD-1 and/or its ligands can be observed in tumors and people with chronic viral infection, including HIV. This upregulation can inhibit T-cell immune surveillance, which may result in tumor growth or poor control of infection.

Pembrolizumab is an IgG4 kappa monoclonal antibody that binds to PD-1, thus blocking the receptor from binding with its ligands. In cancer indications, inhibition of PD-1 induces an antitumor immune response, which in turn reduces tumor growth. The Food and Drug Administration has approved pembrolizumab for treatment of unresectable or metastatic melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and other cancers. Similarly, in animal models of HIV and in vitro studies, PD-1 blockade was associated with a decrease in viral load and an increase in CD8+ T cells. A clinical trial to examine the effects of PD-1 inhibition by pembrolizumab on HIV infection is thus supported by the data.

The purpose of this study is to evaluate, in a randomized, double-blind, placebo-controlled study, the safety and tolerability of a single dose of pembrolizumab in HIV-infected participants who have controlled viremia with a low T-cell count (> 100 cells/mm3 and less than or equal to 350 cells/mm^3). Study participants will be followed for 96 weeks after receiving the study drug and will be assessed for adverse events, CD4+ and CD8+ T-cell counts, PD-1 expression, CD8+ T-cell anti-HIV activity, and viral load. If a single dose of pembrolizumab appears to be safe and tolerable, then larger multi-dose and efficacy studies can be planned.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Julia B Purdy, C.R.N.P.; Phone Number: (301) 451-9109; Email: purdyj@mail.nih.gov
• Study Contact Backup: Name: Joseph A Kovacs, M.D.; Phone Number: (301) 496-9907; Email: jkovacs@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY8664111010 800-411-1222; Email: prpl@cc.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

Individuals must meet all of the following criteria to be eligible for study participation:

Greater than or equal to 18 years of age.

Documented HIV-1 infection (eg, positive standard enzyme-linked immunosorbent assay or rapid HIV-1/HIV-2

antibody test with a confirmatory test such as western blot, or documentation of repeated HIV RNA of > 1000 copies/mL). Outside documentation will be acceptable.

Absolute neutrophil count > 1000/microliter.

Platelet count > 125,000/microliter.

Hemoglobin > 10 g/dL.

Aspartate transaminase (AST) and alanine transaminase (ALT) less than or equal to 1.1 times the upper limit of normal (ULN). Total bilirubin < 1.1 x ULN (unless participant is taking atazanavir or has Gilbert syndrome).

Calculated creatinine clearance (estimated glomerular filtration rate) greater than or equal to 60 mL/min/1.73 m2.

Thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) within normal limits. If TSH is not within normal limits then the participant may be eligible if thyroxine (T4) is within normal limits. Participants will not be excluded if they are on a stable dose of replacement thyroid medication; dose may be adjusted as needed.

No significant underlying pulmonary, cardiac, renal, or hepatic disease, as defined by a need for drug treatment or ongoing physician care.

Under the care of a primary care physician.

Willing to comply with study requirements and procedures including storage of biological specimens for future use in medical research.

Willing to allow genetic testing.

Able to provide informed consent.

Participants of reproductive potential must agree to not become pregnant or to impregnate a partner beginning 30 days before the dose of pembrolizumab through 120 days post dose.

Participants must meet criteria for INR, defined as follows:

1. Has been on a cART regimen for at least 12 months and on a stable regimen for at least 4 weeks.

2. Has HIV suppression, defined as viral load < 40 copies/mL, and documented suppression (below

   detection limits of the utilized assay) for at least 12 months. A viral load of < 500 copies/mL once in the

   year preceding screening will be allowed if there is documentation of a viral load < 40 copies/mL on

   subsequent testing and at screening.

3. CD4+ T-cell count > 100 cells/mm3 and less than or equal to 350 cells/mm3.

EXCLUSION CRITERIA:

Females who are pregnant or breastfeeding.

Has used an investigational drug agent or investigational device within 12 weeks of baseline.

Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

Known allergy to any component of the pembrolizumab formulation.

Systemic steroid therapy or other immunosuppressive therapy in the 3 months prior to enrollment. (Inhaled or topical corticosteroids are permitted.)

Has used an immunotherapeutic agent within 6 months of baseline.

Plans to receive any vaccine within 16 weeks of receiving pembrolizumab.

Has active autoimmune disease or a history of autoimmune disease that has required systemic treatment (eg, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, T4) is not considered a form of systemic treatment.

Has known history of, or any evidence of active, non-infectious pneumonitis.

Malignancy requiring systemic therapy, or a history of malignancy that required systemic therapy within the past 5 years. However, cutaneous basal cell carcinoma or cutaneous Kaposi sarcoma not requiring systemic therapy will not be exclusionary.

Has known active hepatitis B (HBV) or potential for HBV reactivation (eg, hepatitis B surface antigen [HBS] reactive, HBV DNA positive, or isolated anti-core antibody positive; individuals who are anti-HBS antibody positive with or without anti-core Ab are eligible).

Has known active hepatitis C (HCV; eg, HCV RNA [qualitative] is detected). Patients who have sustained virologic response (SVR) to anti-HCV treatment are eligible if at least 24 weeks have passed since achieving SVR.

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements

of the study.

History or other clinical evidence of:

1. Significant or unstable cardiac disease
2. Significant pulmonary disease
3. Severe illness, chronic liver disease, malignancy, immunodeficiency other than HIV, active systemic infection (other than HIV) requiring therapy.

Opportunistic infection requiring maintenance therapy, including toxoplasmosis, fungal infections other than candida (eg, cryptococcosis, histoplasmosis, coccidioidomycosis), atypical mycobacterial infection. Secondary Pneumocystis, candida, and HSV prophylaxis will be permitted.

Active or history of tuberculosis (TB), or positive TB QuantiFERON Gold test.

Known osteoporosis or diabetes mellitus.

Hemoglobin A1c > 6%.

Fasting triglyceride > 300 mg/dL.

Any condition that, in the opinion of the investigator, would make the participant unsuitable for the study.

Co-enrollment in other trials is restricted, other than enrollment on observational studies or expanded access studies for

antiretroviral agents, during the first 48 weeks of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; single dose of 200 mg (IV) infusion	Drug: Pembrolizumab; Pembrolizumab, 200 mg, or placebo via intravenous (IV) infusion, single dose.
Placebo Comparator: 2; single dose (IV infusion)	Other: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The occurrence of Grade 3 or higher AEs.	Assessing Safety Issue	96 weeks after receiving the study drug
Grade 2 or higher autoimmune events requiring corticosteroid therapy.	Assessing Safety Issue	96 weeks after receiving the study drug.

Secondary Outcome Measures

Outcome Measure	Time Frame
Magnitude and duration of decreased expression of PD-1 relative to baseline levels on lymphocytes	96 weeks after receiving the study drug.

Collaborators and Investigators

• Sponsor: National Institutes of Health Clinical Center (CC)
• Investigators: Principal Investigator: Joseph A Kovacs, M.D., National Institutes of Health Clinical Center (CC)

Publications and helpful links

General Publications

• Henderson LJ, Reoma LB, Kovacs JA, Nath A. Advances toward Curing HIV-1 Infection in Tissue Reservoirs. J Virol. 2020 Jan 17;94(3):e00375-19. doi: 10.1128/JVI.00375-19. Print 2020 Jan 17.
• Gay CL, Bosch RJ, Ritz J, Hataye JM, Aga E, Tressler RL, Mason SW, Hwang CK, Grasela DM, Ray N, Cyktor JC, Coffin JM, Acosta EP, Koup RA, Mellors JW, Eron JJ; AIDS Clinical Trials 5326 Study Team. Clinical Trial of the Anti-PD-L1 Antibody BMS-936559 in HIV-1 Infected Participants on Suppressive Antiretroviral Therapy. J Infect Dis. 2017 Jun 1;215(11):1725-1733. doi: 10.1093/infdis/jix191.
• Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006 Sep 21;443(7109):350-4. doi: 10.1038/nature05115. Epub 2006 Aug 20.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2018
• Primary Completion (Estimated): May 30, 2024
• Study Completion (Estimated): November 20, 2024

Study Registration Dates

• First Submitted: December 8, 2017
• First Submitted That Met QC Criteria: December 8, 2017
• First Posted (Actual): December 11, 2017

Study Record Updates

• Last Update Posted (Estimated): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 29, 2024

More Information

Terms related to this study

• Keywords: Immunotherapy; Randomized; PD-1; Immunologic Response; Immunologic Non-Responder
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: 180013; 18-CC-0013

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: .This study is still collecting data so a determination has not yet been decided.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No