A Single Dose of Pembrolizumab in HIV-Infected People

Sponsor

National Institutes of Health Clinical Center (CC) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT03367754

Collaborator

(none)

Enrollment

Location

Arms

75.5

Anticipated Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

...

Condition or Disease	Intervention/Treatment	Phase
Human Immunodeficiency Virus	Other: Placebo Drug: Pembrolizumab	Phase 1

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 Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 6, 2018

Anticipated Primary Completion Date :

May 30, 2024

Anticipated Study Completion Date :

Nov 20, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

The occurrence of Grade 3 or higher AEs. [96 weeks after receiving the study drug]
Assessing Safety Issue
Grade 2 or higher autoimmune events requiring corticosteroid therapy. [96 weeks after receiving the study drug.]
Assessing Safety Issue

Secondary Outcome Measures

Magnitude and duration of decreased expression of PD-1 relative to baseline levels on lymphocytes [96 weeks after receiving the study drug.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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

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:

Significant or unstable cardiac disease
Significant pulmonary disease
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.