PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection
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|ClinicalTrials.gov Identifier: NCT03239899|
Recruitment Status : Recruiting
First Posted : August 4, 2017
Last Update Posted : September 18, 2020
HIV affects millions of people. The disease may "hide" in the brain, even in people with well-controlled HIV without cancer. Then it may "wake up" and continue. The drug pembrolizumab uses the body s immune system to fight cells like cancer cells. It is approved to treat some cancers but not HIV. Researchers want to see if it is safe for HIV-positive people without cancer. This study is not for HIV treatment; only one dose of the drug will be used.
To learn if the drug pembrolizumab, used to treat certain cancers, is safe for HIV-positive people.
Adults ages 18 and older with HIV who are in another NIH protocol
Participants will be screened with:
- Medical history
- Physical and neurological exams
- Blood tests
- Lumbar puncture. The lower back will be numbed. A needle will remove fluid from between back bones.
- FDG-PET/CT. A radioactive sugar will be injected in a thin plastic tube (catheter) inserted in an arm vein. Participants will rest for an hour, urinate, then lie in the scanner. A mask will hold the head still.
Women who can become pregnant cannot take pembrolizumab. Men who take it must use 2 kinds of contraception.
Participants will have up to 7 more visits, which repeat some screening tests.
At 1 visit, participants will get one dose of pembrolizumab by catheter for 30 minutes. They will get allergy and pain medicines.
At 2 visits, participants will have a brain MRI. They will get a contrast agent by catheter. They will lie in a metal cylinder that takes pictures for 1-2 hours. They will get earplugs for loud sounds.
|Condition or disease||Intervention/treatment||Phase|
|HIV Infections||Drug: Pembrolizumab||Phase 1|
Objective In this Phase I, proof-of-concept study, we aim to determine the safety and tolerability of pembrolizumab, an FDA-approved monoclonal antibody against programmed cell death protein (PD)-1, in viremically suppressed human immunodeficiency virus-1 (HIV) positive patients. We will also examine the correlation of immune activation and suppression markers in viremically suppressed HIV positive patients with the effects of pembrolizumab on immune restoration function (e.g. CD4 count, HIV viral load) and immune activation (e.g. HIV-specific T-cell responses). Study Population HIV is estimated to infect 36.7 million people globally, with 1.1 million deaths and 2.1 million new infections occurring yearly. There is no cure. Opportunistic infections and neoplasms contribute to a large portion of mortality and morbidity within the HIV-positive population. Even in well-controlled, viremically suppressed patients, neurologic complications including HIV-associated neurocognitive disorder, continue to contribute to disease morbidity and mortality. There is evidence that HIV reservoirs contribute to the inability to cure HIV infection. In the brain, macrophages and astrocytes harbor HIV. It is theorized that the brain is a potential reservoir for replication competent HIV. PD-1 expression is elevated in patients with HIV compared to uninfected controls. Upregulated PD-1 expression is associated with higher viral load and increased mortality in infections.1 PD-1 co-expression on regulatory T-cells has been shown to correlate with disease progression in perinatally-infected HIV-positive children. Drugs targeting the PD-1 pathway in HIV infection have shown upregulation of T-cell responses that are potentially critical to eradication of infection. Pembrolizumab is an attractive option due to its mechanism of action, although it has been rarely used in the HIV population. Design In this single-center, single-arm, open label, baseline-versus-treatment phase I clinical trial, twelve patients with HIV-1 infection will receive a one-time dose of 2mg/kg pembrolizumab with a baseline study period of 3 weeks, a one-day treatment phase, and a 6-month post treatment phase.
Outcome measures will be collected every 3 to 6 weeks for the duration of the study. Outcome Measures The primary outcome will be the safety and tolerability of pembrolizumab, which will be measured by clinical exam, laboratory studies and adverse event scale PRO-CTCAE measured using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0. In addition, viral and immunologic outcome measures investigating the impact of pembrolizumab on HIV-1 biology and its effects on immune function will be measured including single copy HIV analysis, CD4+ T-cell count, PD- 1 lymphocyte expression and T-cell phenotype analysis, T-cell proliferation against HIV-proteins, CSF cytokine analysis and CSF antibody profiling (LIPS).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||20 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection|
|Actual Study Start Date :||April 9, 2018|
|Estimated Primary Completion Date :||December 31, 2021|
|Estimated Study Completion Date :||December 31, 2021|
Experimental: Pembrolizumab arm
Pembrolizumab 200mg will be administered as a one-time intravenous infusion over 30 minutes during the treatment phase of the study.
Participants will receive one dose of 2mg/kg of pembrolizumab IV at week 0.
- The primary goal of the study is to determine the safety of a single dose of pembrolizumab in HIVpositive patients. [ Time Frame: ongoing ]The primary outcome will be the safety and tolerability of pembrolizumab, which will be measured by clinical exam, laboratory studies and adverse event tabulations using the Common Terminology Criteria for Adverse Events (CTCAE) v5. 0.
- Change in HIV-specific antibody responses in the CSF and serum using LIPS assay. [ Time Frame: research blood draw at week 0, 3,6, 12, 18, 24 and 52 ]We will analyze antibodies to Tat. We will use the Berlin patient s antibody levels as a benchmark for the post-treatment of the study participants to compare the following proteins: gp41, gp120, matrix, p24, nucleocapsid, reverse transcription, integrase, protease, and tat.
- Change in CSF cytokine profile post-study drug [ Time Frame: lumbar puncture at baseline and week 3 ]change between baseline and week 3
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03239899
|Contact: Amanda M Wiebold||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 firstname.lastname@example.org|
|Principal Investigator:||Avindra Nath, M.D.||National Institute of Neurological Disorders and Stroke (NINDS)|