ClinicalTrials.gov
ClinicalTrials.gov Menu

PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03239899
Recruitment Status : Recruiting
First Posted : August 4, 2017
Last Update Posted : August 27, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

Brief Summary:

Background:

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.

Objective:

To learn if the drug pembrolizumab, used to treat certain cancers, is safe for HIV-positive people.

Eligibility:

Adults ages 18 and older with HIV who are in another NIH protocol

Design:

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

Detailed Description:

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 200mg 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 tabulations using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

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 in the CSF and periphery, 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/or CSF antibody profiling (LIPS). These additional studies will offer indirect proof of a HIV viral reservoir in the CNS as well as potential efficacy of pembrolizumab in reversing immune exhaustion against latent HIV.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
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, 2019
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Pembrolizuma Drug: Pembrolizumab
Participants will receive one dose of 2mg/kg of pembrolizumab IV at baseline.




Primary Outcome Measures :
  1. The primary goal of the study is to determine the safety of a single dose of pembrolizumab in HIV-positive patients. [ Time Frame: 24 weeks ]

Secondary Outcome Measures :
  1. To determine the effect of pembrolizumab on HIV-specific T-cell responses. [ Time Frame: 24 weeks ]
  2. To determine the effect of pembrolizumab on CSF PD-1 expression. [ Time Frame: 24 weeks ]
  3. To examine if pembrolizumab changes the CSF expression of HIV-specific antibody responses or CSF cytokine profiles. [ Time Frame: 24 weeks ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • 18 years or older
  • Diagnosis of HIV-1 infection, with positive HIV 1 antibody testing
  • HIV RNA <40 copies/mL in plasma in the last 12 or greater months
  • CD4 count above 350 cells/uL
  • Antiretroviral therapy for 12 months prior to trial
  • Patient must be willing and able to comply with all the aspects of trial design and follow-up.
  • Patients must be able to provide informed consent
  • Participants who are physically able to father a child must agree to use 2 effective methods of contraception (birth control) from the time you enroll in the study until 4 months after your last exposure to pembrolizumab

    • Effective methods of contraception for this study include:

      • hormonal contraception (birth control pills, birth control patches, injected hormones, hormonal implants or vaginal ring),
      • Intrauterine device,
      • Barrier methods (condom or diaphragm) combined with spermicide, and
      • Surgical sterilization (hysterectomy, tubal ligation, or vasectomy).
      • If you have had a hysterectomy, tubal ligation, or vasectomy (or have a partner with a hysterectomy, tubal ligation or vasectomy), you do not have to use 2 methods of birth control.

EXCLUSION CRITERIA:

  • Clinically significant medical disorders that might expose the patient to undue risk of harm confound study outcomes or prevent the patient from completing the study. Examples of such conditions include cardiac disease such as decompensated congestive heart failure, decompensated chronic obstructive pulmonary disease, uncontrolled hypertension, kidney disease requiring dialysis, uncontrolled liver disease, uncontrolled endocrine disease, uncontrolled pulmonary disease, known progressive CNS disease such as Parkinson s disease, dementia, prior tuberculosis infection or ongoing CNS opportunistic infection.
  • Female sex of reproductive potential (this does not include women who are menopausal, post-hysterectomy, post-tubal ligation, or other methods of sterilization/inability to reproduce)
  • Patient has received immunomodulatory/immunosuppressive therapy (including IV steroids but excluding local injections) in the preceding 6 months.
  • Patient with known autoimmunity that would include but is not limited to disorders such as hypo/hyperthyroidism, myasthenia gravis, diabetes mellitus type 1, hemolytic anemia, and immune mediated hepatitis (but excluding patients with hypothyroidism already on thyroid replacement therapy).
  • Prior history of cancer (excluding non-invasive squamous and basal cell carcinoma)
  • Any opportunistic infection in the prior 2 years (excluding thrush) including latent TB (or a positive TB Quantiferon Gold test)
  • Patient has received other investigational drugs within 3 months before enrollment
  • Positive serological or PCR evidence of active or prior infection with HTLV-1/II, Hepatitis B or C. Patients with low-risk hepatitis B core (+), surface antibody (+), surface antigen ( ) and hepatitis B DNA (-) on either tenofovir or TAF therapy for HIV-1 for the duration of the study would not be excluded.
  • Metal in the body which would make having an MRI scan unsafe, such as pacemakers, stimulators, pumps, aneurysm clips, metallic prostheses, artificial heart valves, cochlear implants or shrapnel fragments, or history of welding or metal worker
  • Claustrophobia
  • Inability to lie comfortably on the back for up to two hours. Abnormal screening/baseline blood tests exceeding any of the limits defined below or as deemed exclusionary by the investigators on review:

    • AST and ALT values >1.1 times ULN
    • Fasting triglyceride > 300 mg/dL
    • Total bilirubin >1.1 times ULN (unless participant is taking atazanavir or has Gilbert syndrome)
    • Creatinine Clearance <60 ml/minute
    • Hemoglobin < 10 g/dL
    • Absolute neutrophil count < 1000/ (Micro)L
    • Platelet count <130,000/mm(3)
    • Hemoglobin A1c greater than or equal to 6%
    • 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.
  • An employee or staff of the NIH

Information from the National Library of Medicine

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


Contacts
Contact: Avindra Nath, M.D. (301) 496-1561 natha@mail.nih.gov

Locations
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    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Principal Investigator: Avindra Nath, M.D. National Institute of Neurological Disorders and Stroke (NINDS)

Additional Information:
Publications:
Responsible Party: National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier: NCT03239899     History of Changes
Other Study ID Numbers: 170145
17-N-0145
First Posted: August 4, 2017    Key Record Dates
Last Update Posted: August 27, 2018
Last Verified: August 10, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):
HIV
Brain
Immunotherapy

Additional relevant MeSH terms:
Infection
Communicable Diseases
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Pembrolizumab
Antineoplastic Agents