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

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

Patrocinadores

Patrocinador principal: National Institute of Neurological Disorders and Stroke (NINDS)

Fuente National Institutes of Health Clinical Center (CC)
Resumen breve

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.

Descripción detallada

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.

Estado general Recruiting
Fecha de inicio April 9, 2018
Fecha de Terminación December 31, 2021
Fecha de finalización primaria December 31, 2021
Fase Phase 1
Tipo de estudio Interventional
Resultado primario
Medida Periodo de tiempo
The primary goal of the study is to determine the safety of a single dose of pembrolizumab in HIVpositive patients. ongoing
Resultado secundario
Medida Periodo de tiempo
Change in HIV-specific antibody responses in the CSF and serum using LIPS assay. research blood draw at week 0, 3,6, 12, 18, 24 and 52
Change in CSF cytokine profile post-study drug lumbar puncture at baseline and week 3
Inscripción 20
Condición
Intervención

Tipo de intervención: Drug

Nombre de intervención: Pembrolizumab

Descripción: Participants will receive one dose of 2mg/kg of pembrolizumab IV at week 0.

Etiqueta de grupo de brazo: Pembrolizumab arm

Elegibilidad

Criterios:

- INCLUSION CRITERIA:

- 18 years or older

- Diagnosis of HIV-1 infection, with positive HIV 1 antibody testing

- HIV RNA less than or equal to 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

- Women of childbearing potential must agree to use contraception (defined as two forms of effective birth control), from the time of enrollment until 4 months after the last exposure to pembrolizumab

- 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 as identified on screening studies and by patient history. Examples of such conditions include known cardiac disease such as congestive heart failure, chronic obstructive pulmonary disease, uncontrolled hypertension, kidney disease, liver disease, endocrine disease, pulmonary disease, heart disease, progressive CNS disease such as Parkinson s disease, dementia, prior tuberculosis infection or ongoing CNS opportunistic infection.

- 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 hepatitis B core (+), surface antibody (+), surface antigen ( ) and hepatitis B DNA (-) eligible to participate in the study (provided they are on tenofovir, lamivudine or TAF). Participants with prior hepatitis C who are hepatitis C antibody (+) but hepatitis C RNA (-) with normal liver enzymes and no evidence of cirrhosis on clinical liver ultrasound will be eligible to participate in the study.

- 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 anti-thyroid panel (anti-TPO and anti-TG) test at screening visit.

- 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 or eGFR <60 ml/minute (adjusted for race)

- Hemoglobin < 10 g/dL

- Absolute neutrophil count < 1000/microliter

- Platelet count <100,000/mm(3) (if platelet clumping is present on hematology slide review, platelet count <100,000/mm3 will be considered exclusionary to study)

- 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

Género: All

Edad mínima: 18 Years

Edad máxima: N/A

Voluntarios Saludables: No

Oficial general
Apellido Papel Afiliación
Avindra Nath, M.D. Principal Investigator National Institute of Neurological Disorders and Stroke (NINDS)
Contacto general

Apellido: Amanda M Wiebold

Teléfono: (301) 594-5194

Email: [email protected]

Ubicación
Instalaciones: Estado: Contacto: National Institutes of Health Clinical Center For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 TTY8664111010 [email protected]
Ubicacion Paises

United States

Fecha de verificación

May 21, 2020

Fiesta responsable

Tipo: Sponsor

Palabras clave
Tiene acceso ampliado No
Condición Examinar
Número de brazos 1
Grupo de brazo

Etiqueta: Pembrolizumab arm

Tipo: Experimental

Descripción: Pembrolizumab 200mg will be administered as a one-time intravenous infusion over 30 minutes during the treatment phase of the study.

Información de diseño del estudio

Asignación: N/A

Modelo de intervención: Single Group Assignment

Propósito primario: Treatment

Enmascaramiento: None (Open Label)

Fuente: ClinicalTrials.gov