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A Single Dose of Pembrolizumab in HIV-Infected People

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ClinicalTrials.gov Identifier: NCT03367754
Recruitment Status : Recruiting
First Posted : December 11, 2017
Last Update Posted : September 28, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC)

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.

Sponsoring Institute: National Institute of Health Clinical Center


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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled Study of a Single Dose of Pembrolizumab in HIV-Infected People
Actual Study Start Date : August 6, 2018
Estimated Primary Completion Date : May 30, 2022
Estimated Study Completion Date : November 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

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




Primary Outcome Measures :
  1. The occurrence of Grade 3 or higher AEs. [ Time Frame: 96 weeks after receiving the study drug ]
  2. Grade 2 or higher autoimmune events requiring corticosteroid therapy. [ Time Frame: 96 weeks after receiving the study drug ]

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


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

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

  1. Greater than or equal to 18 years of age.
  2. 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 greater than 1000 copies/mL). Outside documentation will be acceptable.
  3. Absolute neutrophil count greater than 1000/microL.
  4. Platelet count greater than 125,000/microL.
  5. Hemoglobin greater than 10 g/dL.
  6. Aspartate transaminase (AST) and alanine transaminase (ALT) less than 1.5 times the upper limit of normal (ULN). Total bilirubin less than 1.1 x ULN (unless participant is taking atazanavir or has Gilbert syndrome).
  7. Calculated creatinine clearance (estimated glomerular filtration rate) greater than or equal to 60 mL/min/1.73 m^2.
  8. 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.
  9. No significant underlying pulmonary, cardiac, renal, or hepatic disease, as defined by a need for drug treatment or ongoing physician care.
  10. Under the care of a primary care physician.
  11. Willing to comply with study requirements and procedures including storage of biological specimens for future use in medical research.
  12. Willing to allow genetic testing.
  13. Able to provide informed consent.
  14. Males of reproductive potential must agree to not impregnate a partner beginning 30 days before the dose of pembrolizumab through 120 days postdose. Non-reproductive potential for males is defined as azoospermia. Males of reproductive potential must either practice complete and uninterrupted abstinence from heterosexual activity or use two of the following methods of

    contraception with their partners. The 2 methods must include one from each group, both of which must be consistently used.

    • Barrier methods:

      • a. Diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide).
      • b. Cervical cap with spermicide (only for nulliparous partners).
      • c. Contraceptive sponge (only for nulliparous partners).
      • d. Male or female condom (cannot be used together).
    • Non-barrier methods:

      • a. Intrauterine device.
      • b. Hormonal contraception: pill (estrogen/progestin or progestin-only), skin patch, vaginal ring, rod implanted in the skin, or subcutaneous injection.
  15. Participants must meet criteria for INR, defined as follows:

    • a. Has been on a cART regimen for at least 12 months and on a stable regimen for at least 4 weeks.
    • b. Has evidence of viral suppression, defined as viral load less than 40 copies/mL, and documented suppression (below detection limits of the utilized assay) for at least 12 months. A viral load of less than 500 copies/mL once in the year preceding screening will be allowed if there is documentation of a viral load less than 40 copies/mL on subsequent testing and at screening.
    • c. CD4+ T-cell count greater than 100 cells/mm^3 and less than or equal to 350 cells/mm^3.

EXCLUSION CRITERIA:

  1. Has used an investigational drug agent or investigational device within 12 weeks of baseline. However, ARVs obtained through expanded access programs are permitted.
  2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  3. Known allergy to any component of the pembrolizumab formulation.
  4. Systemic steroid therapy or other immunosuppressive therapy in the 3 months prior to enrollment. (Inhaled or topical corticosteroids are permitted.)
  5. Has used an immunotherapeutic agent (eg, cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, sirolimus, therapies targeting tumor necrosis factor- ) within 6 months of baseline necrolysis. Replacement therapy (eg, T4.) is not considered a form of systemic treatment.
  6. Has received any vaccine, live or inactivated, within 30 days of baseline, or plans to receive any vaccine within 16 weeks of receiving pembrolizumab.
  7. 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). Such autoimmune diseases include for example psoriasis, systemic lupus erythematosus, autoimmune uveitis, autoimmune hepatitis, inflammatory colitis, rheumatoid arthritis, Guillain-Barr(SqrRoot)(Copyright) syndrome, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Replacement therapy (eg, T4.) is not considered a form of systemic

    treatment.

  8. Has known history of, or any evidence of active, non-infectious pneumonitis.
  9. 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.
  10. 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).
  11. 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.
  12. Females of reproductive potential or who are pregnant or breastfeeding. Non-reproductive potential for females is defined as any of the following: postmenopausal; surgical sterilization at least 6 weeks before screening; or a congenital or acquired condition that definitively prevents conception. Further, postmenopausal is defined as at least 12 consecutive months with no menses at age 50 or older, or at least 12 consecutive months with no menses at age 45 - 49 plus a high follicle-stimulating hormone level in the postmenopausal range, in participants not using hormonal contraception or hormone replacement therapy.
  13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
  14. History or other clinical evidence of:

    • a. Significant or unstable cardiac disease (eg, angina, congestive heart failure, myocardial infarction).
    • b. Significant pulmonary disease (eg, chronic obstructive pulmonary disease, asthma requiring systemic therapy).
    • c. Severe illness, chronic liver disease, malignancy, immunodeficiency other than HIV, active systemic infection (other than HIV) requiring therapy.
  15. 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.
  16. Active or history of tuberculosis (TB), or positive TB QuantiFERON Gold test.
  17. Known osteoporosis or diabetes mellitus.
  18. Hemoglobin A1c greater than 6%.
  19. Fasting triglyceride greater than 300 mg/dL.
  20. Any condition that, in the opinion of the investigator, would make the participant unsuitable for the study.

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): NCT03367754


Contacts
Contact: Julia B Purdy, C.R.N.P. (301) 451-9109 purdyj@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 Institutes of Health Clinical Center (CC)
Investigators
Principal Investigator: Joseph A Kovacs, M.D. National Institutes of Health Clinical Center (CC)

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT03367754     History of Changes
Other Study ID Numbers: 180013
18-CC-0013
First Posted: December 11, 2017    Key Record Dates
Last Update Posted: September 28, 2018
Last Verified: September 21, 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):
Immunotherapy
Immunologic Non-Responder
Immunologic Response
Randomized
PD-1

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