A Phase I Study to Evaluate the Immunologic Response and Virologic Impact of AGS-004

Study Overview
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Brief Summary
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The purpose of this study is to: find out the intensity and duration of the immune response after multiple injections of the investigational study product AGS-004 made from one's own dendritic cells and one's own strain of HIV; understand the changes in the body's HIV DNA , and HIV-1 RNA in peripheral and resting CD4+ cells prior to and following administration of AGS- 004. find out if low levels of HIV virus that are not detectable by standard HIV RNA assays will decrease following the administration of AGS-004. find out if it is safe to give individuals with HIV multiple injections of AGS-004 made from the person's own dendritic cells and their own strain of HIV. find out if administration of AGS-004 decreases the amount of latent HIV infection in resting CD4 cells

Detailed Description
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This is a phase I, single-site, pilot study of the kinetics of the immunological response and virological impact of AGS-004 administered in participants with durable viral suppression on ART initiated during acute (AHI) and chronic HIV infection (CHI). Patients will be screened for eligibility in Step 1. Those meeting study eligibility and with successful production of Argos (AGS)-004 product will then enter Step 2 with administration of AGS-004. All participants will continue ART throughout the study.

Official Title
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IGHID 1309 -A Phase I Study to Evaluate the Kinetics of the Immunologic Response and Virologic Impact of AGS-004 in HIV-Infected Individuals Suppressed on Antiretroviral Therapy Initiated During Acute and Chronic HIV Infection

Conditions
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HIV

Intervention / Treatment
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* Biological: AGS-004


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmation of HIV-1 infection: Chronic HIV infection (CHI) is defined as documentation of a positive HIV test result by any licensed ELISA test kit and confirmed by Western blot or Multispot HIV-1/HIV-2 assay prior to screening. HIV culture, HIV antigen, plasma HIV RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test. Acute HIV infection (AHI) is defined as a negative or indeterminate enzyme immunoassay (EIA) or a negative HIV RNA test within 45 days of reproducibly detectable plasma HIV RNA by amplification methods. Participants in the AHI arm of this study must have initiated ART within 45 days of AHI diagnosis Ages ≥ 18 to < 65 years old Stable ART regimen for ≥ 6 months prior to Screening (Visit 1) NOTE: The ART regimen is defined by current treatment guidelines. Participants may have had one or more changes in their ART regimen for tolerance, change of guidelines, or dosing simplification. On potent antiretroviral therapy, defined as at least 2 nucleoside/nucleotide reverse transcriptase inhibitors plus a non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, or a protease inhibitor. Other potent fully suppressive antiretroviral combinations will be considered on a case-by-case basis. Prior changes in or elimination of medications for easier dosing schedule, intolerance, or toxicity are permitted. All participants must continue cART throughout the study. Plasma HIV-1 RNA below detected limit by conventional assays (limit of detection determined by assay employed: 75, 50, 40, or 20 copies/mL) for ≥ 1 year A single unconfirmed plasma HIV RNA > limit of detection but < 1000 c/mL allowed if a subsequent assay was below the limit of detection; but none in the 6 months preceding the study screening visit. Plasma HIV-1 RNA < 50 copies/mL at screening (Visit 1) CD4 cell count ≥ 350 cells/mm3 at screening (Visit 1) Availability of an adequate sample of frozen plasma (may have been thawed and re-frozen only once) drawn no more than 90 days (and preferably within 30 days) before starting ART, OR an adequate frozen sample of HIV p24 antigen-positive culture supernatant obtained from culture of resting CD4+ T cells. Note: The VL documented from the pre-ART HIV plasma sample must be ≥8,000 copies/ml before commencing ART regimen (abstracted from medical records). If there is no viral load measurement associated with the pre-ART HIV plasma sample, another pre-ART VL measurement of 8,000 copies/ml can be used to accept the sample for AGS-004 manufacturing. No history of auto-immune disease or auto-immune manifestations No active HCV infection (measureable HCV RNA) within 90 days of eligibility visit (visit 3). No active HBV infection (measureable HBV DNA or HBVsAg+) within 90 days of eligibility visit (visit 3). Ability and willingness of participant to give written informed consent Able and willing to provide adequate locator information Ability and willingness to communicate effectively with study personnel; considered reliable, willing, and cooperative in terms of compliance with the Protocol requirements Adequate vascular access for leukapheresis Able and willing to receive Intradermal (ID) injections without difficulty All female study participants of childbearing potential must agree not to participate in a conception process, and, if participating in sexual activity that could lead to pregnancy, these female participants and their partners must agree to use at least two reliable forms of contraception for at least 21 days prior to study entry and for 12 weeks after the last dose of the study drug product: o Acceptable forms of contraception include the following: Condoms (male or female) with or without spermicidal agent Diaphragm or cervical cap with spermicide Intrauterine device (IUD) Hormonal birth control drugs given by pills, shots, or placed on or under the skin Tubal ligation NuvaRing Potential participant must have adequate organ function as indicated by the following laboratory values: System/Laboratory Value: Hematological: Absolute neutrophil count (ANC): ≥1,500/mcL Platelets: ≥125,000/mcL Hemoglobin: ≥12g/dL Coagulation: Prothrombin Time or INR: ≤1.5x upper limit of normal (ULN) Chemistry: K+ levels: Within normal limits Mg++levels: ≥1.2 mEq/L but <1.5 x ULN Glucose: Screening serum glucose (fasting or non-fasting) <120 mg/dl Albumin: ≥3.3 g/dL Renal: Serum creatinine or calculated creatinine clearance: ≤1.5 x upper limit of normal (ULN) OR ≥ 60mL/min for potential participants with creatinine levels > 1.3 x institutional ULN Hepatic: Serum total bilirubin: Total bilirubin <1.8 times the upper limit of the normal range, unless history of Gilbert's disease or deemed related to treatment with atazanavir. If total bilirubin is elevated, direct bilirubin must be <2 times the ULN range. AST (SGOT) and ALT (SGPT): ≤ 2.5 X ULN Alkaline Phosphatase: ≤ 2.5 X ULN NOTE: Creatinine clearance should be calculated per institutional standard. Exclusion Criteria HIV-2 antibody positive in the absence of a positive HIV-1 Western Blot as measured at the Screening Visit (Visit 1). Untreated syphilis infection (defined as a positive rapid plasma reagin (RPR) without clear documentation of treatment). Received any infusion blood product, immune globulin, or hematopoetic growth factors within 90 days prior to study entry. History of lymph node irradiation or dissection. Use of any of the following within 90 days prior to entry: immunomodulatory, cytokine, or growth stimulating factors such as systemic corticosteroids, cyclosporine, methotrexate, azathioprine, anti-CD25 antibody, IFN, interleukins, interleukin-2 (IL-2), hydroxyurea, thalidomide, sargramostim (granulocyte macrophage-colony stimulating factor [GM-CSF]), dinitrochlorobenzene (DNCB), thymosin alpha, thymopentin, inosiplex, polyribonucleotide, or ditiocarb sodium, coumadin, warfarin, or other Coumadin derivative anticoagulants. Use of any prior HIV vaccine (prophylactic and/or therapeutic) within one year before screening (Visit 1). Prior participation in AGS-004 clinical research study. Treatment interruption of ART for > 1 month since starting the ART from which pre-ART plasma sample was drawn For any serious illness requiring systemic treatment or hospitalization, the participant must either complete therapy or be clinically stable on therapy, in the opinion of the site investigator, for at least 90 days prior to entry. Pregnancy or breastfeeding Any active malignancy that may require chemotherapy or radiation therapy. Evidence of hepatic decompensation in cirrhotic participants: history of ascites, hepatic encephalopathy, or bleeding esophageal varices. History or other clinical evidence of significant or unstable cardiac disease (e.g., angina, congestive heart failure, recent myocardial infarction, significant arrhythmia) or clinically significant electrocardiogram (ECG) abnormalities. Any history of cardiac rhythm disturbance requiring medical or surgical therapy. Any renal disorder deemed clinically significant by the investigator. History or other evidence of severe illness, malignancy, immunodeficiency other than HIV, or any other condition that would make the participant unsuitable for the study in the opinion of the investigator. Compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric illness or a physical illness, e.g., infectious disease. Prisoner recruitment and participation is not permitted. Known allergy or sensitivity to the components of the investigational immunotherapy. Use of systemic corticosteroids and use of topical steroids over a total area exceeding 15 cm2 within 30 days prior to Screening or anticipated need for periodic use of corticosteroids during the study. NOTE: For participants receiving ritonavir (as a booster or protease inhibitor (PI) as part of their ART regimen, the concomitant use of oral/systemic/topical/inhaled/intranasal corticosteroids is prohibited. Any history of acute or chronic pancreatitis. If the HIV care provider or study investigator is unable, as assessed by the study PI or protocol team, to construct a fully active alternative ART regimen based on previous resistance testing and/or treatment history. Known psychiatric or substance abuse disorders that would interfere with one's ability to fully cooperate with the requirements of the trial. Any investigational antiretroviral agents or use of a CCR5 inhibitor at Screening. Active autoimmune disease or condition including, but not limited to: Rheumatoid arthritis (RF positive arthritis with current or recent flare); Inflammatory bowel disease; Systemic lupus erythematosis (clinical evidence confirmed with ANA >1:80); Ankylosing spondylitis; Hashimoto's disease; Scleroderma; Multiple sclerosis; Autoimmune hemolytic anemia (AHA); Immune thrombocytopenic purpura; and, Type I diabetes mellitus (insulin therapy for Type II diabetes is permitted). Participation in another investigational clinical research study (with the exception of an antiretroviral treatment trial that uses FDA approved antiretroviral agents) or use of investigational agents within 30 days prior to Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: ART initiated during AHI<br>Arm A will enroll approximately 6 participants who initiated ART during AHI (acute HIV infection). The target dose of AGS -004 is delivered in three ID (intradermal) injections of 0.2 mL of AGS-004 (0.6 mL total volume) for a total of 1.2 x 107 viable cells. AGS-004 is administered every 4 weeks at weeks 0, 4, 8, and 12 for a total of 4 doses. | Biological: AGS-004<br>* All participants in both arms will receive the same treatment and doses of AGS-004 in Step 2 at weeks 0, 4, 8, and 12.<br>|
| Experimental: Arm B: ART initiated during CHI<br>Arm B will enroll approximately 6 participants who initiated ART during CHI (chronic HIV infection). The target dose of AGS -004 is delivered in three ID (intradermal) injections of 0.2 mL of AGS-004 (0.6 mL total volume) for a total of 1.2 x 107 viable cells. AGS-004 is administered every 4 weeks at weeks 0, 4, 8, and 12 for a total of 4 doses. | Biological: AGS-004<br>* All participants in both arms will receive the same treatment and doses of AGS-004 in Step 2 at weeks 0, 4, 8, and 12.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD8 T cell responses | Measure the duration of HIV-specific CD8 T cell responses by a flow cytometric assay through week 32 | 32 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in low level plasma HIV-1 RNA by single copy assay (SCA) | The change in low level HIV -1 RNA as measured by a single copy assay following AGS-004 administration | Weeks 0, 14 and 32 | 
| Change in frequency of HIV-1 infection of resting CD4+ T cells using the viral outgrowth assay | Change in frequency of HIV-1 infection of resting CD4+ T cells using the viral outgrowth assay following AGS-004 administration | Weeks 0, 14 and 32 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Acute HIV Infection, Chronic HIV Infection, AGS-004, Phase 1, Antiretroviral Therapy, ART, UNC, Argos Therapeutics, The CARE Collaboratory of AIDS, Immunization, vaccination