Study to Assess Safety and Activity of Combination Therapy of VRC07-523LS and Vorinostat on HIV-infected Persons
Condition: HIV-1 Infection
MeSH terms: Infections
Intervention: VRC07-523LS; Vorinostat (VOR)
Intervention description: VRC07-523LS 40 mg/kg administered intravenously per series (total of 2 infusions administered); Vorinostat 400 mg administered orally every 72 hours for 10 doses per series (A total of 20 400-mg doses administered)
Intervention MeSH terms: Vorinostat
Phase: Phase 1
Study type: Interventional
Primary purpose: Prevention
Intervention model: Single Group Assignment
Intervention model description: Single Arm: All participants will receive combination therapy consisting of VRC07-523LS and Vorinostat.
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Maximum age: 64 Years
Healthy volunteers: No
Keywords: VRC07-523LS; Vorinostat; HIV-1; Suppressed; Latency; Reversal; Novel; Monoclonal; Agent; Antibody; Frequency; T Cell; Infection; ART; Resting

Summary:

      Adult participants (18-64 years old) with HIV-1 Infection on ART with a CD4 T cell count ≥
      350 cells/mm3 and viral suppression for ≥ 24 months will be enrolled on this study.
      Participants will receive two series of combination therapy consisting of one (1) intravenous
      (IV) dose of VRC-HIVMAB075-00-AB (VRC07-523LS) followed by 10 oral (PO) doses of Vorinostat
      (VOR) taken every 72 hours. Each series will last approximately 1 month and the two series
      will be separated by at least one month. Combination ART is maintained throughout the study.
      Participants will be on this study for approximately 28 weeks (or about 7 months).

      The purpose of this study is to:

        -  Evaluate the safety of two series of a VRC07-523LS infusion followed by multiple oral
           doses of VOR

        -  Determine if combining VRC07-523LS and VOR can have an impact on non-active HIV virus.
    

Eligibility criteria:

        Inclusion Criteria:

          1. ≥ 18 years and < 65 years of age

          2. Ability and willingness of participant to give written informed consent. Note: Due to
             the lack of foreseeable benefit to study participants, mentally incompetent
             participants will not be enrolled.

          3. HIV infection documented by any licensed rapid HIV test or HIV enzyme or
             chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and
             confirmed by a licensed Western blot or a second antibody test by a method other than
             the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral assay.

             A reactive initial rapid test should be confirmed by either another type of rapid
             assay or an E/CIA that is based on a different antigen preparation and/or different
             test principle (e.g., indirect versus competitive), or a Western blot or a plasma
             HIV-1 RNA viral load.

          4. On continuous antiretroviral therapy (ART defined below under Inclusion Criterion #5)
             for at least 24 months prior to screening.

             Note: Continuous ART prior to screening is defined as not missing more than 9 total
             days in the 3 months prior to screening.

          5. Permitted regimens include:

               1. At least 3 ART agents (not counting ritonavir if less than a 200 mg total daily
                  dose or cobicistat as one of the agents)

                  Note: One of the agents must include an integrase inhibitor, NNRTI
                  (Non-Nucleoside Reverse Transcriptase Inhibitors), or a boosted-PI (protease
                  inhibitor).

                  OR

               2. Two ART agents in which one of the agents is either a boosted PI or an integrase
                  inhibitor.

             Note: Other fully suppressive antiretroviral combinations will be considered on a
             case-by-case basis.

             Note: Prior changes in, or elimination of, medications for easier dosing schedule,
             intolerance, toxicity, improved side effect profile or within a drug class are
             permitted if an alternative suppressive regimen was maintained but not within 30 days
             prior to screening.

             Note: Changes in drug formulation or dose are allowed (e.g., tenofovir disoproxil
             fumarate (TDF) to tenofovir alafenamide (TAF), ritonavir to cobicistat, or separate
             ART agent dosing to fixed-dose combination), but none within 30 days prior to
             screening.

          6. Ability and willingness of participant to continue ART throughout the study.

          7. Able and willing to adhere to protocol therapy, schedule, and is judged adherent to
             antiretroviral therapy.

          8. Plasma HIV-1 RNA <50 copies/mL at 3 time points in the previous 24 months prior to
             screening and never ≥50 copies/mL on 2 consecutive time points in the last 24 months.

             Note: The documented plasma HIV-1 RNA must be performed by any US laboratory that has
             a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.

          9. At least 1 documented plasma HIV-1 RNA result <50 copies/mL ≥24 months but ≤ 36 months
             prior to screening.

         10. Plasma HIV-1 RNA level <50 copies/mL on an FDA-approved HIV RNA assay at screening,
             performed at US CLIA Certified Laboratory (or its equivalent).

         11. CD4 cell count ≥ 350 cells/mm³ obtained within 90 days prior to study entry, performed
             at any US CLIA Certified Laboratory (or its equivalent).

         12. Hepatitis C (HCV) antibody negative result within 60 days prior to study entry or, if
             the participant is HCV antibody positive, a negative HCV RNA within 60 days prior to
             study entry .

         13. Hepatitis B surface antigen (HBsAg) negative within 60 days prior to study entry.

         14. Interferon-gamma release assay (IGRA) for tuberculosis (TB) with negative results
             within 60 days prior to study entry.

             Note: Participants with a prior positive TB IGRA and documented evidence of completed
             prophylaxis treatment may enroll in the study and do not need to undergo IGRA at
             screening. Participants with a prior positive IGRA who have not completed prophylaxis
             treatment will be excluded.

         15. Men and women who are not of reproductive potential (see below) are eligible without
             requiring the use of contraceptives. Acceptable documentation of sterilization and
             menopause is specified below.

             a) Written or oral documentation communicated by clinician or clinician's staff of one
             of the following:

               1. Physician report/letter

               2. Operative report or other source documentation in the patient record (a
                  laboratory report of azoospermia is required to document successful vasectomy in
                  any partner assigned male sex at birth, hysterectomy, oophorectomy, non-surgical
                  permanent sterilization, or tubal ligation.)

               3. Discharge summary

               4. Documented or participant-reported absence of a period for ≥ one year must be
                  confirmed with Follicle stimulating hormone-release factor (FSH) measurement
                  elevated into the menopausal range as established by the reporting laboratory.

         16. All participants must agree not to participate in a conception process (e.g., active
             attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization,
             egg donation) while on study and for 4 months after their last infusion.

         17. All men participating in sexual activity that could lead to pregnancy must agree to
             consistently use at least one of the following forms of birth control for at least 21
             days prior to Visit 3 and for 4 months after their last infusion:

             a) Condoms (male or female) with or without a spermicidal agent b) Diaphragm or
             cervical cap with spermicide c) Intrauterine device (IUD) d) Tubal ligation e)
             Hormone-based contraceptive f) Successful vasectomy

             Note: For female partners who are receiving ritonavir or cobicistat, estrogen-based
             contraceptives are not reliable and an alternative method should be suggested.

         18. Ability and willingness to provide adequate locator information.

         19. Ability and willingness to communicate effectively with study personnel; considered
             reliable, willing, and cooperative in terms of compliance with the protocol
             requirements.

         20. Adequate vascular access for infusion and leukapheresis.

         21. Able to swallow pills without difficulty.

         22. Agrees not to enroll on another study of an investigational research agent during the
             study period.

             Note: Investigational research agent is defined as any unlicensed investigational drug
             not yet approved by the FDA for intended use in humans.

         23. Adequate organ function as indicated by the following laboratory values:

        Hematological: Absolute neutrophil count (ANC) ≥1,500 /mm^3; Platelets ≥125,000 / mm^3;
        Hemoglobin ≥ 13 g/dL (male) and ≥ 11 g/dL (females)

        Coagulation: Prothrombin Time or International Normalized Ratio (INR) ≤1.5x upper limit of
        normal (ULN)

        Chemistries: K+ levels - Within normal limits; Mg++ levels ≥ 1.2 milliequivalents/L but
        <1.5 x ULN; Glucose - Screening serum glucose ≤ Grade 1 (fasting or non- fasting); Albumin
        ≥ 3.3 g/dL

        Renal: Creatinine clearance determined by the chronic kidney disease (CKD)-Epi equation

        Hepatic: Serum total bilirubin - Total bilirubin < 1.5 X ULN. If total bilirubin is
        elevated, direct bilirubin must be < 2 times the ULN range.

        Note: If participant is on an atazanavir-containing therapy, then a direct bilirubin should
        be measured instead of the total bilirubin and must be ≤ 1.0 mg/dL.; aspartate
        aminotransferase (AST, SGOT) and alanine transaminase (ALT, SGPT) ≤ 1.25 X ULN; Alkaline
        Phosphatase ≤ 2.0 X ULN; Lipase < 1.6 X ULN; Urinalysis: Urine Protein - Negative or trace
        allowed ULN = upper limit of normal

        Exclusion Criteria:

          1. Known allergy or sensitivity to components of VOR

          2. Serious adverse reactions to VRC07-523LS formulation components, VRC01 or VRC01LS,
             including history of anaphylaxis and related symptoms such as hives, respiratory
             difficulties, angioedema, and/or abdominal pain.

          3. Women without documentation of an FSH level indicating menopause, hysterectomy or
             bilateral oophorectomy, bilateral tubal ligation, or non-surgical sterilization.

          4. Receipt of compounds with histone deacetylase (HDAC) inhibitor-like activity, such as
             valproic acid within 30 days prior to screening. Potential participants may screen
             after a 30-day washout period.

          5. Any investigational research agent within 30 days before study entry.

             Note: Co-enrollment in observational only studies is permitted.

             Note: Co-enrollment in other studies using FDA approved medication that are not
             otherwise listed as prohibited will be evaluated by the study PI and permitted on a
             case by case basis.

          6. Plasma HIV RNA ≥150 copies/mL in the 6 months prior to screening.

          7. Weight > 115 kg

          8. Untreated syphilis infection (defined as a positive rapid plasma reagin (RPR) without
             clear documentation of treatment).

             Note: In cases of untreated syphilis, participant may rescreen following documentation
             of adequate treatment of syphilis

          9. Current treatment for HCV with antiviral therapy or participants who have received HCV
             treatment within 6 months prior to screening.

         10. Use of any of the following within 90 days prior to entry: immunosuppressive,
             immunomodulatory, cytokine, or growth stimulating factors such as systemic
             corticosteroids, cyclosporine, methotrexate, azathioprine, anti-CD25 antibody,
             interferon (IFN), interleukin-2 (IL-2).

             Not Exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3]
             topical steroids for mild, uncomplicated dermatitis; or [4] a single course of oral
             /parental prednisone or equivalent at doses <2mg/kg/day and length of therapy <11 days
             with completion at least 30 days prior to enrollment.

         11. Current use of Coumadin, warfarin, or other Coumadin derivative anticoagulants.

         12. Prior receipt of HIV immunotherapy within 6 months prior to screening.

         13. Prior receipt of more than three doses of Vorinostat.

         14. Prior receipt of humanized or human monoclonal antibodies (mAbs) within 2 months prior
             to screening, whether licensed or investigational, will have eligibility determined by
             the study PI on a case-by-case basis.

         15. Received any infusion blood product, immune globulin, or hematopoietic growth factors
             within 90 days prior to study entry.

         16. Pregnancy or breast-feeding.

         17. 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, for at least 90 days prior to screening.

         18. History of autoimmune disease

             Not exclusionary: Persons with mild, stable, and uncomplicated autoimmune disease that
             does not require immunosuppressive medication and that, in the judgement of the site
             investigator (or designee), is likely not subject to exacerbation and likely not to
             complicate adverse event (AE) assessments.

         19. Use of topical steroids over a total area exceeding 15 cm-2 within 30 days prior to
             Screening.

         20. Treatment for an active AIDS-defining opportunistic infection within 90 days prior to
             Screening.

         21. History of malignancy within the last 5 years.

             Note: A history of non-melanoma skin cancer (e.g., basal cell carcinoma or squamous
             cell skin cancer) is not exclusionary with documentation of complete resection at
             least 3 months prior to enrollment).

         22. Compulsorily detained (involuntarily incarcerated) for treatment of either a
             psychiatric illness or a physical illness, e.g., infectious disease.

         23. Known psychiatric, medical, occupational, or substance abuse disorders that would
             interfere with participant's ability to fully cooperate with the requirements of the
             trial as assessed by the study investigator (or designee).

             Specifically exclusionary: [1] recent psychosis; [2] ongoing risk for suicide; or [3]
             recent history of suicide attempt or gesture.

         24. History or other clinical evidence of a significant medical condition that includes
             but is not limited to:

             a) A process that would affect the immune response b) A process that would require
             medication that affects the immune response c) Any contraindication to repeated
             injections, infusions, or blood draws d) A condition or process (e.g., chronic
             urticarial or recent injection or infusion with evidence of residual inflammation) for
             which signs and symptoms could be confused with reactions to the study product

         25. Current anti-tuberculosis therapy

         26. Diabetes Mellitus type 1

             Note: Individuals with type 2 diabetes who meet inclusion criteria for glucose
             (Inclusion Criterion #23) are not excluded.

         27. History of coronary artery disease, congestive heart failure, or cardiac arrhythmia
             requiring current treatment prior to study screening.

         28. Hypertension - Exclude for blood pressure consistently >150 mm Hg systolic and >100 mm
             Hg diastolic.

             Note: Elevated BP occurring during research leukapheresis procedures completed within
             the past 12 months are excluded from this requirement. Acceptable isolated elevations
             must be noted as acceptable and signed by study PI or designee.

         29. Unstable asthma (e.g., sudden acute attacks occurring without an obvious trigger) or
             either of the following in the past 12 months:

               1. >1 exacerbation of symptoms treated with oral/parental corticosteroids;

               2. Emergency care, urgent care, hospitalization, or intubation for asthma.

         30. Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or
             platelet disorder requiring special precautions)

         31. Seizure disorder: History of seizure(s) within past three years or use of medications
             used to prevent or treat seizure(s) at any time within the past 3 years.

         32. History of asplenia - absence of normal spleen function as indicated by:

               1. Splenectomy

               2. Sickle cell disease

         33. History of hereditary angioedema, acquired angioedema, or idiopathic angioedema.

         34. Prisoner recruitment and participation is not permitted.