N-803 Combined With the Broadly Neutralizing Antibodies Plus or Minus haNK Cells for HIV

Study Overview
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Brief Summary
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To assess the safety of combination immune therapy in HIV-infected participants whose HIV is controlled with ART, by determining the incidence and severity of adverse events.

Detailed Description
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This is a phase 1b study to examine the safety, tolerability and efficacy of the combination of 4 immunotherapies for treatment of HIV in participants with controlled HIV viremia and stable CD4 counts on antiretroviral therapy (ART). The study will be conducted in two separate phases using two distinct to groups of participants where each group will have 10 individuals enrolled. Treatment will consist of N-803, VRC07-523LS, PGT121, and haNK, with N-803 given for 3 cycles of 9 weeks/cycle. N-803 will be given every 3 weeks (3 doses/cycle), bNAbs will be given every 9 weeks, and haNK cells administered on the same day as each infusion of N-803. Total study duration will be 27 weeks. Group 1 will receive only N-803 and the bNAbs; they will not receive the haNK™ cells. When 2 participants are enrolled and on active treatment for one month in Group 1, the Safety Monitoring Committee will review all data and if there are no safety concerns raised in the data recorded from administration of the interventions to those participants, Group 1 will continue. When Group 1 is complete, the SMC will again review all data before Group 2 can proceed with enrollment. The protocol for Group 2 will be identical to the one followed by Group 1, except that they will receive haNK™ cells at 2 × 109 cells/dose IV on the same day as each dose of N-803. Optional tissue biopsies (lymph node and colonoscopy to collect gut-associated lymphoid tissue (GALT)) will occur at baseline and again 9 weeks after the last infusion of bNAbs. We aim to perform biopsies on least 8 out of 10 participants in each group.

Official Title
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A Phase 1B Study of N-803 Combined With the Broadly Neutralizing Antibodies VRC07-523LS and PGT121 Plus or Minus haNK Cells for Reduction of HIV Reservoirs

Conditions
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Hiv, HIV/AIDS, HIV Infections, AIDS, AIDS and Infections, Aids/Hiv Problem

Intervention / Treatment
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* Biological: N-803 and bNAbs
* Biological: haNK™ Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection On continuous antiretroviral therapy for > 12 months without any interruptions of greater than 14 consecutive days in the last 12 months Screening plasma HIV RNA levels < 20 copies/mL on all available determinations in past 12 months (isolated single values ≥ 20 but < 200 copies/mL will be allowed if they were preceded and followed by viral load determinations < 20 copies/mL) Screening CD4+ T-cell count ≥ 400 cells/mm3 Exclusion Criteria: Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study Active or recent malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months; minor surgical removal of localized skin cancers (squamous cell carcinoma, basal cell carcinoma) are not exclusionary Chronic liver disease defined as Class B and C on the Child-Pugh scale Active and poorly controlled atherosclerotic cardiovascular disease (ASCVD), as defined by 2013 ACC/AHA guidelines, including a previous diagnosis of any of the following: (a) acute myocardial infarction, (b) acute coronary syndromes, (c) stable or unstable angina, (d) coronary or other arterial revascularization, (e) stroke, (f) transient ischemic attack (TIA), or (g) peripheral arterial disease grade IIa or greater History of AIDS-defining illness within the past 5 years History of potential immune-mediated medical conditions requiring concomitant treatment with immunomodulatory drugs, and/or exposure to any immunomodulatory drug in the 4 weeks prior to study enrollment Exposure to any experimental therapies within 90 days of study entry

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1: N-803 and bNAbs Only<br>Group 1 will receive only N-803 and the bNAbs; they will not receive the haNK™ cells | Biological: N-803 and bNAbs<br>* Treatment will consist of N-803, VRC07-523LS, PGT121, and haNK, with N-803 given for 3 cycles of 9 weeks/cycle. N-803 will be given every 3 weeks (3 doses/cycle) and bNAbs will be given every 9 weeks.<br>|
| Experimental: Group 2: N-803 and bNAbs with haNK™ Cells<br>The protocol for Group 2 will be identical to the one followed by Group 1, except that they will receive haNK™ cells on the same day as each dose of N-803. | Biological: N-803 and bNAbs<br>* Treatment will consist of N-803, VRC07-523LS, PGT121, and haNK, with N-803 given for 3 cycles of 9 weeks/cycle. N-803 will be given every 3 weeks (3 doses/cycle) and bNAbs will be given every 9 weeks.<br>Biological: haNK™ Cells<br>* Treatment will consist of N-803, VRC07-523LS, PGT121, and haNK, with N-803 given for 3 cycles of 9 weeks/cycle. N-803 will be given every 3 weeks (3 doses/cycle), bNAbs will be given every 9 weeks, and haNK cells administered on the same day as each infusion of N-803.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Number of Adverse Events Grades 3, 4, 5 | Number of serious adverse events (SAEs) graded 3 (severe pain; interferes with oral intake), 4 (life-threatening consequences; urgent intervention needed), and 5 (death) experienced in the haNK cell group compared to the group receiving no haNK cells. Lower number of SAEs indicated greater treatment safety. | 27 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of HIV Reservoir in PBMCs | HIV RNA in peripheral blood mononuclear cells (PBMCs) will be quantified using next gen sequencing. Percent reduction in HIV RNA reservoirs in these cells will be compared between groups. Greater percent reduction in viral reservoirs in haNK cell group indicates greater efficacy of haNK cell therapy compared to no haNK cell therapy. | 27 weeks |