A Phase I Clinical Trial of the Safety, Tolerability, and Efficacy of IL-15 Superagonist (N-803) With and Without Combination Broadly Neutralizing Antibodies to Induce HIV-1 Control During Analytic Treatment Interruption
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 118
- 试验地点
- 28
- 主要终点
- Occurrence of a Grade ≥3 adverse event (AE) that is at least possibly related to N-803, as judged by the Clinical Management Committee (CMC)
研究概览
简要总结
The purpose of this study is to evaluate the safety, tolerability, and efficacy of N-803, an IL-15 superagonist, with or without combination broadly neutralizing antibodies (bNAbs), to induce HIV-1 control during analytic treatment interruption (ATI).
详细描述
This study will evaluate the safety, tolerability, and efficacy of N-803, an IL-15 superagonist, with or without combination broadly neutralizing antibodies (bNAbs), to induce HIV-1 control during analytic treatment interruption (ATI).
Participants will be screened for eligibility and undergo leukapheresis, and a subset will also undergo optional rectal biopsy and/or lymph node fine needle aspirations (FNAs) (Step 1).
After pre-entry and determination of eligibility in Step 1, participants will be randomized before Step 2 entry to either the N-803 only arm (Arm A) or the N-803 with combination bNAbs arm (Arm B):
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Arm A will receive a dose of N-803, 6 mcg/kg, subcutaneously 1 week after Step 2 entry and then every 3 weeks for a total of eight doses (during the first 22 weeks).
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Arm B will receive the following (during the first 22 weeks):
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Combination bNAb at Step 2 entry with VRC07-523LS dosed at 20 mg/kg and 10-1074 dosed at 30 mg/kg, intravenously;
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A dose of N-803, 6 mcg/kg, subcutaneously 1 week after Step 2 entry and then every 3 weeks for a total of eight doses;
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A second dose of 10-1074 at week 9 of Step 2 dosed at 30 mg/kg, intravenously
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •HIV-1 infection
- •On ART for at least 96 weeks prior to randomization
- •On ART regimen containing an integrase inhibitor and two nucleoside reverse transcriptase inhibitors (NRTIs) or dolutegravir/lamivudine for at least 6 weeks prior to randomization.
- •CD4 cell count >450 cells/mm^3 within 90 days prior to randomization
- •CD4 cell count nadir ≥200 cells/mm^
- •Plasma HIV-1 RNA levels of <50 copies/mL for at least 96 weeks prior to randomization
- •Select laboratory results within 90 days of randomization
- •IC90 to 10-1074 of ≤1.5 mcg/mL, 10-1074 maximum percent inhibition (MPI) ≥98%, and IC80 to VRC07-523LS of ≤1 mcg/mL on the Monogram PhenoSense assay.
- •QTcF interval ≤440 msec within 90 days prior to randomization.
- •For cisgender women and transgender men of reproductive potential, negative urine or serum pregnancy test within 30 days prior to randomization
- •Cisgender women and transgender men of reproductive potential must agree to use two methods of contraception, if participating in sexual activity that could lead to pregnancy.
- •Cisgender men and transgender women participants engaging in sexual activity that could lead to pregnancy and who are of reproductive potential must agree to use a barrier method of contraception
- •Willingness to abstain from sexual intercourse or use a barrier method of contraception consistently
- •Willingness to participate in an ATI.
- •Weight >50 kg and <115 kg.
- •Completion of pre-entry leukapheresis
排除标准
- •History of AIDS-defining illness, with the exception of recurrent pneumonia.
- •History of or current clinical cardiovascular disease
- •Current clinically significant acute or chronic medical condition
- •History of HIV-associated neurocognitive disease
- •History of an HIV-associated malignancy
- •ART initiated during acute HIV infection
- •Current receipt of ART other than NRTI and integrase inhibitor.
- •Resistance to one or more drugs in two or more ARV drug classes.
- •Receipt of any therapeutic HIV vaccine or monoclonal antibody therapy (anti-HIV or otherwise) at any time in the past.
- •History of prior immunoglobulin (IgG) therapy.
- •History of use of any immunomodulatory medications within 6 months prior to randomization
- •Participation in another clinical study of an investigational product currently or within past 12 weeks
- •Breastfeeding or pregnancy
研究组 & 干预措施
Arm B: N-803 in combination with 10-1074 and VRC07-523LS
Participants will receive N-803 in combination with 10-1074 and VRC07-523LS as follows:
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At Step 2 entry:
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VRC07-523LS 20 mg/kg
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10-1074 30 mg/kg
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At Step 2, week 1: N-803 6 mcg/kg every 3 weeks for eight doses
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At Step 2, week 9: 10-1074 30 mg/kg
干预措施: N-803 (IL-15 Superagonist) (Biological)
Arm B: N-803 in combination with 10-1074 and VRC07-523LS
Participants will receive N-803 in combination with 10-1074 and VRC07-523LS as follows:
-
At Step 2 entry:
-
VRC07-523LS 20 mg/kg
-
10-1074 30 mg/kg
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At Step 2, week 1: N-803 6 mcg/kg every 3 weeks for eight doses
-
At Step 2, week 9: 10-1074 30 mg/kg
干预措施: VRC07-523LS (Biological)
Arm B: N-803 in combination with 10-1074 and VRC07-523LS
Participants will receive N-803 in combination with 10-1074 and VRC07-523LS as follows:
-
At Step 2 entry:
-
VRC07-523LS 20 mg/kg
-
10-1074 30 mg/kg
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At Step 2, week 1: N-803 6 mcg/kg every 3 weeks for eight doses
-
At Step 2, week 9: 10-1074 30 mg/kg
干预措施: 10-1074 (Biological)
Arm A: N-803 only
Participants will receive N-803 6 mcg/kg 1 week after Step 2 entry and then every 3 weeks for a total of eight doses.
干预措施: N-803 (IL-15 Superagonist) (Biological)
结局指标
主要结局
Occurrence of a Grade ≥3 adverse event (AE) that is at least possibly related to N-803, as judged by the Clinical Management Committee (CMC)
时间窗: Step 2 week 1 to week 52
Proportion of participants requiring dose reduction
时间窗: From step 2 week 4 to step 2 week 22
Eight doses of N-803 are scheduled at distinct time points (Step 2 weeks 1, 4, 7, 10, 13, 16, 19 and 22). Proportion of participants requiring dose reduction is calculated as the number of participants who receive a reduced dose of N-803 at any of the 7 scheduled doses occurring after the first dose, divided by the total number of participants receiving N-803.
Number of N-803 doses completed
时间窗: From step 2 week 1 to step 2 week 22
Eight doses of N-803 are scheduled at the distinct time points listed in Time Frame. At each timepoint, dose completion status is recorded. Number of N-803 doses completed is the total number completed doses across all 8 timepoints.
Proportion of participants with plasma HIV-1 RNA <200 copies/mL 8 weeks after interruption of ART
时间窗: At step 3 week 8
次要结局
- Cell-associated HIV-1 RNA(At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32)
- Proportion of participants with antidrug antibodies(At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46)
- Occurrence of a Grade ≥2 AE that is at least possibly related to VRC07-523LS or 10-1074(Step 2 week 0 to week 52)
- Measurement of plasma viremia by HIV-1 single copy assay(At step 1 pre-entry evaluation and step 2 weeks 0, 1, 7, 13, 22 and 32)
- PK parameters: AUC0-τ of 10-1074(At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46)
- Occurrence of a Grade ≥2 AE without regard to relationship to study treatment(Study entry to participant's last study visit, at approx. study week 100)
- Occurrence of a Grade ≥2 AE that is at least possibly related to N-803, as judged by the CMC(Step 2 week 1 to week 52)
- Measurement of HIV-1 reservoir (dQVOA)(At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32)
- Proportion of participants with plasma HIV-1 RNA <200 copies/mL at 4, 12 and 24 weeks after interruption of ART in Step 3(At step 3 weeks 4, 12, and 24)
- PK parameters: AUC0-τ of VRC07-523LS(At step 2 weeks 0, 1, 4, 7, 9, 10, 13, 16, 19, 22, 26, 32 and 46)
- Total HIV-1 DNA(At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32)
- Measurement of intact proviral DNA(At Step 2 weeks 0, 1, 7, 13, 19, 22, 26 and 32)