A Phase 1b/2 Dose Escalation Study of the Safety, Pharmacokinetics, and Efficacy of the Combination of TMB-365 and TMB-380 in HIV-1 Infected Individuals Suppressed With Combination Antiretroviral Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 6
- 主要终点
- Safety of TMB-365 and TMB-380 Given Intravenously (Sentinel and Core)
研究概览
简要总结
TMB-365 is a monoclonal antibody that binds to the CD4 receptor. TMB-380, aka VRC-07-523LS is a monoclonal antibody that binds to HIV. Both interfere with HIV entry. This study is designed to test various doses of the combination of the antibodies for safety and pharmacokinetics in suppressed subjects on cART. Once dosing is established based on safety and PK, the optimally dosed combinations will be assessed as maintenance therapy in HIV infected suppressed individuals discontinuing oral cART for 24 weeks.
详细描述
This study is a phase 1b / 2 adaptive open-label dose escalation study of the combination of TMB-365 and TMB-380. This adaptive study design will be comprised of Sentinel Groups (N=10) and Core Groups (N=20). Safety and pharmacokinetic (PK) data obtained from Sentinel group participants will guide the conduct of Core Group execution.
Participants will be HIV-infected and suppressed for at least 6 months on continuous daily oral combination antiretroviral therapy (cART). Continuous is defined as no more than 3 consecutive days of missed cART. There are three doses of each antibody being explored, 2400 mg, 3200 mg, and 4800 mg.
Sentinel Groups Sentinel Groups will be comprised of 10 cART suppressed HIV-1 infected volunteers who receive a single IV dose of the combination of TMB-365 and TMB-380 while continuing cART.
Sentinel Group 1 will be dosed with 2400 mg of each antibody and will continue daily oral cART throughout the screening, infusion, and post-infusion observation period of 12 and be assessed for safety and pharmacokinetics.
Sentinel group 2 will dose both antibodies at 3200 mg. The third sentinel group will dose both antibodies at 4800 mg.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must meet all of the following criteria to be included in the study:
- •Male or female at least 18 years of age and no greater than 60 years on the day of Screening.
- •Asymptomatic HIV-1 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 Geenius™ or a second antibody test by a method other than the initial rapid HIV and/or E/CIA test, or by HIV-1 antigen, plasma HIV-1 RNA viral load at or piror to screening.
- •On continuous suppressive cART for 6 months prior to screening with one documented HIV-1 RNA level below the level of detection within 3 months of screening. Continuous cART is defined as no interruptions greater than 3 consecutive days. cART is defined as a DHHS recommended regimen. Study participants should be on a stable regimen, at least 3 months.
- •Screening plasma HIV-1 RNA below the limit of detection.
- •CD4+ T cell count >350 cells/mm3
- •Laboratory values obtained within 30 days prior to the first dose:
- •Hemoglobin > 10.0 g/dL;
- •Platelet count ≥ 100,000/mm3;
- •Absolute neutrophil count ≥ 1,000/mm3;
- •Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 1.5 x upper limit of normal (ULN); and
- •Creatinine clearance (CrCl) of ≥ 50 mL/min.
- •Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
- •In the opinion of the principal investigator or designee, has understood the information provided; written informed consent needs to be given before any study-related procedures are performed.
- •Females of childbearing potential, sexually active with a male sex partner, must agree to use one effective method of contraception from the time of signing the consent to completion of the study, and agree to pregnancy testing as per the Schedule of Events and Procedures. Females of childbearing potential are female participants who are not surgically sterile (no history of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy), are not postmenopausal (at least one year without menses), and are not otherwise sterile by medical evaluation.
排除标准
- •Participants having or meeting any of the following conditions or characteristics will be excluded from the study:
- •Suppressed subjects who have not been on a stable DHHS recommended cART regimen for at least 3 months.
- •Receipt of any monoclonal antibody for the treatment or prevention of HIV infection except for Sentinel subjects eligible for enrollment into Core groups.
- •Suppressed subjects receiving cabotegravir and rilpivirine intramuscularly as maintenance therapy for HIV-1 infection.
- •Pregnant, planning a pregnancy during the trial period, or lactating.
- •Known allergy/sensitivity or any hypersensitivity to components of the study drug or its formulation, or known allergy to a MAb.
- •Major psychiatric illness including any history of schizophrenia or severe psychosis, uncontrolled bipolar disorder requiring acute therapy, or suicide attempt in the previous three years.
- •Serious illness requiring systemic treatment and/or hospitalization within 21 days prior to the first dose.
- •Receipt of immunomodulatory agents (e.g., interleukins, interferons, cyclosporine, high dose systemic corticosteroids), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 180 days prior to the first dose.
- •Any chronic or acute medical condition, including chronic Hepatits B infection, chronic Hepatitis C infection with viremia, and drug use and alcohol abuse, which in the opinion of the investigator would interfere with evaluation of the study drug.
- •Lack of adequate venous access.
- •Individuals who have experienced virologic failure during treatment with two or more cART treatment regimens and those being treated with regimens containing either ibalizumab, enfuvirtide, maraviroc, and fostemsavir. Note that a change in treatment regimen for intolerance does not meet criteria for virologic failure.
研究组 & 干预措施
Sentinel Group 1
10 HIV-1 infected subjects will receive one infusion of 2400 mg of each antibody, TMB-365 and TMB-380 and be followed for safety and pharmacokinetics. Oral suppressive cART will be continued throughout the course of the study participation.
干预措施: TMB-365/TMB-380 (Drug)
Sentinel Group 2
10 HIV-1 infected subjects will receive one infusion of 3200 mg of each antibody, TMB-365 and TMB-380 and be followed for safety and pharmacokinetics. Oral suppressive cART will be continued throughout the course of the study participation.
干预措施: TMB-365/TMB-380 (Drug)
Sentinel Group 3
10 HIV-1 infected subjects will receive one infusion of 4800 mg of each antibody, TMB-365 and TMB-380 and be followed for safety and pharmacokinetics. Oral suppressive cART will be continued throughout the course of the study participation.
干预措施: TMB-365/TMB-380 (Drug)
Core Group 1
20 HIV-1 infected subjects will receive 4800 mg infusions of each antibody, TMB-365 and TMB-380 every 8 weeks and be followed for safety, pharmacokinetics, and ability to maintain antiviral activity. Oral suppressive cART will be discontinued for 24 weeks then resumed at week 24 with follow-up at week 28.
干预措施: TMB-365/TMB-380 (Drug)
结局指标
主要结局
Safety of TMB-365 and TMB-380 Given Intravenously (Sentinel and Core)
时间窗: 12 weeks (Sentinel Group 1), 16 weeks (Sentinel Group 2, 3), 28 weeks (Core Group)
Grade 3, Grade 4, Serious Adverse reactions related to TMB-365 and TMB-380 infusions
Pharmacokinetics of a Single Dose TMB-365 Given Intravenously (Sentinel)
时间窗: Week 8
In the Sentinel Group, participants received a single dose of TMB-365 and TMB-380 at 2400 mg, 3200 mg, or 4800 mg each. TMB-365 concentrations were measured using a validated ELISA, and the Week 8 concentration was used to guide dose selection for the Core Group.
Pharmacokinetics of TMB-365 Given Intravenously Every 8 Weeks (Core)
时间窗: Week 8, 16, and 24
Core Group participants received 4800 mg every 8 weeks.TMB-365 concentrations were measured using a validated ELISA. Trough concentrations are reported.
Pharmacokinetics of a Single Dose TMB-380 Given Intravenously (Sentinel)
时间窗: Week 8
In the Sentinel Group, participants received a single dose of TMB-365 and TMB-380 at 2400 mg, 3200 mg, or 4800 mg each. TMB-380 concentrations were measured using a validated ELISA, and the Week 8 concentration was used to guide dose selection for the Core Group.
Pharmacokinetics of TMB-380 Given Intravenously Every 8 Weeks (Core)
时间窗: Weeks 8, 16, and 24
Core Group participants received 4800 mg every 8 weeks.TMB-380 concentrations were measured using a validated ELISA. Trough concentrations are reported.
Antiviral Activity of the Combination of TMB-365 in Combination With TMB-380 as Maintenance Therapy (Core)
时间窗: Week 24
Plasma HIV-1 level below 50 copies/mL in study subjects at week 24 during maintenance therapy with TMB-365/TMB-380 infusions in Core Subjects only.
次要结局
- Resistance to TMB-365 and TMB-380 (Core)(24 weeks)