Generation of SARS-CoV-2-specific T Lymphocytes From Recovered Donors and Administration to High-risk COVID-19 Patients
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 182
- 试验地点
- 4
- 主要终点
- Establishment of a CoV-2-STs bank
研究概览
简要总结
Open-label phase I (single-center)/ phase II (multicenter) with randomization 2:1
详细描述
Phase I (single-center): The investigators will administer CoV-2-STs in a dose escalation regimen of 2 dose levels (DL1: 1,5x10^7 CoV-2-STs in total; DL2: 2x10^7 CoV-2-STs/m^2). 3 patients will be treated at each dose level (traditional 3+3 design) following by a 12-day wait period to assess safety of the infusions prior to escalating the next dose level (maximum 12 patients). The maximum tolerated dose will be determined Phase II (multicenter): Randomization 2:1, 60 patients will receive the standard of care (SOC) plus CoV-2-STs (ARM A) at the optimum dose which will be determined in phase I and 30 patients will receive only SOC (Arm Β) Phase II (multicenter, extension): Randomization 2:1, 53 patients will be enrolled in Arm A to receive SOC and up to two doses of COV-2-STs and 27 patients will receive only SOC.
Randomization: Patients who meet the eligibility criteria after signing the informed consent form they will randomly be assigned at 2:1 ratio to each of the 2 treatment groups. Patients assigned to arm A will be HLA-typed for HLA-A, B and DRB1 within 24h, and a suitable for them T cell product will be selected from the cell bank. If a suitable product is found, they will continue to arm A, otherwise, they will be assigned to arm B.
Objectives:
i) To determine the feasibility of establishing a bank with GMP-compliant generated SARS-CoV-2 specific T-cells (CoV-2-STs), well-characterized in terms of specificity, phenotype and expression of human leucocyte antigens (HLA), which will be produced by 30 COVID-19 recovered donors with broad HLA diversity in order to be suitable for administration to at least 90 COVID-19 patients ii) To determine the safety of CoV-2-ST administration as cellular immunotherapy in COVID-19 patients, who meet specific inclusion criteria iii) To determine the efficacy of CoV-2-ST administration as cellular immunotherapy in COVID-19 patients, who meet specific inclusion criteria
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Hospitalized patients, SARS-CoV-2 PCR positive, within 8 days from the onset of the symptoms (immunosuppressed patients are excluded from the time limit when they become chronic carriers of the virus), who have:
- •Pneumonia or/and SatO2 ≤94% on room air or/and respiratory rate ≥24breaths/min AND
- •lymphopenia CD3+≤650/μl or/and ALC≤1000/microl AND
- •Increased values of D-dimers (≥2Χ) or/and ferritin (>1000ng/ml) or/and CRP (≥3Χ) or/and LDH (≥2Χ)
排除标准
- •Age ≤18 and ≥80 years old
- •Onset of symptoms >8 days (immunosuppressed patients are excluded from the time limit when they become chronic carriers of the virus)
- •Corticosteroid administration at a dose of >0.75mg/kg (methylprednisolone equivalent)
- •Multiple organ failure
- •ARDS (acute respiratory distress syndrome)
- •Mechanical ventilation
- •Patients who received ATG, or Campath, or other T-cell-suppressing monoclonal antibody within 28 days prior to admission
- •Patients with concomitant confirmed infection from another pathogen or with very high procalcitonin (PCT) that may indicate additional infection
- •Enrollment in another clinical trial
- •Pregnancy
- •Inability to sign informed consent form
- •Judged ineligible by at the treating physician (treating physician's discretion)
- •Bilirubin ≥2x of upper normal limit
- •AST ≥ 2x of upper normal limit
- •Creatinine ≥ 2x of upper normal limit or with dialysis/hemodialysis needs
- •Karnofsky score ≤50
结局指标
主要结局
Establishment of a CoV-2-STs bank
时间窗: Within 2 months before recruitment initiation
• Thirty, multi-dose, GMP-generated and released CoV-2-ST products
Establishment of a CoV-2-STs bank of broad HLA coverage
时间窗: Within 2 months before recruitment initiation
CoV-2-ST products of a broad HLA repertoire
Pharmacodynamic endpoint-1 (Phase I)
时间窗: Up to the completion of Ph I
•Determination of optimal dose (maximum tolerated dose)
Pharmacodynamic endpoint-2 (Phase I and II)
时间窗: Up to the completion of Ph I and II
• In vivo expansion of CoV-2-STs after administration
Pharmacodynamic endpoint-3 (Phase II)
时间窗: Up to the completion of Ph II
• Persistence of circulating donor CoV-2-STs by microchimerism analysis
Efficacy endpoint-1 (Phase II)
时间窗: Day 30 and Day 60 (end of follow up)
• Recovery and time to recovery. Recovery is defined as a value of 1 to 3 on the 8-point WHO ordinal scale (OS). Time to recovery is the days passed from Day 0 to the 1st day of a score 1 to 3 on the OS for those who recovered or the days passed from Day 0 to the last follow-up for the rest.
Efficacy endpoint-2 (Phase II)
时间窗: Day 30 and Day 60 (end of follow up)
• Survival by days 30 and 60. Survival is defined as the time-to-event from Day 0 to the date of death or the last follow-up
Safety endpoints (Phase I and II)
时间窗: End-of-follow up (day 60) for all patients in Ph I and Ph II
* acute toxicity related to the CoV-2-ST infusion, by clinical and laboratory assessments * cytokine release syndrome, by clinical and laboratory assessments * number of adverse and/or serious adverse events
次要结局
- Efficacy endpoint-1 (Phase II)(Day 30 for all enrolled patients)
- Efficacy endpoint-2 (Phase II)(End-of-follow up (day 60))
- Efficacy endpoint-3 (Phase II)(Day 20 for all enrolled patients)
- Safety endpoint (Phase I and II)(End-of-follow up (day 60))
研究者
Evangelia Yannaki
PI, Director of the Gene and Cell Therapy Center, Hematology-HCT Unit
George Papanicolaou Hospital