Treatment of Chemo-refractory Viral Infections After Allogeneic Stem Cell Transplantation With Multispecific T Cells Against CMV, EBV and AdV: A Phase III, Prospective, Multicentre Clinical Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 149
- 试验地点
- 66
- 主要终点
- Disease Progression
研究概览
简要总结
Haematopoietic stem cell transplantation (HSCT) can expose patients to a transient but marked immunosuppression, during which viral infections are an important cause of morbidity and mortality. Adoptive transfer of virus-specific T cells is an attractive approach to restore protective T-cell immunity in patients with refractory viral infections after allogeneic HSCT. The aim of this Phase III trial is to confirm efficacy of this treatment in children and adults.
详细描述
For a growing number of patients suffering from various conditions as, e.g., haematological malignancies or diverse genetic disorders, haematopoietic stem cell transplantation (HSCT) or bone marrow transplantation offer the only possible curative options. However, HSCT is associated with three major risks: graft rejection, graft-versus-host disease (GvHD) and opportunistic, mostly viral, infections or reactivations resulting from delayed immune reconstitution. Delayed immune reconstitution, however, often is the direct result of the severe pre-transplantation conditioning treatment and T-cell depletion of the transplant necessary to fight the risks of graft rejection and GvHD. Therefore, the risk for life-threatening opportunistic, mostly viral, infections is increased in post-transplantation patients. The most common infections after HSCT are Cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Adenovirus (AdV).
The standard treatment approach for viral infections/reactivations is chemotherapy which shows limited efficacy and does not restore immunity. Therefore, effective new treatment options are required for this condition.
Previous investigations have shown that sufficient T-cell immunity is essential for the control and prevention of viral reactivations and newly occurring infections after HSCT. The infusion of T-cells is therefore a promising new approach to treat immune-comprised patients. However, infusion with unselected T cells is associated with an increased risk for GvHD due to the high content of alloreactive T cells. A very promising approach to minimize this problem is to remove alloreactive T cells and enrich, isolate and purify virus-specific T cells.
This approach has been studied for nearly two decades and the data published up to date indicate that virus-specific T-cell responses after adoptive T-cell transfer protect against virus-related complications post HSCT and restore T-cell immunity, in particular for AdV-, CMV- and EBV-infections. Despite these promising results, virus-specific T-cell transfer is not yet translated into daily clinical practice due to the lack of prospective clinical trials confirming the efficacy of this treatment approach.
The overall goal of this Phase III, double-blind placebo-controlled study is to test efficacy of multivirus-specific T cells to bring this treatment method in clinical routine. Multivirus-specific T cells generated in this study will be directed against all three most common post-HSCT viral infections: AdV, CMV and EBV. Thus, T-cell immunity will be restored to fight and prevent new viral infections.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Randomization will be stratified with respect to three age groups: Children up to 6 years, children >6 and up to 18 years, and adults >18 years. Accordingly, for each stratum, a separate randomization list will be provided. Randomization will be performed by a representative of the Simbec-Orion Group who will be independent in the sense that he / she will otherwise not be involved in the TRACE trial.
入排标准
- 年龄范围
- 2 Months 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult or paediatric patients (> 2 months of age) after allogeneic stem cell transplantation (SCT) (no time restrictions apply) suffering from new or reactivated CMV or EBV or AdV infection refractory to standard antiviral treatment for two weeks (defined as no decrease or insignificant decrease of less than 1log in viral load over two weeks) as confirmed by quantitative blood PCR analysis.
- •Original HSCT-donor available with an immune response at least to the virus causing the therapy-refractory (=underlying) infection.
- •Written informed consent given (patient or legal representative) prior to any study-related procedures.
排除标准
- •Patient with acute GvHD > grade II or extensive chronic GvHD at the time of IMP transfer
- •Patient receiving steroids (>1 mg/kg BW Prednisone equivalent) at Screening.
- •Therapeutic donor lymphocyte infusion (DLI) from 4 weeks prior to IMP infusion until 8 weeks post IMP infusion. Prescheduled prophylactic DLI ≤3x105 T cells/kg BW in case of T-cell depleted HSCT is not considered an exclusion criterion.
- •Patient with organ dysfunction or failure as determined by Karnofsky (patients >16 years) or Lansky (patients ≤16 years) score ≤30%
- •Concomitant enrolment in another clinical trial interfering with the endpoints of this study
- •Any medical condition which could compromise participation in the study according to the investigator's assessment
- •Progression of underlying disease (disease that has led to the indication of HSCT, e.g. leukaemia) that will limit the life expectance below the duration of the study
- •Second line or experimental antiviral treatment other than Ganciclovir/Valganciclovir, Foscarnet, Cidofovir and Rituximab until 8 weeks after IMP Infusion or prophylactic Treatment other than Aciclovir or Letermovir throughout the study except approved by sponsor
- •Known HIV infection. In case patients do not have a negative HIV test performed within 6 months before enrolment in the study, HIV negativity has to be confirmed by a negative laboratory test.
- •Female patient who is pregnant or breast-feeding. Female patient of child-bearing potential (i.e. post menarche and not surgically sterilized) or male patient of reproductive potential not willing to use an effective method of birth control from Screening until the last follow-up visit (FU6, Visit 8).
- •Note: Women of childbearing potential must have a negative serum pregnancy test at study entry ≤7 days before IMP administration on Day
- •Acceptable birth control methods are hormonal oral contraceptive ('pill'), contraceptive injection or patch, intrauterine pessar or the combination of two barrier methods. The combination of female and male condomes is NOT acceptable. If the male partner is sterilized, no further contraceptive is required. Women of post-menopausal status (no menses for 12 months without an alternative medical cause) are also not required to use contraceptives during the study.
- •Known hypersensitivity to iron dextran
- •Patients unwilling or unable to comply with the protocol or unable to give informed consent.
结局指标
主要结局
Disease Progression
时间窗: day 7 until week 8 after treatment
Percentage of patients with progression between Day 7 and Week 8 after T-cell Transfer to determine efficacy of multispecific T-cell transfer in patients with chemo-refractory viral infections after allogeneic stem cell transplantation
Viral clearance
时间窗: 8 weeks after treatment
Percentage of patients with viral clearance (defined as two consecutive negative PCRs) to determine efficacy of multispecific T-cell transfer in patients with chemo-refractory viral infections after allogeneic stem cell transplantation
次要结局
- Time to viral load change of underlying viral infection(15 weeks after treatment)
- Incidence of chronic GvHD(15 weeks after treatment)
- Time to newly occuring GvHD(15 weeks after treatment)
- Clinical response/resolution of symptoms of underlying viral infection(8 weeks after treatment)
- Incidence of acute GvHD(15 weeks after treatment)
- Percentage of viral decrease(8 weeks after treatment)
- Effect on the patient's T-cell phenotype in vivo(Screening until Week 15)
- Physical examination(Screening to Week 8)
- Vital Sign - blood pressure(Screening to Week 8)
- Incidence of acute toxicity(15 minutes, 30 minutes, 2 hours and 4 hours post T-cell/placebo transfer)
- Necessity of antiviral chemotherapy(Day 7 until Week 8)
- Duration of antiviral chemotherapy(8 weeks after treatment)
- Days of hospitalization(8 weeks)
- Life quality in adults(Screening and Week 8)
- Time from inclusion to administration of the IMP(Screening until Day 0 (treatment day))
- Change in viral load of underlying viral infection(8 weeks after treatment)
- Severity of GvHD(week 8 and 15 week after treatment)
- Severity of acute toxicity(15 minutes, 30 minutes, 2 hours and 4 hours post T-cell/placebo transfer)
- Overall survival(15 weeks after treatment)
- Incidence of viral infections other than underlying viral infection(15 weeks)
- Vital Signs - body temperature(Screening to Week 8)
- Viral reactivations(15 weeks after treatment)
- Effect on the patient's number of expanded T cells(Screening until Week 15)
- Quality of the IMP and performance of the CliniMACS® Prodigy(Before IMP release (between Screening and Day 0))
- Vital Signs - heart rate(Screening to Week 8)
- Concomitant medication until Week 15(15 weeks after treatment)
- Life quality in children(Screening and Week 8)
- Evaluation of the drop-out rate(at Day 0 (planned treatment day))
- Adverse events(15 weeks)
- Vital Signs - body weight(Screening to Week 8)
- Incidence of abnormal laboratory values(Screening to Week 8)
- Concomitant medication until Week 8(8 weeks after treatment)
- Vital Signs - respiratory rate(Screening to Week 8)
研究者
Tobias Feuchtinger
Prof. Dr. med Tobias Feuchtinger
University Hospital Freiburg