TK008: Randomized Phase III Trial of Haploidentical HCT With or Without an Add Back Strategy of HSV-Tk Donor Lymphocytes in Patients With High Risk Acute Leukemia
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 92
- 试验地点
- 36
- 主要终点
- Disease-free Survival (DFS)
研究概览
简要总结
The main objective of this randomized trial is to compare disease-free survival (DFS) in high risk leukemia patients who underwent haploidentical HCT followed by an add back strategy of HSV-Tk donor lymphocytes or standard haploidentical HCT
详细描述
Delayed immune-reconstitution remains one of the main limitation of haploidentical stem cell transplantation. The risk of severe infections remains high for several months and CD3+ reconstitution could take more than 10 months. The low number of lymphocytes infused with the graft, the degree of HLA (Human Leukocyte Antigen) disparity, and a reduced thymic function in adults and differences in host/donor antigen presenting cells are contributing causes.
The infusions of HSV-TK engineered lymphocytes may represent a significant therapeutic improvement in haploidentical HCT (hematopoietic cell transplantation), because it remarkably may enhance both GvL (Graft versus Leukemia) activity, thus reducing the occurrence of disease relapse, and post-transplant immune reconstitution in the absence of chronic immune suppression, thus decreasing the rate of both post-transplant opportunistic infections and transplant-related mortality. Furthermore, the efficient control of GvHD achieved via the suicide mechanism allows also the multiple infusion of HSV-TK-treated donor lymphocytes, when needed, that might further improve post-transplant host immune reconstitution, and survival in patients receiving haplo-HCT. Finally, this therapeutic approach can become a valuable option for all candidates, including patients with advanced disease and older age.
The proposed clinical trial represents an innovative therapeutic treatment for patients affected by high risk acute leukemia, who have undergone haploidentical stem cell transplantation.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years
- •Any of the following conditions:
- •AML and ALL in 1st complete remission (CR1)
- •AML and ALL in 2nd or subsequent CR
- •secondary AML in CR
- •AML and ALL in 1st or 2nd relapse or primary refractory
- •Family donor with patient-donor number of HLA mismatches ≥ 2 (full haploidentical), or family donors sharing one HLA-haplotype with the patient
- •Stable clinical conditions and life expectancy > 3 months
- •PS ECOG < 2
- •Serum creatinine < 1.5 x ULN
- •Bilirubin < 1.5 x ULN; transaminases < 3 x ULN
- •Left ventricular ejection fraction > 45%
- •QTc interval < 450 ms
- •DLCO > 50%
- •Patients, or legal guardians, and donors must sign an informed consent indicating that they are aware this is a research study and have been told of its possible benefits and toxic side effects
排除标准
- •Patients with life-threatening condition or complication other than their basic condition
- •Contraindication to haploidentical HCT as defined by the Investigator
- •Patients with active CNS disease
- •Pregnant or lactation.
- •Exclusion criteria for HSV-Tk infusion:
- •Infections requiring administration of ganciclovir or valganciclovir at the time of infusion
- •GvHD requiring systemic immunosuppressive therapy
- •Ongoing systemic immunosuppressive therapy after haploidentical HCT
- •Administration of G-CSF after haploidentical HCT
- •HSV-Tk cells can be administered after an adequate patient wash-out period (24 hours)
研究组 & 干预措施
B
T-cell depleted or T-cell replete strategies
干预措施: T-cell depleted or T-cell replete strategies (Other)
A
HSV-TK engineering donor Lymphocytes
干预措施: HSV-Tk (Genetic)
结局指标
主要结局
Disease-free Survival (DFS)
时间窗: From the date of randomization, assessed up to 12 months
Defined as the measure from the date of randomization until the date of relapse (or progression), or death from any cause, whichever occurs first. Disease relapse or progression was determined by the Investigator based on the following disease examination: * Morphology (bone marrow or peripheral blood) * Confirmation of mixed or full chimerism (evaluation of the degree of chimerism between donor/host, according to institutional clinical practice, on bone marrow or peripheral blood) * Cytogenetic and/or molecular and/or other tests, according to institutional clinical practice (bone marrow or peripheral blood).
次要结局
- Engraftment Rate(At day 15 after HCT, monthly for 6 months after HCT and then at month 9 and 12)
- Cumulative Incidence of Relapse (CIR)(from the date of randomization to the date of the first occurrence of relapse, assessed up to 12 months)
- Quality of Life (QoL) and Medical Care Utilization (MCU) in Both Arms(from randomization up to 12 months)
- Immune Reconstitution (IR)(Weekly up to IR after engraftment of HCT, monthly for 6 months from date of IR and then at month 9 and 12)
- Cumulative Incidence of Grade 2, 3, or 4 Acute GvHD (aGvHD)(from the date of HCT until the date of the first occurrence of aGvHD, assessed up to 6 months)
- Cumulative Incidence of Chronic GvHD (cGvHD)(From the date of HCT until the date of the first occurrence of cGvHD, assessed up to 12 months)
- Evaluate the Acute and Long-term Toxicity Related to the HSV-Tk Infusions(From HSV-Tk infusions to the date of resolution, assessed up to 12 months)
- Overall Survival (OS)(From the date of randomization to the date of death, assessed up to 12 months)
- Duration of GvHD Episodes(From the date of start until the date of resolution and duration of immunosuppressive treatments administered for controlling GvHD assessed up to 12 months)
- Incidence and Duration of Infectious Episodes and Infectious Disease Mortality(From randomization to the date of resolution, assessed up to 12 months)
- Non-relapse Mortality (NRM)(From the date of randomization to the date of death, assessed up to 12 months.)