A Randomized, Multicenter Phase III Study to Assess the Efficacy of Panobinostat Maintenance Therapy vs. Standard of Care Following Allogeneic Stem Cell Transplantation in Patients With High-risk AML or MDS (ETAL-4 / HOVON-145)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 52
- 试验地点
- 19
- 主要终点
- Overall survival (OS)
研究概览
简要总结
Aim of this prospective randomized trial is to compare maintenance treatment with panobinostat interspersed with donor lymphocyte infusions (DLI) versus the standard approach of pre-emptive DLI alone in patients with poor-risk AML/MDS having favorably received an allogeneic HSCT followed by engraftment, donor chimerism and hematopoietic reconstitution.
详细描述
Allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to improve the outcome of poor-risk AML and MDS in both younger and older patients. Reduced-intensity conditioning (RIC) regimen have partially abrogated the problem of regimen-related toxicity. However, graft-versus-host disease (GvHD) remains a major cause of non-relapse morbidity and mortality. Despite a strong graft versus leukemia (GvL) effect after allogeneic HSCT, the relapse rate after transplantation in poor-risk leukemia patients is still too high, necessitating new approaches to exploit GvL in a more optimized way. In addition, minimizing the GvHD reaction remains an important goal. One attractive strategy may be the administration of epigenetic therapy early after HSCT in order to optimize the GvL effect, to provide a direct anti-leukemic effect, and to control GvHD. Two preceding phase I/II studies have suggested that post-transplant administration of the histone deacetylase (HDAC) inhibitor panobinostat may be associated with a reduced relapse rate, while allowing for control of GvHD. Based on these two studies, the hypothesis of the present trial is that panobinostat can be an effective drug in preventing relapse by optimizing GvL in MDS and AML patients with high-risk features after HSCT, while at the same time reducing GvHD. It has been designed to test this hypothesis in a prospective randomized trial comparing maintenance with panobinostat interspersed with donor lymphocyte infusions (DLI) versus the standard approach of pre-emptive DLI alone in patients with poor-risk AML/MDS having favorably received an allogeneic HSCT followed by engraftment, donor chimerism and hematopoietic reconstitution.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult patients (18-70 years of age)
- •AML (except acute promyelocytic leukemia with PML-RARA and AML with BCR-ABL1) according to WHO 2016 classification with high-risk features defined as one or more of the following criteria:
- •refractory to or relapsed after at least one cycle of standard chemotherapy
- •> 10% bone marrow blasts at day 14-21 of the first induction cycle
- •adverse risk according to ELN 2017 risk stratification by genetics (Appendix 2) regardless of stage
- •secondary to MDS or radio-/chemotherapy
- •MRD positive before HSCT based on flow cytometry or PCR
- •MDS with excess blasts (MDS-EB) according to the WHO 2016 classification, or high-risk or very high-risk according to IPSS-R
- •First allogeneic HSCT scheduled within the next 4-6 weeks using one of the following donors, conditioning regimens and strategies for GvHD prophylaxis:
- •Matched sibling or matched unrelated donor (i.e. 10/10 or 9/10 HLA-matched) or haploidentical family donor
- •Conditioning regimens:
- •Reduced-intensity conditioning:
- •a. Fludarabine/Melphalan b. Fludarabine/Busulfan2 (FB2) (2) Myeloablative conditioning:
- •Fludarabine/Busulfan4 (FB4)
- •Busulfan/Cyclophosphamide (BU/CY)
- •Fludarabine/TBI 8 Gy
- •Cyclophosphamide/TBI 12 Gy (3) Fludarabine/Cyclophosphamide/TBI 2 Gy in combination with post-Tx cyclophosphamide (TP-CY) only (4) Thiotepa/Busulfan/Fludarabine (TBF) in the context of an haploidentical HSCT only (5) In case of active disease at HSCT, salvage chemotherapy prior to conditioning is permitted
- •c. Strategies for GvHD prophylaxis:
- •HLA-matched donors:
- •a. CSA + MMF +/- ATG b. CSA + MTX +/- ATG c. PT-CY + CSA
- •Haploidentical donors:
- •d. PT-CY + CSA + MMF
- •No history of significant cardiac disease and absence of active symptoms, otherwise documented left ventricular EF ≥ 40%
- •Written informed consent for registration
排除标准
- •Prior treatment with a DAC inhibitor
- •Hypersensitivity to the active substance or to any of the excipients of panobinostat
- •HIV or HCV antibody positive
- •Psychiatric disorder that interferes with ability to understand the study and give informed consent, and/or impacts study participation or follow-up.
- •Female patients who are pregnant or breast feeding
- •History of another primary malignancy that is currently clinically significant or currently requires active intervention
研究组 & 干预措施
Panobinostat
Panobinostat 20 mg oral three times weekly every second week
干预措施: Panobinostat (Drug)
结局指标
主要结局
Overall survival (OS)
时间窗: 5 years
OS is measured from date of randomization to the date of death or date of last follow up. Observations of patients alive at last follow up will be censored at date of last follow up.
次要结局
- Percentage of patients who are free of systemic immunosuppressive therapy at one and two years after HSCT(2 years)
- Event-free survival (EFS)(5 years)
- Cumulative incidence, time and cause of non-relapse mortality (NRM)(5 years)
- Cumulative incidence of new onset or aggravation of acute GvHD grade III-IV(5 years)
- Cumulative incidence and maximal grade of severity of chronic GvHD requiring systemic treatment within one year after HSCT(1 year)
- Percentage of patients completing the one year study treatment and duration of panobinostat administration in patients who discontinue study treatment prematurely(1 year)
- Patient-reported HRQoL during panobinostat maintenance therapy(4 years)
- Disease-free survival (DFS)(5 years)
- Cumulative incidence of hematologic relapse(5 years)
- Percentage of patients with minimal residual disease (MRD) conversion from baseline to 6 months after HSCT(6 months)
研究者
Gesine Bug
Director of Transplant Program, Principal Investigator
Goethe University