Treatment of Newly Diagnosed Moderate or Severe Chronic Graft-versus-host Disease With Prednisone and Everolimus (PredEver First) - A Prospective Multicenter Phase IIA Study -
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 38
- 试验地点
- 6
- 主要终点
- rate of treatment success
研究概览
简要总结
In this study patients with moderate to severe chronic graft-versus-host disease will be treated with a combination of prednisone and everolimus. Patients will be treated on the study for a maximum of 12 months and followed up for another 12 months.
The primary hypothesis of this study is that the addition of everolimus to prednisone increases response rates without increasing treatment related mortality or mortality due to relapse of underlying disease.
详细描述
Background
2.1 Chronic graft-versus-host disease
Chronic graft-versus-host disease (cGvHD) is the most common long-term complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with an incidence of up to 70% in recipients of peripheral blood stem cells. Chronic GvHD is associated with impaired immunity, compromised functional status and quality of life and is besides relapse of underlying malignancy still the leading cause of morbidity and mortality beyond day 100 after allo-HSCT. The pathophysiology of cGvHD is still not well understood, however efforts made in the last years indicate a role of persistent allo-reactive T cells, B cells that produce auto- or allo-antibodies against the host antigens as well as donor antigen presenting cells (APC) that replace host APCs thus leading to indirect antigen presentation of allo-antigens. Persistent alloreactivity may be due to defective peripheral and central tolerance mechanisms as a result of failure of control by regulatory T cells (Tregs) and/or impaired negative selection of T cells in the thymus.
Corticosteroids have constituted the backbone of treatment of cGvHD over the past 4 decades. Addition of calcineurin inhibitors (CNI) to steroids in first-line therapy did not lead to significant improvement of response or patient outcome. The expanding therapeutic arsenal of cGvHD also includes many other agents which have been evaluated in second-line therapy such as mTOR inhibitors, extracorporeal photopheresis, mycophenolate mofetil, rituximab, alemtuzumab, thalidomide, imatinib, pentostatin, low dose methotrexate amongst others. The median duration of immunosuppression of 23 months and the high 3 year non-relapse mortality of up to 40% emphasize the urgent need for new first line treatment strategies.
3 Study rationale
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Patient's written informed consent
- •Women and men capable of reproduction must agree to use adequate contraceptive measures (condom, intrauterine devices, oral contraceptives) until three months after termination of treatment
- •Age ≥ 18 years
- •Diagnosis of classic chronic GvHDcGvHD according to NIH criteria [33] and fulfilment of criteria for moderate or severe cGvHD or o Diagnosis of overlap syndrome according to NIH criteria [33] and fulfilment of criteria for moderate or severe cGvHD and ≤ clinical grade 2 of acute GvHD of the gut and no grade 4 acute GvHD of the skin.
- •NB: A maximum of 30 patients with overlap syndrome will be included in the trial.
排除标准
- •Late persistent or recurrent acute GvHD without evidence of cGvHD
- •Relapsed or progressive malignant disease (other than minimal residual disease diagnosed by molecular methods)
- •Severe uncontrolled infections
- •Pregnant or lactating women
- •Inability to tolerate 1 mg/kg prednisone
- •Inability to take oral medication
- •Known hypersensitivity to everolimus
- •History of mTOR- inhibitor associated non-infectious pneumonitis
- •Participation in another interventional clinical trial with intervention within < 30 days
- •Prior use of mTOR- inhibitor (everolimus or sirolimus) for treatment of acute GvHD
- •Prior systemic treatment for chronic GvHD>of cGvHD ≥ 72h
- •Psychiatric illness that would prevent granting of informed consent
- •Active viral infection with HIV, hepatitis B or hepatitis C
- •Severe cardiovascular disease (uncontrolled arrhythmias, congestive heart failure NYHA III or IV, or symptomatic ischemic heart disease)
- •History of mTOR- inhibitor or CNI-associated TMA that led to discontinuation of mTOR- inhibitor or CNI
- •Patients with neutrophils < 1000 1,000/µl and / /or platelets < 20.,000/ul µl at time of screening
- •Donor lymphocyte infusion within the last 30 days
- •Pre-existing hyperlipidemia prior to treatment with calcineurin inhibitor or mTOR inhibitor
- •Wound healing complications
- •Active lymphoma as well as other malignancies
- •Edema (angioneurotic or peripheral)
- •Peptic ulcer
- •Severe colitis ulcerosa
- •Diverticulitis
- •Severe osteoporosis
- •Poorly- controlled hypertension
- •Glaucoma (angle closure or open angle)
- •Cornea ulcer or cornea-injuries
- •Severe diabetes mellitus
研究组 & 干预措施
PredEver
Prednisone and Everolimus
干预措施: PredEver (Drug)
结局指标
主要结局
rate of treatment success
时间窗: at 6 months
Patient being alive and having achieved a CR or PR of cGvHD without addition of secondary systemic treatment for cGvHD (see below) and without development of relapse of underlying disease. Addition of any immunosuppressive or immunomodulatory systemic therapy aimed at treating or controlling symptoms of chronic GvHDcGvHD is considered treatment failure. Examples of secondary systemic therapies include (but are not limited to) cyclosporine ACSA, tacrolimus, methotrexate, mycophenolate, rituximab, azathioprine, pentostatine, cyclophosphamid, chloroquine, imatinib, dasatinib, thalidomide, alemtuzumab, etanercept, antithymocyte globulin, infliximab, basiliximab, daclizumab, extracorporeal photopheresis, psoralen with UVA-irradiation (PUVA), pulsed steroid exceeding a dose of 2 mg/kg/day.
次要结局
- the overall survival rate of patients treated with prednisone and everolimus for chronic GvHDcGvHD(1 year)
- time to treatment failure(average time up to 12 months from start of treatment)
- speed of response(average time up to 12 months from start of treatment)
- Relapse of underlying disease(1 year)
- side effects(1 year)
研究者
PD Dr. med. Francis Ayuketang Ayuk
PD Dr. med.
Universitätsklinikum Hamburg-Eppendorf