Risk-stratified Sequential Treatment of Post-transplant Lymphoproliferative Disease (PTLD) With 4 Courses of Rituximab SC Followed by 4 Courses of Rituximab SC, 4 Courses of Rituximab SC Combined With CHOP-21 or 6 Courses of Rituximab SC Combined With Alternating CHOP-21 and DHAOx: The PTLD-2 Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 60
- 试验地点
- 18
- 主要终点
- Event free survival (EFS) of low-risk patients in the intention to treat population with following definitions for low-risk and event:
研究概览
简要总结
Post-transplant lymphoproliferative disorders (PTLD) differ clinically from lymphoma in the general (immunocompetent) population due to their higher incidence and their frequent association with Epstein-Barr virus. Previous clinical trials have shown their remarkably good response to rituximab as well as to chemotherapy.
The PTLD-1 trial demonstrated the efficacy and safety of sequential immunochemotherapy with 4 courses of rituximab IV followed by 4 cycles of CHOP chemotherapy. Compared to trials of rituximab monotherapy in PTLD, median overall survival was extended from 2.4 to 6.5 years. Compared to previous trials of chemotherapy, complications were reduced. In addition, we noted that those patients who already had a good response to the first four cycles of rituximab did better overall than those who did not. As a consequence, the PTLD-1/3 trial introduced risk-stratification in sequential treatment according to the response to the first 4 courses of rituximab monotherapy. Those patients with a complete remission went on to receive four further courses of rituximab whereas those who did not received rituximab and CHOP chemotherapy. Interim results have demonstrated that it is safe to restrict chemotherapy treatment in this manner and thus established the concept of treatment stratification based on the response to rituximab.
The PTLD-2 trial is the next step in the development of this strategy. Compared to the PTLD-1/3 trial, the key difference is the use of subcutaneous instead of intravenous rituximab application. Interim results from an ongoing trial of patients with follicular lymphoma (NCT01200758) have shown that subcutaneous administration results in increased blood levels and in non-inferior remission rates. Furthermore, the stratification strategy is refined based on observations from the previous PTLD-1 and PTLD1/3 trials: Risk groups are now defined not only based on response to rituximab therapy but also on the international prognostic index (IPI, a well-established lymphoma risk score) and the transplanted organ. The major advantage of this new stratification is an extended low-risk group that is eligible for subcutaneous rituximab monotherapy: Patients with a low risk of disease progression, defined as those who achieve a complete remission after the first four courses of subcutaneous rituximab monotherapy and those with an IPI of 0 to 2 who achieve a partial remission at interim staging, will go on with rituximab monotherapy. Patients with high IPI who achieve a partial remission, patients with stable disease at interim staging and non-thoracic transplant recipients with progressive disease at interim staging will be considered high risk. These patients will go on with 4 cycles of rituximab plus CHOP chemotherapy similar to the PTLD-1/3 protocol. Thoracic transplant recipients refractory to rituximab will be considered very high risk and will go on with rituximab subcutaneous plus alternating chemotherapy with CHOP and DHAOx.
The trial hypothesis is that the new protocol will improve the event-free survival, a measure integrating unfavorable events such as death, disease progression and treatment complications, particularly infections, in the low risk-group compared to the results of the PTLD-1 trial. In very high-risk patients data from the PTLD-1 and PTLD-1/3 trial have shown that the current treatment is not sufficient to control the disease. Death due to disease progression was observed in more than 80% of patients. Here, rituximab combined with alternating chemotherapy cycles of CHOP and DHAOx (+GCSF) may increase treatment efficacy with an acceptable toxicity profile.
In summary, the PTLD-2 trials tests if the substitution of subcutaneous for intravenous rituximab and an updated stratification strategy that deescalates treatment for those at low risk and escalates treatment for those at very high risk can further improve the overall efficacy and safety of PTLD therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •CD20-positive PTLD with or without EBV association, confirmed after biopsy or resection of tumor
- •Measurable disease of > 2 cm in diameter and/or bone marrow involvement
- •Patients having undergone heart, lung, liver, kidney, pancreas, small intestine transplantation or a combination of the organ transplantations mentioned
- •Clinically insufficient response to an upfront reduction of immunosuppression with or without antiviral therapy
- •Age at least 18 years
- •Not legally incapacitated
- •Written informed consent from the trial subject has been obtained
排除标准
- •Complete surgical extirpation of the tumor or irradiation of residual tumor masses
- •Upfront treatment with rituximab or chemotherapy
- •Known allergic reactions against foreign proteins
- •Concomitant diseases, which exclude the administration of therapy as outlined by the study protocol
- •Meningeal and CNS involvement
- •Known to be HIV-positive
- •Pregnant women and nursing mothers
- •Failure to use highly-effective contraceptive methods
- •Persons held in an institution by legal or official order
- •Persons with any kind of dependency on the investigator or employed by the sponsor or investigator
- •Life expectancy less than 6 weeks
研究组 & 干预措施
Low-risk
All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, patients will be considered low-risk if they reached a complete remission with the first 4 applications of rituximab monotherapy or if they reached a partial remission and had a baseline IPI of 0, 1 or 2. Patients considered low-risk will receive rituximab sc consolidation.
干预措施: Rituximab sc (Drug)
Low-risk
All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, patients will be considered low-risk if they reached a complete remission with the first 4 applications of rituximab monotherapy or if they reached a partial remission and had a baseline IPI of 0, 1 or 2. Patients considered low-risk will receive rituximab sc consolidation.
干预措施: Rituximab sc consolidation (Drug)
High risk
All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, patients will be considered high-risk, if the reached a partial remission and were IPI 3, 4 or 5 at time of diagnosis of PTLD, if they show stable disease or if they had progressive disease but are not recipients of heart or lung transplants. Patients considered high-risk will receive four more applications of rituximab sc combined with CHOP chemotherapy every 3 weeks at days 50, 71, 92 and 113.
干预措施: Rituximab sc (Drug)
High risk
All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, patients will be considered high-risk, if the reached a partial remission and were IPI 3, 4 or 5 at time of diagnosis of PTLD, if they show stable disease or if they had progressive disease but are not recipients of heart or lung transplants. Patients considered high-risk will receive four more applications of rituximab sc combined with CHOP chemotherapy every 3 weeks at days 50, 71, 92 and 113.
干预措施: Rituximab sc combined with CHOP chemotherapy (Drug)
Very high-risk
All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, heart and lung transplant recipients and patients with a combination of organs transplanted including a heart or lung transplant who show disease progression during rituximab monotherapy or at interim staging will be considered very high-risk. Patients considered very high-risk will receive six more applications of rituximab sc combined with alternating chemotherapy with CHOP and DHAOx.
干预措施: Rituximab sc (Drug)
Very high-risk
All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, heart and lung transplant recipients and patients with a combination of organs transplanted including a heart or lung transplant who show disease progression during rituximab monotherapy or at interim staging will be considered very high-risk. Patients considered very high-risk will receive six more applications of rituximab sc combined with alternating chemotherapy with CHOP and DHAOx.
干预措施: Rituximab sc combined with alternating chemotherapy with CHOP and DHAOx (Drug)
结局指标
主要结局
Event free survival (EFS) of low-risk patients in the intention to treat population with following definitions for low-risk and event:
时间窗: two years
Time from start of treatment to event with following definitions for low-risk and event: 1. Low-risk: * all patients in complete remission at interim staging, i.e. 4 weeks after the four weekly courses of rituximab SC monotherapy * all patients in partial remission at interim staging with an initial international prognostic index (IPI) of 0,1 or 2 2. Events: * any grade III or IV infection during the treatment period * treatment discontinuation from any reason * disease progression at any time * death from any reason
次要结局
- Response at interim staging(day 50)
- Response after full treatment(three months)
- Duration of response(two years)
- Progression-free survival(two years)
- Time to progression(two years)
- Treatment-related mortality(three months)
- Overall survival(Two years)