A Randomized Phase III Multicenter Trial Assessing Efficacy and Toxicity of a Combination of Rituximab and Lenalidomide (R2) vs Rituximab Alone as Maintenance After Chemoimmunotherapy With Rituximab-chemotherapy (R-CHT) for Relapsed/Refractory FL Patients Not Eligible for Autologous Transplantation (ASCT).
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 128
- 试验地点
- 49
- 主要终点
- PFS
研究概览
简要总结
A randomized phase III multicenter trial assessing efficacy and toxicity of a combination of Rituximab and Lenalidomide (R2) vs Rituximab alone as maintenance after chemoimmunotherapy with Rituximab-chemotherapy (R-CHT) for relapsed/refractory FL patients not eligible for autologous transplantation (ASCT)
详细描述
Among Non-Hodgkin lymphomas (NHL), Follicular Lymphoma (FL) is the second one in terms of frequency, accounting for about 25% of all NHL cases in the western hemisphere. A predominance in females is reported, and the median age at the diagnosis is 60 years.
FL cells originates from normal counterparts germinal B cells. At a molecular level, the pathology is thought to be dependent on multiple DNA alterations. However, a large amount of patients (approximately 85%) have t(14;18), with a consequent overexpression of anti-apoptotic protein BCL-2.
An additional hallmark of pathology is bone marrow involvement (70% of patients), while this is seldom noticed in other organs. Finally, 20% of patients show high levels of serum lactate dehydrogenase (LDH) and/or B symptoms.
FL is actually considered an incurable disease. Although FL responds well to initial chemotherapy, most patients will eventually relapse, requiring multiple subsequent therapeutic regimens during the course of disease to achieve new period of remission, that are nevertheless shorter. Relapsed/refractory FL in advanced stage, especially in older patients, has a relatively poor prognosis, and several patients die for infectious complications and/or progressive disease. This subset of patients usually do not survive more than 5 years.
Thus there is a need for new, less toxic and more active treatment in particular for patients with recurrent disease. The addition of Rituximab to chemotherapy showed a clear benefit in terms of overall response rate, quality of response, event-free survival and, in most studies, overall survival; nevertheless, relapses still occur. Moreover Rituximab also proved highly effective when employed as maintenance treatment either following chemotherapy or Rituximab-supplemented chemotherapy. The success of Rituximab maintenance led to the widespread opinion that in the context of indolent lymphomas novel "smart" drugs characterized by a good safety profile need to be carefully evaluated not only in the induction but also in the maintenance setting.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 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
- •Follicular lymphoma grade I, II and IIIa according to the WHO classification. Rebiopsy at study entry is strongly encouraged but mandatory only in case of suspected transformation (elevated LDH or rapidly-growing disease or unusual relapse presentation).
- •First or second relapse or progression following R-chemotherapy (Rituximab maintenance and IF radiotherapy are not considered treatment lines).
- •Previous treatment with Bendamustine can be considered eligible if relapse occurred after ≥ 24 months.
- •Age >18 years.
- •Patients not eligible for high dose chemotherapy and ASCT because of: age ≥ 65 years, impaired PS or organ function due to major comorbidities or relapsed or refractory disease after previous ASCT before 65 of age.
- •Stage II, III or IV according to Ann Arbor at relapse.
- •Need of treatment according to SIE-SIES-GITMO guidelines for follicular lymphoma: stage II-IV with systemic symptoms, high tumor burden (i.e. >3 lymph nodes measuring >3 cm or a single lymph node >7 cm), extranodal disease, cytopenia due to marrow involvement, spleen involvement (≥16 cm by CT), leukemic phase, serious effusion, symptomatic or life endangering organ involvement, rapid lymphoma progression, consistently increased LDH levels.
- •Must be able to adhere to the study visit schedule and other protocol standards.
- •ECOG performance status ≤ 2 (except when PS impairment is related to lymphoma).
- •Be willing and able to comply with the protocol for the duration of the study.
- •Absolute neutrophil count (ANC) ≥ 1.5 x 10 9/L unless due to marrow involvement by lymphoma; and platelets count ≥ 75 x 109/L unless due to marrow involvement by lymphoma.
- •Calculated creatinine clearances ≥ 40 ml/min.
- •Agree to be using effective contraception for the entire treatment period according to standard guidelines for patients receiving lenalidomide
排除标准
- •Any lymphoma subtype other than FL including transformed FL
- •Grade 3b follicular lymphoma.
- •Radiotherapy within 3 months prior to study entry
- •Major surgery (excluding lymph node biopsy) within 28 days prior to registration.
- •HIV positive serology. HBV and HCV positive patients will be not excluded from the study if the hepatic enzymes are within the ranges later defined. HBV occult carriers patients will be given lamivudine as prophylaxis starting one week before chemotherapy. HbsAg, HBcAb, HBV-DNA and HCV-RNA levels will be monitored twice every month in HCV or HBV positive patients.
- •Life expectancy < 6 months.
- •Known sensitivity or allergy to murine products.
- •Prior history of malignancies, other than follicular lymphoma, unless the subject has been free of the disease for > 3 years with the exception of adequately cured localized non-melanoma skin cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast or incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
- •Prior use of lenalidomide.
- •Neuropathy > Grade
- •Myocardial infarction within the last 6 months
- •Presence or history of CNS involvement by lymphoma.
- •Subjects who are at a high risk for a thromboembolic event and are not willing to take venous thromboembolic (VTE) prophylaxis.
- •Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) > 3x upper limit of normal (ULN), except in subjects with documented liver involvement by lymphoma
- •Total bilirubin > 2.0 mg/dl (34 umol/L) except in cases of Gilberts Syndrome and documented liver involvement by lymphoma
- •Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
- •Pregnant or lactating females.
- •Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study, or which confounds the ability to interpret data from the study.
研究组 & 干预措施
R-MANT
A) Rituximab
干预措施: R-MANT (Drug)
R2-MANT
A) Rituximab B) Lenalidomide
干预措施: R2-MANT (Drug)
结局指标
主要结局
PFS
时间窗: 2 years from randomization
Progression-free survival
次要结局
- Rate of molecular relapse(2 years from randomization)
- OS(2 years from randomization)
- Toxicity (Common Terminology Criteria for Adverse Event version 4.03 (CTCAE)(2 years from randomization)
- Rate of molecular remission(2 years from randomization)
- Rate of molecular conversion(2 years from randomization)
- Quality of Life(QoL)(2 years from randomization)
- The incremental cost-effectiveness ratio(2 years from randomization)