Randomized Phase II Trial on Fitness- and Comorbidity- Tailored Treatment in Elderly Patients With Newly Diagnosed Primary CNS Lymphoma (FIORELLA Trial)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 72
- 试验地点
- 34
- 主要终点
- Two years Progression Free Survival (PFS) - part A
研究概览
简要总结
Primary central nervous system lymphomas are rare aggressive malignancies, usually treated in two steps: an induction phase (where a combination of chemotherapy is given) followed by a consolidation phase (where patients usually receive one of the following: whole-brain irradiation, chemotherapy supported by autologous stem-cell transplantation, other type of chemotherapy, or are just observed).
The feasibility of this overall strategy, for several reasons, is limited in elderly patients .
This study involves patients aged ≥70 years. The more fit patients will receive the standard chemotherapy combination (high-dose methotrexate, procarbazine and rituximab) as induction. Responding patients will receive either procarbazine or lenalidomide as maintenance therapy; the aim is to evaluate the efficacy of these two drugs.
The more fragile patients will receive a less aggressive therapy consisting of concomitant whole-brain radiotherapy, temozolomide and rituximab as induction therapy, followed by temozolomide as maintenance treatment; the aim is to evaluate the efficacy of this combination of treatment.
详细描述
Primary central nervous system lymphomas (PCNSL) are rare aggressive malignancies, mostly of B-cell origin, representing 4% of intracranial neoplasms and 4-6% of extranodal non-Hodgkin's lymphomas (NHL). Despite improvements in treatment, PCNSL is associated with an aggressive course and unsatisfactory outcome. The median age at diagnosis is 61 years and age over 60 years has been reported to be an independent factor for a poorer outcome.
The modern treatment of PCNSL includes two phases: induction and consolidation. The induction phase usually consists of a polychemotherapy combination, including high-dose methotrexate as a critical drug, while there are at least four different strategies that can be used as consolidation: whole-brain irradiation, myeloblative chemotherapy supported by autologous stem-cell transplantation, non-myeloblative chemotherapy, observation (only in patients who achieve complete remission after induction).
The feasibility of this overall strategy is limited, for several reasons, in elderly patients with newly diagnosed PCNSL. High-doses of antimetabolite-based chemotherapy, the standard induction for patients younger than 70 years, is often not feasible in elderly patients. Among maintenance strategies, simple observation results in unacceptably high relapse rate and associated mortality while whole-brain irradiation and aggressive chemotherapies are associated with unacceptable toxicity and poor outcome. Thus, new strategies aimed at obtaining durable responses with an acceptable tolerability and reduced risk of neurocognitive decline are needed and these strategies should be tailored not only based on the patients' age but also on their specific co-morbidities and general health conditions.
For the present trial, all patients aged ≥70 years taken into care at the participating sites will be invited to participate and after informed consent signature their baseline data will be collected in the trial database, including data of patients resulting in screening failure. This will allow to verify any potential screening bias by comparing the characteristics of included and excluded patients. Patients fulfilling the eligibility criteria are then screened for their suitability to receive a more or less aggressive anticancer treatment and assigned to two different treatment strategies accordingly.
Part A:
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
- 70 Years 至 —（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically assessed diagnosis of CD20+ diffuse large B-cell lymphoma.
- •Diagnostic sample obtained by stereotactic or surgical biopsy, CSF cytology examination or vitrectomy.
- •Lymphoma exclusively localized in the central nervous system (brain parenchyma and/or meningeal/CSF dissemination and/or eyes and/or cranial nerves).
- •Previously untreated patients (previous or ongoing steroid therapy admitted).
- •Age ≥70 years
- •Patients not eligible for high-dose chemotherapy supported by autologous stem cell transplant
- •ECOG PS ≤
- •Adequate bone marrow, cardiac, renal, and hepatic function
- •No previous or concurrent malignancies with the exception of surgically cured carcinoma in-situ of the cervix, carcinoma of the skin or other cancers without evidence of disease at least for 3 years (patients with a previous lymphoma at any time are NOT eligible).
- •Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
- •No concurrent treatment with other experimental drugs.
- •Patients receiving oral lenalidomide or procarbazine must agree to avoid sharing the study medication with another person and to return all unused study drug to the investigator.
- •Male patients must agree to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide, during dose interruptions and for up to 7 days after treatment discontinuation, even if they have undergone a successful vasectomy.
- •Informed consent from the patient, or legal representative, obtained before registration.
排除标准
- •Lymphoma entity other than diffuse large B-cell lymphoma.
- •Extra-CNS disease.
- •Lymphoma exclusively localized in the eyes
- •Lymphoma infiltration of the cranial nerves as exclusive site of disease
- •Previous antineoplastic treatment for the PCNSL.
- •Patients eligible for ASCT.
- •HBsAg- and HCV-positive patients; HBsAg- and HCV-positive patients. HBcAb+ is not exclusion criteria in the absence of detectable levels HBVDNA.
- •HIV disease or immunodeficiency.
- •Severe concomitant illnesses/medical conditions (e.g. impaired respiratory and/or cardiac function, uncontrolled diabetes mellitus despite optimal medical management).
- •Active infectious disease.
- •Hypersensitivity to any active principle and/or any excipient according to the contraindications reported in the Summary of Product Characteristics (SmPCs) of the anticancer drugs used in the study
研究组 & 干预措施
Lenalidomide (experimental arm of part A)
Patients in part A will receive 2 courses of induction chemo-immunotherapy:
Rituximab 375 mg/m2 i.v. on days -6, 1, 15, 29; Methotrexate 3 g/m2 0.5 g/m2 in 15 min. +2.5 g/m2 in 3-hr inf. on days 2,16,30; Procarbazine 60 mg/m2/d oral on days 2 to 11.
The duration of each treatment course is 43 days. Patients will then be randomized to receive lenalidomide or procarbazine as maintenance therapy.
Lenalidomide is given 25 mg/d per os, days 1 to 21 every 4 weeks for 24 courses
干预措施: Rituximab (Drug)
Lenalidomide (experimental arm of part A)
Patients in part A will receive 2 courses of induction chemo-immunotherapy:
Rituximab 375 mg/m2 i.v. on days -6, 1, 15, 29; Methotrexate 3 g/m2 0.5 g/m2 in 15 min. +2.5 g/m2 in 3-hr inf. on days 2,16,30; Procarbazine 60 mg/m2/d oral on days 2 to 11.
The duration of each treatment course is 43 days. Patients will then be randomized to receive lenalidomide or procarbazine as maintenance therapy.
Lenalidomide is given 25 mg/d per os, days 1 to 21 every 4 weeks for 24 courses
干预措施: Methotrexate (Drug)
Lenalidomide (experimental arm of part A)
Patients in part A will receive 2 courses of induction chemo-immunotherapy:
Rituximab 375 mg/m2 i.v. on days -6, 1, 15, 29; Methotrexate 3 g/m2 0.5 g/m2 in 15 min. +2.5 g/m2 in 3-hr inf. on days 2,16,30; Procarbazine 60 mg/m2/d oral on days 2 to 11.
The duration of each treatment course is 43 days. Patients will then be randomized to receive lenalidomide or procarbazine as maintenance therapy.
Lenalidomide is given 25 mg/d per os, days 1 to 21 every 4 weeks for 24 courses
干预措施: Procarbazine (Drug)
Lenalidomide (experimental arm of part A)
Patients in part A will receive 2 courses of induction chemo-immunotherapy:
Rituximab 375 mg/m2 i.v. on days -6, 1, 15, 29; Methotrexate 3 g/m2 0.5 g/m2 in 15 min. +2.5 g/m2 in 3-hr inf. on days 2,16,30; Procarbazine 60 mg/m2/d oral on days 2 to 11.
The duration of each treatment course is 43 days. Patients will then be randomized to receive lenalidomide or procarbazine as maintenance therapy.
Lenalidomide is given 25 mg/d per os, days 1 to 21 every 4 weeks for 24 courses
干预措施: Lenalidomide (Drug)
Procarbazine (comparator arm of part A)
Patients in part A will receive 2 courses of induction chemo-immunotherapy:
Rituximab 375 mg/m2 i.v. on days -6, 1, 15, 29; Methotrexate 3 g/m2 0.5 g/m2 in 15 min. +2.5 g/m2 in 3-hr inf. on days 2,16,30; Procarbazine 60 mg/m2/d oral on days 2 to 11.
The duration of each treatment course is 43 days. Patients will then be randomized to receive lenalidomide or procarbazine as maintenance therapy.
Procarbazine is given 100 mg/d per os, days 1 to 5 every 4 weeks for 6 courses
干预措施: Rituximab (Drug)
Procarbazine (comparator arm of part A)
Patients in part A will receive 2 courses of induction chemo-immunotherapy:
Rituximab 375 mg/m2 i.v. on days -6, 1, 15, 29; Methotrexate 3 g/m2 0.5 g/m2 in 15 min. +2.5 g/m2 in 3-hr inf. on days 2,16,30; Procarbazine 60 mg/m2/d oral on days 2 to 11.
The duration of each treatment course is 43 days. Patients will then be randomized to receive lenalidomide or procarbazine as maintenance therapy.
Procarbazine is given 100 mg/d per os, days 1 to 5 every 4 weeks for 6 courses
干预措施: Methotrexate (Drug)
Procarbazine (comparator arm of part A)
Patients in part A will receive 2 courses of induction chemo-immunotherapy:
Rituximab 375 mg/m2 i.v. on days -6, 1, 15, 29; Methotrexate 3 g/m2 0.5 g/m2 in 15 min. +2.5 g/m2 in 3-hr inf. on days 2,16,30; Procarbazine 60 mg/m2/d oral on days 2 to 11.
The duration of each treatment course is 43 days. Patients will then be randomized to receive lenalidomide or procarbazine as maintenance therapy.
Procarbazine is given 100 mg/d per os, days 1 to 5 every 4 weeks for 6 courses
干预措施: Procarbazine (Drug)
Radiotherapy, temozolomide and rituximab (single arm part B)
Patients ineligible for high-dose-methotrexate will be treated in the single-arm phase II part B of the trial and will receive
- whole-brain radiotherapy (2340 cGy in 5 weekly fractions)
- temozolomide 75 mg/m2/d during radiotherapy
- 4 weekly doses of rituximab 375 mg/m2, starting on day 2 of the whole-brain radiotherapy.
Patients will then receive maintenance therapy with 12 courses of temozolomide administered on days 1-5, every 4 weeks at a dose of 150 mg/m2/d at the first course, and of 200 mg/m2/d at the subsequent courses.
干预措施: Rituximab (Drug)
Radiotherapy, temozolomide and rituximab (single arm part B)
Patients ineligible for high-dose-methotrexate will be treated in the single-arm phase II part B of the trial and will receive
- whole-brain radiotherapy (2340 cGy in 5 weekly fractions)
- temozolomide 75 mg/m2/d during radiotherapy
- 4 weekly doses of rituximab 375 mg/m2, starting on day 2 of the whole-brain radiotherapy.
Patients will then receive maintenance therapy with 12 courses of temozolomide administered on days 1-5, every 4 weeks at a dose of 150 mg/m2/d at the first course, and of 200 mg/m2/d at the subsequent courses.
干预措施: Radiotherapy (Radiation)
Radiotherapy, temozolomide and rituximab (single arm part B)
Patients ineligible for high-dose-methotrexate will be treated in the single-arm phase II part B of the trial and will receive
- whole-brain radiotherapy (2340 cGy in 5 weekly fractions)
- temozolomide 75 mg/m2/d during radiotherapy
- 4 weekly doses of rituximab 375 mg/m2, starting on day 2 of the whole-brain radiotherapy.
Patients will then receive maintenance therapy with 12 courses of temozolomide administered on days 1-5, every 4 weeks at a dose of 150 mg/m2/d at the first course, and of 200 mg/m2/d at the subsequent courses.
干预措施: Temozolomide (Drug)
结局指标
主要结局
Two years Progression Free Survival (PFS) - part A
时间窗: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years.
The primary objective is to evaluate whether lenalidomide administered as maintenance treatment after achievement of disease stabilization or better response by standard induction therapy results in a higher 2-year PFS rate as compared to procarbazine maintenance. The corresponding primary endpoint is the difference in 2-years PFS between the two treatment arms.
Two years Progression Free Survival (PFS) - part B
时间窗: From date of maintenance start until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
次要结局
- Duration of response (part A)(From date of first assessment of response (PR or CR) until the date of first documented progression, assessed up to 2 years from randomization.)
- Response Rates (part B)(From the start of the treatment until disease progression, assessed up to 2 years from start of maintenance.)
- Relapse rates and patterns(From the start of the treatment until disease progression, assessed up to 2 years from start of maintenance.)
- Incidence of Treatment-Emergent Adverse Events(From the 2 weeks preceding treatment start through study completion, an average of 2.5 years)
- Overall survival (OS)(From date of induction treatment start until the date of death from any cause or the date of the last visit in patients still alive at study end, assessed up to 2 years from start of maintenance.)
- Early and late neurotoxicity(From maintenance up to 2 years.)