Prospective, Multi-center Phase I/II Trial of Lenalidomide and Dose-Adjusted EPOCH-R in MYC-Associated B-Cell Lymphomas
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 55
- 试验地点
- 6
- 主要终点
- Dose-limiting Toxicity (Phase I)
研究概览
简要总结
This phase I/II trial studies the side effects and best dose of lenalidomide when given together with combination chemotherapy and to see how well they work in treating patients with v-myc myelocytomatosis viral oncogene homolog (avian) (MYC)-associated B-cell lymphomas. Lenalidomide may stop the growth of B-cell lymphomas by blocking the growth of new blood vessels necessary for cancer growth and by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Giving lenalidomide together with combination chemotherapy may be an effective treatment in patients with B-cell lymphoma.
详细描述
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of lenalidomide when added to dose-adjusted (DA)-etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, rituximab (EPOCH-R) (hereby termed "DA-EPOCH-RR") in patients with double hit lymphoma (DHL) lymphomas. (Phase I) II. To determine the 1- and 2-year progression free survival (PFS) of DA-EPOCH-RR in patients with DHL lymphomas. (Phase II)
SECONDARY OBJECTIVES:
I. Overall response rate, complete response, and duration of response. II. Quality of life (QOL) measures using standardized scales. III. Toxicity assessment using version 4.0 of the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) criteria.
IV. Overall survival (OS) at 1 and 2 years.
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
- •B-cell lymphoma with comprehensive immunohistochemistry (IHC) panel establishing lineage (CD20, CD3) and cell of origin (CD10, BCL6 and MUM1) in addition to proliferative/prognostic markers (Ki-67, C-myc and BCL2). DHL will be identified using cytogenetics and/or immunohistochemistry as detailed in section 4.1.2 below.
- •To define DHL, patients must have evidence of C-myc [defined as: Cytogenetic evidence (FISH or karyotype) of C-myc breaks (Increased copy number in itself is not considered positivity for C-myc) OR Positive IHC defined as >40% of the lymphoma cells staining for C-myc] PLUS either:
- •Breaks in BCL-2 via cytogenetic studies or
- •BCL-2 immunopositivity in >70% of lymphoma cells.
- •Patients are allowed to have received radiotherapy before enrollment if radiation was given to alleviate pain and/or neurologic compromise as long as there remains areas of measurable disease present. Further, at the investigator's discretion and for patients who are unstable, one cycle of R-CHOP is allowed prior to enrollment but no more than one cycle. For purposes of this trial, prednisone or other corticosteroids used for non-lymphomatous conditions will be allowed. In addition, a prior/recent short course (< 2 weeks) of steroids for symptom relief of lymphoma-related symptoms will be allowed.
- •AST and ALT < 3 x upper limit of normal (ULN), and total bilirubin <1.5 x ULN (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement with NHL or stable chronic liver disease per investigator assessment).
- •Patients must have adequate renal function by virtue of GFR > 50 ml/minute using Cockroft-Gault formula.
- •Patients must have adequate bone marrow function (platelets >100,000 and ANC >1,200). Patients with bone marrow involvement are allowed at the investigator's discretion regardless of cytopenias.
- •Age ≥ 18 years.
- •All study participants must be registered into the mandatory lenalidomide REMS® program, and be willing and able to comply with the requirements of the REMS® program.
- •Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the lenalidomide REMS® program. (Please see study schema for further details)
- •Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).
- •Ability to read, understand, and sign a written informed consent approved by each institutional IRB. Alternatively, patients with legal guardians who can read, understand, and sign written informed consent may also enroll.
排除标准
- •Prior therapy for lymphoma
- •Known CNS involvement
- •Known HIV positive status
- •Pregnant females
- •Burkitt and/or precursor lymphoblastic leukemia/lymphoma.
- •Prior pomalidomide exposure
- •Known hypersensitivity to lenalidomide or thalidomide
- •The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
- •Subjects who have currently active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement with NHL or stable chronic liver disease per investigator assessment).
- •Treatment with any known non-marketed drug substance or experimental therapy within 4 weeks prior to enrollment, or currently participating in any other interventional clinical study for NHL or any other illness (except observational, prevention, and/or registry trials).
- •No current malignancy. Subjects who have been free of malignancy for at least 2 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma (any site) are eligible. Women with a history of cervical cancers are allowed.
- •Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C.
- •History of significant cerebrovascular disease in the past 3 months or ongoing event with active symptoms or sequelae.
- •Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive, the subject will be excluded if unable to tolerate and/or receive anti-Hepatitis-B therapy. Positive serology because of prior vaccination is allowed.
- •Positive serology for hepatitis C (HC) defined as a positive test for HCAb.
- •Inability to comply with study or follow-up testing and procedures.
研究组 & 干预措施
Treatment (lenalidomide, DA-EPOCH-R)
INDUCTION PHASE: Patients receive lenalidomide PO daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
DA-EPOCH-R: Patients receive etoposide IV continuously on days 1-4, prednisone PO BID on days 1-5, vincristine sulfate IV continuously on days 1-4, doxorubicin hydrochloride IV continuously on days 1-4, cyclophosphamide IV over 15 minutes on day 5, and rituximab IV over 4 hours on day 1 (per institutional guidelines). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION PHASE: Patients who are transplantation (HSCT)-eligible receive BEAM-conditioning regimen followed by autologous (auto)-HSCT or HSCT at the discretion of the treating physician. Patients who do not undergo HSCT in first remission receive lenalidomide maintenance for 12 months.
干预措施: lenalidomide (Drug)
Treatment (lenalidomide, DA-EPOCH-R)
INDUCTION PHASE: Patients receive lenalidomide PO daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
DA-EPOCH-R: Patients receive etoposide IV continuously on days 1-4, prednisone PO BID on days 1-5, vincristine sulfate IV continuously on days 1-4, doxorubicin hydrochloride IV continuously on days 1-4, cyclophosphamide IV over 15 minutes on day 5, and rituximab IV over 4 hours on day 1 (per institutional guidelines). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION PHASE: Patients who are transplantation (HSCT)-eligible receive BEAM-conditioning regimen followed by autologous (auto)-HSCT or HSCT at the discretion of the treating physician. Patients who do not undergo HSCT in first remission receive lenalidomide maintenance for 12 months.
干预措施: etoposide (Drug)
Treatment (lenalidomide, DA-EPOCH-R)
INDUCTION PHASE: Patients receive lenalidomide PO daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
DA-EPOCH-R: Patients receive etoposide IV continuously on days 1-4, prednisone PO BID on days 1-5, vincristine sulfate IV continuously on days 1-4, doxorubicin hydrochloride IV continuously on days 1-4, cyclophosphamide IV over 15 minutes on day 5, and rituximab IV over 4 hours on day 1 (per institutional guidelines). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION PHASE: Patients who are transplantation (HSCT)-eligible receive BEAM-conditioning regimen followed by autologous (auto)-HSCT or HSCT at the discretion of the treating physician. Patients who do not undergo HSCT in first remission receive lenalidomide maintenance for 12 months.
干预措施: prednisone (Drug)
Treatment (lenalidomide, DA-EPOCH-R)
INDUCTION PHASE: Patients receive lenalidomide PO daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
DA-EPOCH-R: Patients receive etoposide IV continuously on days 1-4, prednisone PO BID on days 1-5, vincristine sulfate IV continuously on days 1-4, doxorubicin hydrochloride IV continuously on days 1-4, cyclophosphamide IV over 15 minutes on day 5, and rituximab IV over 4 hours on day 1 (per institutional guidelines). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION PHASE: Patients who are transplantation (HSCT)-eligible receive BEAM-conditioning regimen followed by autologous (auto)-HSCT or HSCT at the discretion of the treating physician. Patients who do not undergo HSCT in first remission receive lenalidomide maintenance for 12 months.
干预措施: vincristine sulfate (Drug)
Treatment (lenalidomide, DA-EPOCH-R)
INDUCTION PHASE: Patients receive lenalidomide PO daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
DA-EPOCH-R: Patients receive etoposide IV continuously on days 1-4, prednisone PO BID on days 1-5, vincristine sulfate IV continuously on days 1-4, doxorubicin hydrochloride IV continuously on days 1-4, cyclophosphamide IV over 15 minutes on day 5, and rituximab IV over 4 hours on day 1 (per institutional guidelines). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION PHASE: Patients who are transplantation (HSCT)-eligible receive BEAM-conditioning regimen followed by autologous (auto)-HSCT or HSCT at the discretion of the treating physician. Patients who do not undergo HSCT in first remission receive lenalidomide maintenance for 12 months.
干预措施: doxorubicin hydrochloride (Drug)
Treatment (lenalidomide, DA-EPOCH-R)
INDUCTION PHASE: Patients receive lenalidomide PO daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
DA-EPOCH-R: Patients receive etoposide IV continuously on days 1-4, prednisone PO BID on days 1-5, vincristine sulfate IV continuously on days 1-4, doxorubicin hydrochloride IV continuously on days 1-4, cyclophosphamide IV over 15 minutes on day 5, and rituximab IV over 4 hours on day 1 (per institutional guidelines). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION PHASE: Patients who are transplantation (HSCT)-eligible receive BEAM-conditioning regimen followed by autologous (auto)-HSCT or HSCT at the discretion of the treating physician. Patients who do not undergo HSCT in first remission receive lenalidomide maintenance for 12 months.
干预措施: cyclophosphamide (Drug)
Treatment (lenalidomide, DA-EPOCH-R)
INDUCTION PHASE: Patients receive lenalidomide PO daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
DA-EPOCH-R: Patients receive etoposide IV continuously on days 1-4, prednisone PO BID on days 1-5, vincristine sulfate IV continuously on days 1-4, doxorubicin hydrochloride IV continuously on days 1-4, cyclophosphamide IV over 15 minutes on day 5, and rituximab IV over 4 hours on day 1 (per institutional guidelines). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION PHASE: Patients who are transplantation (HSCT)-eligible receive BEAM-conditioning regimen followed by autologous (auto)-HSCT or HSCT at the discretion of the treating physician. Patients who do not undergo HSCT in first remission receive lenalidomide maintenance for 12 months.
干预措施: rituximab (Biological)
Treatment (lenalidomide, DA-EPOCH-R)
INDUCTION PHASE: Patients receive lenalidomide PO daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
DA-EPOCH-R: Patients receive etoposide IV continuously on days 1-4, prednisone PO BID on days 1-5, vincristine sulfate IV continuously on days 1-4, doxorubicin hydrochloride IV continuously on days 1-4, cyclophosphamide IV over 15 minutes on day 5, and rituximab IV over 4 hours on day 1 (per institutional guidelines). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION PHASE: Patients who are transplantation (HSCT)-eligible receive BEAM-conditioning regimen followed by autologous (auto)-HSCT or HSCT at the discretion of the treating physician. Patients who do not undergo HSCT in first remission receive lenalidomide maintenance for 12 months.
干预措施: quality-of-life assessment (Other)
Treatment (lenalidomide, DA-EPOCH-R)
INDUCTION PHASE: Patients receive lenalidomide PO daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
DA-EPOCH-R: Patients receive etoposide IV continuously on days 1-4, prednisone PO BID on days 1-5, vincristine sulfate IV continuously on days 1-4, doxorubicin hydrochloride IV continuously on days 1-4, cyclophosphamide IV over 15 minutes on day 5, and rituximab IV over 4 hours on day 1 (per institutional guidelines). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION PHASE: Patients who are transplantation (HSCT)-eligible receive BEAM-conditioning regimen followed by autologous (auto)-HSCT or HSCT at the discretion of the treating physician. Patients who do not undergo HSCT in first remission receive lenalidomide maintenance for 12 months.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Dose-limiting Toxicity (Phase I)
时间窗: Up to 21 days
Number of patients with dose-limiting toxicity (DLT) defined as any grade 4 non-hemaotologic toxicity or any recurrent grade 3 non-hematologic toxicity despite optimal medical management
Progression-free Survival
时间窗: Assessed up to 5 years
Time elapsed between treatment initiation and tumor progression or death from any cause, whichever occurs first.
Progression-free Survival at 1 Year
时间窗: 1 year
The percentage of patients alive and progression-free at 1 year.
Progression-free Survival at 2 Years
时间窗: 2 years
Percentage of patients alive and progression-free at 2 years.
次要结局
- Progression-free Survival at 18 Weeks(18 weeks)
- Overall Response Rate(Up to 18 weeks)
- Anti-tumor Activity(Up to 18 weeks)
- Duration of Response (Rate at 2 Years)(2 years)