Prospective Phase II Study of a High Dose, Short Course Regimen (R-CODOX-M/IVAC) Including CNS Penetration and Intensive IT Prophylaxis in HIV-Associated Burkitt's and Atypical Burkitt's Lymphoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 34
- 试验地点
- 13
- 主要终点
- Overall Survival (OS) at 1 Year
研究概览
简要总结
RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving rituximab together with combination chemotherapy may kill more cancer cells.
PURPOSE: This phase II trial is studying how well giving rituximab together with combination chemotherapy works in treating patients with newly diagnosed, HIV-associated Burkitt's lymphoma.
详细描述
OBJECTIVES:
Primary
- Determine the efficacy of rituximab, cyclophosphamide, vincristine, doxorubicin hydrochloride, and high-dose methotrexate (R-CODOX-M ) alone or alternating with rituximab and ifosfamide, etoposide phosphate, and high-dose cytarabine (IVAC) and intrathecal CNS prophylaxis in patients with newly diagnosed, previously untreated, HIV-associated Burkitt's lymphoma or atypical Burkitt's lymphoma.
- Determine the safety of this regimen in these patients.
Secondary
- Evaluate downstream effectors of apoptosis as mechanisms of chemotherapy resistance and prognosis and perform exploratory analysis of their relationship to treatment effect.
- Evaluate multi-drug resistance gene expression as a mechanism of chemotherapy resistance and prognosis and perform exploratory analysis of their relationship to treatment effect.
- Confirm the use of flow cytometry in the identification of occult leptomeningeal disease and determine whether abnormal flow cytometry is predictive when CNS cytology is negative for malignant cells.
- Determine the biologic and prognostic significance of Epstein-Barr virus (EBV)-positive Burkitt's lymphoma in the highly active antiretroviral therapy era and perform exploratory analysis of their relationship to treatment effect.
- Compare genotyping in patients with HIV-associated Burkitt's lymphoma with that of patients who are HIV-negative and determine whether they are uniform in their genetic profile or whether some cases are more like diffuse large B-cell lymphoma.
- Determine if EBV detection in cerebrospinal fluid at diagnosis is predictive of leptomeningeal disease.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Regimen A (R-CODOX-M chemotherapy)
Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
干预措施: filgrastim (Biological)
Regimen A (R-CODOX-M chemotherapy)
Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
干预措施: pegfilgrastim (Biological)
Regimen A (R-CODOX-M chemotherapy)
Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
干预措施: rituximab (Biological)
Regimen A (R-CODOX-M chemotherapy)
Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
干预措施: cyclophosphamide (Drug)
Regimen A (R-CODOX-M chemotherapy)
Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
干预措施: cytarabine (Drug)
Regimen A (R-CODOX-M chemotherapy)
Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
干预措施: doxorubicin hydrochloride (Drug)
Regimen A (R-CODOX-M chemotherapy)
Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
干预措施: leucovorin calcium (Drug)
Regimen A (R-CODOX-M chemotherapy)
Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
干预措施: liposomal cytarabine (Drug)
Regimen A (R-CODOX-M chemotherapy)
Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
干预措施: methotrexate (Drug)
Regimen A (R-CODOX-M chemotherapy)
Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
干预措施: therapeutic hydrocortisone (Drug)
Regimen A (R-CODOX-M chemotherapy)
Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.
干预措施: vincristine sulfate (Drug)
Regimen B (rituximab and IVAC chemotherapy)
Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
干预措施: filgrastim (Biological)
Regimen B (rituximab and IVAC chemotherapy)
Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
干预措施: pegfilgrastim (Biological)
Regimen B (rituximab and IVAC chemotherapy)
Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
干预措施: rituximab (Biological)
Regimen B (rituximab and IVAC chemotherapy)
Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
干预措施: cytarabine (Drug)
Regimen B (rituximab and IVAC chemotherapy)
Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
干预措施: etoposide (Drug)
Regimen B (rituximab and IVAC chemotherapy)
Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
干预措施: ifosfamide (Drug)
Regimen B (rituximab and IVAC chemotherapy)
Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
干预措施: liposomal cytarabine (Drug)
Regimen B (rituximab and IVAC chemotherapy)
Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
干预措施: methotrexate (Drug)
Regimen B (rituximab and IVAC chemotherapy)
Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
干预措施: therapeutic hydrocortisone (Drug)
结局指标
主要结局
Overall Survival (OS) at 1 Year
时间窗: 1 year post treatment
次要结局
- Failure-free Survival (FFS)(6-8 weeks post treatment, every 4 months post-treatment for 2 years)
- Event-free Survival (EFS)(6-8 weeks post treatment, every 4 months post-treatment for 2 years)
- Incidence of Infection-related Deaths(baseline through 2 years post-treatment)
- Degree of Disconcordance Between Flow Cytometry and CNS Cytology Results(baseline)
- Correlation of EBV Load Measurements With OS, FFS, and EFS(baseline through 2 years post-treatment)
- Utility of Flow Cytometry in Detecting Leptomeningeal Disease(baseline and 6-8 weeks post-treatment)
- Complete Response Rate(6-8 weeks post treatment, every 4 months post-treatment for 2 years)
- Correlation of C-flip Expression, p53 Mutations, and Multidrug Resistance Expression With OS, FFS, and EFS(baseline through 2 years post-treatment)
- Biologic and Prognostic Significance of Epstein-Barr Virus (EBV) at Diagnosis and Correlation With OS, FFS, and EFS(baseline through 2 years post-treatment)
- Toxicity(baseline through 2 years post-treatment)