A Phase II Study of Bortezomib and Vorinostat in Patients With Refractory or Relapsed MLL Rearranged Hematologic Malignancies
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Overall Response Rate in All Participants
研究概览
简要总结
This study will test the safety and effectiveness of adding bortezomib and vorinostat to other chemotherapy drugs commonly used to treat relapsed or refractory leukemia. Both drugs have been approved by the Food and Drug Administration (FDA) to treat other cancers in adults, but they have not yet been approved tor treatment younger patients with leukemia.
PRIMARY OBJECTIVE
- To estimate the overall response rate of patients with MLL rearranged (MLLr) hematologic malignancies receiving bortezomib and vorinostat in combination with a chemotherapy backbone.
SECONDARY OBJECTIVES
- Estimate event-free and overall-survival.
- Describe toxicities experienced by participants during treatment.
OTHER PRESPECIFIED OBJECTIVES
- To identify all genomic lesions by comprehensive whole genome, exome and transcriptome sequencing on all patients.
- To compare minimal residual disease (MRD) results by three modalities: flow cytometry, polymerase chain reaction (PCR) and deep sequencing.
详细描述
All participants will undergo diagnostic lumbar puncture and intrathecal (IT) chemotherapy [Cytarabine, methotrexate, hydrocortisone (ITMHA)] prior to cycle 1. Throughout all phases of therapy, dexrazoxane will be given as supportive care for all participants prior to receiving mitoxantrone or doxorubicin.
STRATUM 1: MYELOID MALIGNANCIES:
Induction:
- Cytarabine, Days 1-5
- Bortezomib, Days 1, 4, 8, 11, 15, 18
- Vorinostat, Days 1-4, 8-11, 15-18
- ITMHA.for those with CNS1, Day 1
- ITMHA for those with CNS 2/3, Days 1, 4, 8, 11*, 15*, 18* and 22* (* Twice weekly until two negative CSF; CNS3 patients must receive at least 6 doses)
- Participants with cumulative anthracycline <460 mg/m2 also receive Mitoxantrone on Day 1
- Responders may receive up to 6 courses. ITMHA will be limited to day 1 for subsequent courses
Maintenance (bridge) therapy (1 cycle before stem cell transplant if needed)::
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
- — 至 21 Years（Child, 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
Stratum 1: Myeloid Malignancies
Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.
干预措施: Bortezomib (Drug)
Stratum 1: Myeloid Malignancies
Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.
干预措施: Vorinostat (Drug)
Stratum 1: Myeloid Malignancies
Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.
干预措施: Mitoxantrone (Drug)
Stratum 1: Myeloid Malignancies
Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.
干预措施: Cytarabine (Drug)
Stratum 1: Myeloid Malignancies
Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.
干预措施: Methotrexate (Drug)
Stratum 1: Myeloid Malignancies
Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.
干预措施: Hydrocortisone (Drug)
Stratum 2: ALL and MLM
Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
干预措施: Bortezomib (Drug)
Stratum 2: ALL and MLM
Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
干预措施: Vorinostat (Drug)
Stratum 2: ALL and MLM
Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
干预措施: Mitoxantrone (Drug)
Stratum 2: ALL and MLM
Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
干预措施: Cytarabine (Drug)
Stratum 2: ALL and MLM
Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
干预措施: Methotrexate (Drug)
Stratum 2: ALL and MLM
Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
干预措施: Hydrocortisone (Drug)
Stratum 2: ALL and MLM
Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
干预措施: Erwinia L-Asparaginase (Drug)
Stratum 2: ALL and MLM
Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
干预措施: Peg-L-Asparaginase (Drug)
Stratum 2: ALL and MLM
Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
干预措施: Dexamethasone (Drug)
Stratum 2: ALL and MLM
Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
干预措施: Mercaptopurine (Drug)
Stratum 2: ALL and MLM
Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
干预措施: Doxorubicin (Drug)
结局指标
主要结局
Overall Response Rate in All Participants
时间窗: End of first treatment block (up to 2 months)
For the purpose of the statistical analysis of the primary objective, response is assessed at the end of first treatment block at maximum tolerated dose of vorinostat (i.e., Induction Ia or Ib for myeloid and Induction for lymphoid and mixed lineage). Any eligible patient who starts first treatment block is considered evaluable. Response of CR, CRi, PR, or PRi is considered a success; otherwise a failure, which will include the cases of No-response, as well as off- treatment or off-study before response can be assessed, except cases found ineligible after enrollment. A patient found ineligible after enrollment will be taken off study and replaced by enrolling an additional MLLr patient. The rate (probability) of response will be estimated by the sample proportion of patients who responded (CR, CRi, PR, PRi) to Induction, along with the 99% confidence interval and lower confidence bound. Three interim analyses will be performed to monitor the possible lack of efficacy.
次要结局
- Number of Participants With 3 Year Event Free Survival (EFS)(Three years after the last enrollment)
- Number of Participants With 3-year Overall Survival (OS)(Three years after the last enrollment)
- Number of Participant With 10-year Event Free Survival(Ten years after the last enrollment)
- Number of Participants With 10-year Overall Survival(Ten years after the last enrollment)
- Number of Participants With 5- Year Event Free Survival(Five years after the last enrollment)
- Number of Participants With 5-year Overall Survival(Five years after the last enrollment)
- Number of Relevant Toxicities Related to Therapy(From on-therapy date up to 18 months)