Azacitidine/Vorinostat/GemBuMel With Autologous Stem-Cell Transplant (SCT) in Patients With Refractory Lymphomas
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 61
- 试验地点
- 1
- 主要终点
- Frequency of DLT
研究概览
简要总结
The goal of this clinical research study is to find the highest tolerable dose of azacitidine that can be given with vorinostat, gemcitabine, busulfan, and melphalan, with a stem cell transplant, and with or without rituximab. Researchers also want to learn about the safety and level of effectiveness of this combination.
详细描述
Study Groups:
If you have been found to be eligible to take part in this study and you agree, you will be assigned to a dose level of azacitidine based on when you join this study. Up to 7 dose levels of azacitidine will be tested. At least 3 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of azacitidine is found.
All participants will receive the same dose level of vorinostat, gemcitabine, busulfan, and melphalan, and all patients with B-cell cancer will receive the same dose of rituximab. However, if the first group has bad side effects, the dose level of gemcitabine may be lowered for all other groups.
Busulfan Test Dose:
You will receive a test dose of busulfan by vein over about 60 minutes. This low-level test dose of busulfan is to check how the level of busulfan in your blood levels changes over time. This information will be used to decide the next dose needed to reach the target blood level that matches your body size. You will most likely receive this as an outpatient during the week before you are admitted to the hospital. If it cannot be given as an outpatient, you will be admitted to the hospital on Day -12 (12 days before your stem cells are returned to your body) and the test dose will be given on Day -11.
研究设计
- 研究类型
- Interventional
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 15 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 15 to 65 years.
- •Patients with Hodgkin's lymphoma with one or more of the following: a) Less than complete response to first-line chemotherapy. b) Relapse within 12 months of completion of first-line chemotherapy. c) Relapse within a prior irradiation field. d) Less than complete metabolic response to second-line chemotherapy. e) Second relapse or beyond. f) Extranodal disease at the time of relapse. g) Presence of B symptoms at the time of persistent disease upon completion of first-line chemotherapy, relapse or progressive disease. h) Bulky disease (defined as any lesion greater than 5 cm) at the time of persistent disease upon completion of first-line chemotherapy, relapse or progressive disease.
- •Patients with non-Hodgkin's lymphoma and one or more of the following:
- •Diffuse large B-cell lymphoma with one or more of the following: a) Primary refractory disease. b) Relapse within 12 months of completion of first-line therapy. c) Secondary IPI >
- •d) Less than PR to first-line salvage chemotherapy. e) Kinetic failure after salvage chemotherapy; f) Prior treatment with 3 or more lines of therapy. g) Patients with double-hit or triple-hit NHL, in any state of the disease.
- •Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) in any stage of the disease.
- •Angioimmunoblastic T-cell lymphoma (AITL) in any stage of the disease.
- •Refractory or recurrent Burkitt¹s lymphoma.
- •Any other lymphoma that is refractory or relapsed and that does not qualify for treatment protocols of higher priority.
- •Adequate renal function, as defined by estimated serum creatinine clearance >/=50 ml/min (MDRD method from National Kidney Disease Education Program, NKDEP) and/or serum creatinine </= 1.8 mg/dL.
- •Adequate hepatic function, as defined by SGOT and/or SGPT </= 3 x upper limit of normal; serum bilirubin and alkaline phosphatase </= 2 x upper limit of normal.
- •Adequate pulmonary function with FEV1, FVC and DLCO >/= 50% of expected corrected for hemoglobin.
- •Adequate cardiac function with left ventricular ejection fraction >/= 40%. No uncontrolled arrhythmias or symptomatic cardiac disease.
- •Zubrod performance status <
- •Negative Beta HCG text in a woman with child-bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization.
排除标准
- •Patients with grade >/= 3 non-hematologic toxicity from previous therapy that has not resolved to </= grade
- •Patients with prior whole brain irradiation.
- •Patients with active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA >/=10,000 copies/mL, or >/= 2,000 IU/mL).
- •Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology.
- •Patients with active inflammatory bowel disease.
- •Active infection requiring parenteral antibiotics.
- •HIV infection, unless the patient is receiving effective antiretroviral therapy with undetectable viral load and normal CD4 counts.
- •Patients having received radiation therapy in the month prior to enrollment.
研究组 & 干预措施
Azacitidine + Vorinostat + Gemcitabine + Busulfan + Melphalan
Busulfan test dose 32 mg/m2 by vein either as outpatient before Day -12 or as inpatient on Day -11. Busulfan pharmacokinetics performed with test dose and first dose on Day -8. Doses on Days -6 and -5 adjusted to target an AUC of 4,000 microMol.min-1. Dexamethasone 8 mg by vein twice a day from Day -11 AM to Day -2 PM. Caphosol oral rinses 30 mL four times a day used from Day -9. Oral glutamine, 15 g four times a day, swished, gargled and swallowed from Day -9. Pyridoxine 100 mg by vein or mouth three times a day from Day -1. Vorinostat 1000 mg by vein on Day -11 through Day -2. Gemcitabine loading dose 75 mg/m2 by vein followed by 22775 mg/m2 by vein on Day -8. Melphalan 60 mg/m2 by vein on Days -3 and -2. Azacitidine starting dose 15 mg/ m2 by vein on Day -11. Stem cell transplant on Day 0. Patients with CD20+ tumors receive rituximab 375 mg/m2 by vein on Days -9.
干预措施: Azacitidine (Drug)
Azacitidine + Vorinostat + Gemcitabine + Busulfan + Melphalan
Busulfan test dose 32 mg/m2 by vein either as outpatient before Day -12 or as inpatient on Day -11. Busulfan pharmacokinetics performed with test dose and first dose on Day -8. Doses on Days -6 and -5 adjusted to target an AUC of 4,000 microMol.min-1. Dexamethasone 8 mg by vein twice a day from Day -11 AM to Day -2 PM. Caphosol oral rinses 30 mL four times a day used from Day -9. Oral glutamine, 15 g four times a day, swished, gargled and swallowed from Day -9. Pyridoxine 100 mg by vein or mouth three times a day from Day -1. Vorinostat 1000 mg by vein on Day -11 through Day -2. Gemcitabine loading dose 75 mg/m2 by vein followed by 22775 mg/m2 by vein on Day -8. Melphalan 60 mg/m2 by vein on Days -3 and -2. Azacitidine starting dose 15 mg/ m2 by vein on Day -11. Stem cell transplant on Day 0. Patients with CD20+ tumors receive rituximab 375 mg/m2 by vein on Days -9.
干预措施: Vorinostat (Drug)
Azacitidine + Vorinostat + Gemcitabine + Busulfan + Melphalan
Busulfan test dose 32 mg/m2 by vein either as outpatient before Day -12 or as inpatient on Day -11. Busulfan pharmacokinetics performed with test dose and first dose on Day -8. Doses on Days -6 and -5 adjusted to target an AUC of 4,000 microMol.min-1. Dexamethasone 8 mg by vein twice a day from Day -11 AM to Day -2 PM. Caphosol oral rinses 30 mL four times a day used from Day -9. Oral glutamine, 15 g four times a day, swished, gargled and swallowed from Day -9. Pyridoxine 100 mg by vein or mouth three times a day from Day -1. Vorinostat 1000 mg by vein on Day -11 through Day -2. Gemcitabine loading dose 75 mg/m2 by vein followed by 22775 mg/m2 by vein on Day -8. Melphalan 60 mg/m2 by vein on Days -3 and -2. Azacitidine starting dose 15 mg/ m2 by vein on Day -11. Stem cell transplant on Day 0. Patients with CD20+ tumors receive rituximab 375 mg/m2 by vein on Days -9.
干预措施: Gemcitabine (Drug)
Azacitidine + Vorinostat + Gemcitabine + Busulfan + Melphalan
Busulfan test dose 32 mg/m2 by vein either as outpatient before Day -12 or as inpatient on Day -11. Busulfan pharmacokinetics performed with test dose and first dose on Day -8. Doses on Days -6 and -5 adjusted to target an AUC of 4,000 microMol.min-1. Dexamethasone 8 mg by vein twice a day from Day -11 AM to Day -2 PM. Caphosol oral rinses 30 mL four times a day used from Day -9. Oral glutamine, 15 g four times a day, swished, gargled and swallowed from Day -9. Pyridoxine 100 mg by vein or mouth three times a day from Day -1. Vorinostat 1000 mg by vein on Day -11 through Day -2. Gemcitabine loading dose 75 mg/m2 by vein followed by 22775 mg/m2 by vein on Day -8. Melphalan 60 mg/m2 by vein on Days -3 and -2. Azacitidine starting dose 15 mg/ m2 by vein on Day -11. Stem cell transplant on Day 0. Patients with CD20+ tumors receive rituximab 375 mg/m2 by vein on Days -9.
干预措施: Busulfan (Drug)
Azacitidine + Vorinostat + Gemcitabine + Busulfan + Melphalan
Busulfan test dose 32 mg/m2 by vein either as outpatient before Day -12 or as inpatient on Day -11. Busulfan pharmacokinetics performed with test dose and first dose on Day -8. Doses on Days -6 and -5 adjusted to target an AUC of 4,000 microMol.min-1. Dexamethasone 8 mg by vein twice a day from Day -11 AM to Day -2 PM. Caphosol oral rinses 30 mL four times a day used from Day -9. Oral glutamine, 15 g four times a day, swished, gargled and swallowed from Day -9. Pyridoxine 100 mg by vein or mouth three times a day from Day -1. Vorinostat 1000 mg by vein on Day -11 through Day -2. Gemcitabine loading dose 75 mg/m2 by vein followed by 22775 mg/m2 by vein on Day -8. Melphalan 60 mg/m2 by vein on Days -3 and -2. Azacitidine starting dose 15 mg/ m2 by vein on Day -11. Stem cell transplant on Day 0. Patients with CD20+ tumors receive rituximab 375 mg/m2 by vein on Days -9.
干预措施: Melphalan (Drug)
Azacitidine + Vorinostat + Gemcitabine + Busulfan + Melphalan
Busulfan test dose 32 mg/m2 by vein either as outpatient before Day -12 or as inpatient on Day -11. Busulfan pharmacokinetics performed with test dose and first dose on Day -8. Doses on Days -6 and -5 adjusted to target an AUC of 4,000 microMol.min-1. Dexamethasone 8 mg by vein twice a day from Day -11 AM to Day -2 PM. Caphosol oral rinses 30 mL four times a day used from Day -9. Oral glutamine, 15 g four times a day, swished, gargled and swallowed from Day -9. Pyridoxine 100 mg by vein or mouth three times a day from Day -1. Vorinostat 1000 mg by vein on Day -11 through Day -2. Gemcitabine loading dose 75 mg/m2 by vein followed by 22775 mg/m2 by vein on Day -8. Melphalan 60 mg/m2 by vein on Days -3 and -2. Azacitidine starting dose 15 mg/ m2 by vein on Day -11. Stem cell transplant on Day 0. Patients with CD20+ tumors receive rituximab 375 mg/m2 by vein on Days -9.
干预措施: Dexamethasone (Drug)
Azacitidine + Vorinostat + Gemcitabine + Busulfan + Melphalan
Busulfan test dose 32 mg/m2 by vein either as outpatient before Day -12 or as inpatient on Day -11. Busulfan pharmacokinetics performed with test dose and first dose on Day -8. Doses on Days -6 and -5 adjusted to target an AUC of 4,000 microMol.min-1. Dexamethasone 8 mg by vein twice a day from Day -11 AM to Day -2 PM. Caphosol oral rinses 30 mL four times a day used from Day -9. Oral glutamine, 15 g four times a day, swished, gargled and swallowed from Day -9. Pyridoxine 100 mg by vein or mouth three times a day from Day -1. Vorinostat 1000 mg by vein on Day -11 through Day -2. Gemcitabine loading dose 75 mg/m2 by vein followed by 22775 mg/m2 by vein on Day -8. Melphalan 60 mg/m2 by vein on Days -3 and -2. Azacitidine starting dose 15 mg/ m2 by vein on Day -11. Stem cell transplant on Day 0. Patients with CD20+ tumors receive rituximab 375 mg/m2 by vein on Days -9.
干预措施: Caphosol (Other)
Azacitidine + Vorinostat + Gemcitabine + Busulfan + Melphalan
Busulfan test dose 32 mg/m2 by vein either as outpatient before Day -12 or as inpatient on Day -11. Busulfan pharmacokinetics performed with test dose and first dose on Day -8. Doses on Days -6 and -5 adjusted to target an AUC of 4,000 microMol.min-1. Dexamethasone 8 mg by vein twice a day from Day -11 AM to Day -2 PM. Caphosol oral rinses 30 mL four times a day used from Day -9. Oral glutamine, 15 g four times a day, swished, gargled and swallowed from Day -9. Pyridoxine 100 mg by vein or mouth three times a day from Day -1. Vorinostat 1000 mg by vein on Day -11 through Day -2. Gemcitabine loading dose 75 mg/m2 by vein followed by 22775 mg/m2 by vein on Day -8. Melphalan 60 mg/m2 by vein on Days -3 and -2. Azacitidine starting dose 15 mg/ m2 by vein on Day -11. Stem cell transplant on Day 0. Patients with CD20+ tumors receive rituximab 375 mg/m2 by vein on Days -9.
干预措施: Glutamine (Drug)
Azacitidine + Vorinostat + Gemcitabine + Busulfan + Melphalan
Busulfan test dose 32 mg/m2 by vein either as outpatient before Day -12 or as inpatient on Day -11. Busulfan pharmacokinetics performed with test dose and first dose on Day -8. Doses on Days -6 and -5 adjusted to target an AUC of 4,000 microMol.min-1. Dexamethasone 8 mg by vein twice a day from Day -11 AM to Day -2 PM. Caphosol oral rinses 30 mL four times a day used from Day -9. Oral glutamine, 15 g four times a day, swished, gargled and swallowed from Day -9. Pyridoxine 100 mg by vein or mouth three times a day from Day -1. Vorinostat 1000 mg by vein on Day -11 through Day -2. Gemcitabine loading dose 75 mg/m2 by vein followed by 22775 mg/m2 by vein on Day -8. Melphalan 60 mg/m2 by vein on Days -3 and -2. Azacitidine starting dose 15 mg/ m2 by vein on Day -11. Stem cell transplant on Day 0. Patients with CD20+ tumors receive rituximab 375 mg/m2 by vein on Days -9.
干预措施: Pyridoxine (Drug)
Azacitidine + Vorinostat + Gemcitabine + Busulfan + Melphalan
Busulfan test dose 32 mg/m2 by vein either as outpatient before Day -12 or as inpatient on Day -11. Busulfan pharmacokinetics performed with test dose and first dose on Day -8. Doses on Days -6 and -5 adjusted to target an AUC of 4,000 microMol.min-1. Dexamethasone 8 mg by vein twice a day from Day -11 AM to Day -2 PM. Caphosol oral rinses 30 mL four times a day used from Day -9. Oral glutamine, 15 g four times a day, swished, gargled and swallowed from Day -9. Pyridoxine 100 mg by vein or mouth three times a day from Day -1. Vorinostat 1000 mg by vein on Day -11 through Day -2. Gemcitabine loading dose 75 mg/m2 by vein followed by 22775 mg/m2 by vein on Day -8. Melphalan 60 mg/m2 by vein on Days -3 and -2. Azacitidine starting dose 15 mg/ m2 by vein on Day -11. Stem cell transplant on Day 0. Patients with CD20+ tumors receive rituximab 375 mg/m2 by vein on Days -9.
干预措施: Rituximab (Drug)
结局指标
主要结局
Frequency of DLT
时间窗: Enrollment up to day 30 post transplant for each dosing cohort
Maximum tolerated dose (MTD) of azacitidine based on DLT was defined as any Grade 4 nonhematologic and noninfectious toxicity or any grade 3 mucositis or skin toxicity lasting \> 3 days at peak severity. For dose finding, the continunal reassessment method was used with a target DLT probability per cohort of 25%. Azacitidine doses were chosen adaptively for sucessive cohorts with a minimum size of 2 patients. Toxicity scoring followed the National Cancer Institute Common Toxicity Criteria, version 3.
Participants With Event-free Survival (EFS)
时间窗: Enrollment up to 100 days post transplant.
EFS is defined as the time from transplantation to either relapse, second tumors, or death, whichever occurred first, or last contact. EFS was analzyed by the individual disease groups rather than the cohort dose levels.
次要结局
未报告次要终点