Belinostat Combined With Azacitidine/Gemcitabine/Busulfan/Melphalan With Autologous Stem-Cell Transplantation in Refractory or Relapsed Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Maximum Tolerated Dose (MTD) of Belinostat Combined with Azacitidine and Gemcitabine/Busulfan/Melphalan (AZA-GemBuMel) in Participants with Refractory or Poor-Risk Relapsed Lymphoma
研究概览
简要总结
The goal of this clinical research study is to find the highest tolerable dose of belinostat that can be given in combination with azacitidine, gemcitabine, busulfan, and melphalan to patients who are scheduled to have a stem cell transplant. If you have diffuse large B-cell lymphoma (DLBCL), you will also receive rituximab. Researchers also want to learn about the safety and effectiveness of this combination.
详细描述
Study Groups:
If you are found to be eligible to take part in this study, you will be assigned to a dose level of belinostat based on when you join this study. Up to 5 dose levels of belinostat will be tested. At least 2 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 belinostat is found.
All participants will receive the same dose level of azacitidine, gemcitabine, busulfan, melphalan. All patients with DLBCL will also receive the same dose of rituximab. However, if the first group has intolerable side effects, the dose level of gemcitabine may be lowered for all other groups.
Busulfan Test Dose:
In stem cell transplants, the days before you receive your stem cells are called minus days. The day you receive the stem cells is called Day 0. The days after you receive your stem cells are called plus days.
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
- 15 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with:
- •DLBCL with one of the following: 2.1.
- •Primary refractory (no CR to 1st line). 2.1.
- •High-risk relapse (CR1 <6 months, secondary IPI >1, high LDH). 2.1.
- •Refractory relapse: No response (SD or PD) to >/= 1 line of salvage. 2.
- •Hodgkin's with one of the following: 2.2.
- •Primary refractory (no CR to 1st line or PD within 3 months). 2.2.
- •High-risk relapse (CR1 <1 year, extranodal relapse, B symptoms). 2.2.
- •Refractory relapse: No response (SD or PD) to >/= 1 line of salvage. 2.
- •T-NHL with one of the following: 2.3.
- •Primary refractory (</= CR to 1st line or relapse within 6 months). 2.3.
- •Nonresponsive (SD/PD) to >/= 1 line of salvage. 2.
- •Burkitt's or lymphoblastic lymphoma with one of the following: 2.4.
- •Primary refractory (</= CR to 1st line or relapse within 6 months). 2.4.
- •Refractory to at least 1 line of salvage (SD/PD).
- •Adequate renal function, as defined by estimated serum creatinine clearance >/= 50 ml/min and/or serum creatinine </= 1.8 mg/dL.
- •Adequate hepatic function (SGOT and/or serum glutamate pyruvate transaminase (SGPT) </= 3 x upper limit of normal (ULN); bilirubin and ALP </= 2 x ULN.
- •Adequate pulmonary function with forced expiratory volume at one second (FEV1), forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (DLCO) (corrected for Hgb) >/= 50%.
- •Adequate cardiac function with left ventricular ejection fraction >/= 40%. No uncontrolled arrhythmias or symptomatic cardiac disease.
- •Negative Beta human chorionic gonadotropin (HCG) in woman with child-bearing potential.
排除标准
- •Grade >/= 3 non-hematologic toxicity from previous therapy that has not resolved to </= G
- •Prior whole brain irradiation.
- •Corrected QT interval (QTc) longer than 500 ms.
- •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.
- •Active infection requiring parenteral antibiotics.
- •HIV infection, unless receiving effective antiretroviral therapy with undetectable viral load and normal cluster of differentiation 4 (CD4) counts.
- •Radiation therapy in the month prior to enrollment.
研究组 & 干预措施
Belinostat/Gem/Bu/Mel + AutoSCT
Busulfan "test dose" administered by vein on Day -10. Test dose of 32 mg/m2 based on actual body weight. Busulfan pharmacokinetics performed with the test dose and the first dose on Day -8. Doses on Days -6 and -5 subsequently adjusted to target an area under curve (AUC) of 4,000 microMol.min-1.
Caphosol oral rinses 30 mL four times a day used from Day -8. Oral Glutamine, 15 g swished, gargled and swallowed four times a day starting on Day -8.
Pyridoxine 100 mg by vein or mouth three times a day staring on Day -1. Starting dose of Belinostat 100 mg/ m2/day by vein on Day -9 through Day -2. Azacitidine 15 mg/m2/day by vein on Day -9 through Day -2. Participants with cluster of differentiation antigen 20 (CD20+) tumors receive Rituximab 375 mg/m2 by vein on Day -9.
Gemcitabine 75 mg/m2 by vein administered as a loading dose followed by prolonged infusion on Days -8 and -3.
Melphalan 60 mg/m2/d by vein on Day -2. Stem cell transplant by vein given on Day 0.
干预措施: Busulfan (Drug)
Belinostat/Gem/Bu/Mel + AutoSCT
Busulfan "test dose" administered by vein on Day -10. Test dose of 32 mg/m2 based on actual body weight. Busulfan pharmacokinetics performed with the test dose and the first dose on Day -8. Doses on Days -6 and -5 subsequently adjusted to target an area under curve (AUC) of 4,000 microMol.min-1.
Caphosol oral rinses 30 mL four times a day used from Day -8. Oral Glutamine, 15 g swished, gargled and swallowed four times a day starting on Day -8.
Pyridoxine 100 mg by vein or mouth three times a day staring on Day -1. Starting dose of Belinostat 100 mg/ m2/day by vein on Day -9 through Day -2. Azacitidine 15 mg/m2/day by vein on Day -9 through Day -2. Participants with cluster of differentiation antigen 20 (CD20+) tumors receive Rituximab 375 mg/m2 by vein on Day -9.
Gemcitabine 75 mg/m2 by vein administered as a loading dose followed by prolonged infusion on Days -8 and -3.
Melphalan 60 mg/m2/d by vein on Day -2. Stem cell transplant by vein given on Day 0.
干预措施: Caphosol (Drug)
Belinostat/Gem/Bu/Mel + AutoSCT
Busulfan "test dose" administered by vein on Day -10. Test dose of 32 mg/m2 based on actual body weight. Busulfan pharmacokinetics performed with the test dose and the first dose on Day -8. Doses on Days -6 and -5 subsequently adjusted to target an area under curve (AUC) of 4,000 microMol.min-1.
Caphosol oral rinses 30 mL four times a day used from Day -8. Oral Glutamine, 15 g swished, gargled and swallowed four times a day starting on Day -8.
Pyridoxine 100 mg by vein or mouth three times a day staring on Day -1. Starting dose of Belinostat 100 mg/ m2/day by vein on Day -9 through Day -2. Azacitidine 15 mg/m2/day by vein on Day -9 through Day -2. Participants with cluster of differentiation antigen 20 (CD20+) tumors receive Rituximab 375 mg/m2 by vein on Day -9.
Gemcitabine 75 mg/m2 by vein administered as a loading dose followed by prolonged infusion on Days -8 and -3.
Melphalan 60 mg/m2/d by vein on Day -2. Stem cell transplant by vein given on Day 0.
干预措施: Glutamine (Drug)
Belinostat/Gem/Bu/Mel + AutoSCT
Busulfan "test dose" administered by vein on Day -10. Test dose of 32 mg/m2 based on actual body weight. Busulfan pharmacokinetics performed with the test dose and the first dose on Day -8. Doses on Days -6 and -5 subsequently adjusted to target an area under curve (AUC) of 4,000 microMol.min-1.
Caphosol oral rinses 30 mL four times a day used from Day -8. Oral Glutamine, 15 g swished, gargled and swallowed four times a day starting on Day -8.
Pyridoxine 100 mg by vein or mouth three times a day staring on Day -1. Starting dose of Belinostat 100 mg/ m2/day by vein on Day -9 through Day -2. Azacitidine 15 mg/m2/day by vein on Day -9 through Day -2. Participants with cluster of differentiation antigen 20 (CD20+) tumors receive Rituximab 375 mg/m2 by vein on Day -9.
Gemcitabine 75 mg/m2 by vein administered as a loading dose followed by prolonged infusion on Days -8 and -3.
Melphalan 60 mg/m2/d by vein on Day -2. Stem cell transplant by vein given on Day 0.
干预措施: Pyridoxine (Drug)
Belinostat/Gem/Bu/Mel + AutoSCT
Busulfan "test dose" administered by vein on Day -10. Test dose of 32 mg/m2 based on actual body weight. Busulfan pharmacokinetics performed with the test dose and the first dose on Day -8. Doses on Days -6 and -5 subsequently adjusted to target an area under curve (AUC) of 4,000 microMol.min-1.
Caphosol oral rinses 30 mL four times a day used from Day -8. Oral Glutamine, 15 g swished, gargled and swallowed four times a day starting on Day -8.
Pyridoxine 100 mg by vein or mouth three times a day staring on Day -1. Starting dose of Belinostat 100 mg/ m2/day by vein on Day -9 through Day -2. Azacitidine 15 mg/m2/day by vein on Day -9 through Day -2. Participants with cluster of differentiation antigen 20 (CD20+) tumors receive Rituximab 375 mg/m2 by vein on Day -9.
Gemcitabine 75 mg/m2 by vein administered as a loading dose followed by prolonged infusion on Days -8 and -3.
Melphalan 60 mg/m2/d by vein on Day -2. Stem cell transplant by vein given on Day 0.
干预措施: Belinostat (Drug)
Belinostat/Gem/Bu/Mel + AutoSCT
Busulfan "test dose" administered by vein on Day -10. Test dose of 32 mg/m2 based on actual body weight. Busulfan pharmacokinetics performed with the test dose and the first dose on Day -8. Doses on Days -6 and -5 subsequently adjusted to target an area under curve (AUC) of 4,000 microMol.min-1.
Caphosol oral rinses 30 mL four times a day used from Day -8. Oral Glutamine, 15 g swished, gargled and swallowed four times a day starting on Day -8.
Pyridoxine 100 mg by vein or mouth three times a day staring on Day -1. Starting dose of Belinostat 100 mg/ m2/day by vein on Day -9 through Day -2. Azacitidine 15 mg/m2/day by vein on Day -9 through Day -2. Participants with cluster of differentiation antigen 20 (CD20+) tumors receive Rituximab 375 mg/m2 by vein on Day -9.
Gemcitabine 75 mg/m2 by vein administered as a loading dose followed by prolonged infusion on Days -8 and -3.
Melphalan 60 mg/m2/d by vein on Day -2. Stem cell transplant by vein given on Day 0.
干预措施: Azacitidine (Drug)
Belinostat/Gem/Bu/Mel + AutoSCT
Busulfan "test dose" administered by vein on Day -10. Test dose of 32 mg/m2 based on actual body weight. Busulfan pharmacokinetics performed with the test dose and the first dose on Day -8. Doses on Days -6 and -5 subsequently adjusted to target an area under curve (AUC) of 4,000 microMol.min-1.
Caphosol oral rinses 30 mL four times a day used from Day -8. Oral Glutamine, 15 g swished, gargled and swallowed four times a day starting on Day -8.
Pyridoxine 100 mg by vein or mouth three times a day staring on Day -1. Starting dose of Belinostat 100 mg/ m2/day by vein on Day -9 through Day -2. Azacitidine 15 mg/m2/day by vein on Day -9 through Day -2. Participants with cluster of differentiation antigen 20 (CD20+) tumors receive Rituximab 375 mg/m2 by vein on Day -9.
Gemcitabine 75 mg/m2 by vein administered as a loading dose followed by prolonged infusion on Days -8 and -3.
Melphalan 60 mg/m2/d by vein on Day -2. Stem cell transplant by vein given on Day 0.
干预措施: Gemcitabine (Drug)
Belinostat/Gem/Bu/Mel + AutoSCT
Busulfan "test dose" administered by vein on Day -10. Test dose of 32 mg/m2 based on actual body weight. Busulfan pharmacokinetics performed with the test dose and the first dose on Day -8. Doses on Days -6 and -5 subsequently adjusted to target an area under curve (AUC) of 4,000 microMol.min-1.
Caphosol oral rinses 30 mL four times a day used from Day -8. Oral Glutamine, 15 g swished, gargled and swallowed four times a day starting on Day -8.
Pyridoxine 100 mg by vein or mouth three times a day staring on Day -1. Starting dose of Belinostat 100 mg/ m2/day by vein on Day -9 through Day -2. Azacitidine 15 mg/m2/day by vein on Day -9 through Day -2. Participants with cluster of differentiation antigen 20 (CD20+) tumors receive Rituximab 375 mg/m2 by vein on Day -9.
Gemcitabine 75 mg/m2 by vein administered as a loading dose followed by prolonged infusion on Days -8 and -3.
Melphalan 60 mg/m2/d by vein on Day -2. Stem cell transplant by vein given on Day 0.
干预措施: Melphalan (Drug)
Belinostat/Gem/Bu/Mel + AutoSCT
Busulfan "test dose" administered by vein on Day -10. Test dose of 32 mg/m2 based on actual body weight. Busulfan pharmacokinetics performed with the test dose and the first dose on Day -8. Doses on Days -6 and -5 subsequently adjusted to target an area under curve (AUC) of 4,000 microMol.min-1.
Caphosol oral rinses 30 mL four times a day used from Day -8. Oral Glutamine, 15 g swished, gargled and swallowed four times a day starting on Day -8.
Pyridoxine 100 mg by vein or mouth three times a day staring on Day -1. Starting dose of Belinostat 100 mg/ m2/day by vein on Day -9 through Day -2. Azacitidine 15 mg/m2/day by vein on Day -9 through Day -2. Participants with cluster of differentiation antigen 20 (CD20+) tumors receive Rituximab 375 mg/m2 by vein on Day -9.
Gemcitabine 75 mg/m2 by vein administered as a loading dose followed by prolonged infusion on Days -8 and -3.
Melphalan 60 mg/m2/d by vein on Day -2. Stem cell transplant by vein given on Day 0.
干预措施: Stem Cell Transplant (Procedure)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Belinostat Combined with Azacitidine and Gemcitabine/Busulfan/Melphalan (AZA-GemBuMel) in Participants with Refractory or Poor-Risk Relapsed Lymphoma
时间窗: 30 days
For purpose of dose-finding, "toxicity" defined as any of the following events occurring within 30 days from the start of Belinostat infusion : 1. any grade 4 or 5 non-hematologic toxicity, or 2. any grade 3 or 4 mucositis, or 3. any grade 3 or 4 skin toxicity lasting \> 5 days at peak severity Optimal dose defined as that for which the posterior mean of Pr(toxicity within 30 days \| dose) given the current data is closest to 0.30.
次要结局
- Treatment Related Mortality (TRM100)(100 days after stem cell transplant)