Safety of Vorinostat in Combination With Bortezomib, Doxorubicin and Dexamethasone (VBDD) in Patients With Refractory or Relapsed Multiple Myeloma, A Phase I/II Study, Short Title: VBDD
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 34
- 试验地点
- 1
- 主要终点
- Maximal Tolerated Dose (MTD)
研究概览
简要总结
Primary objective of the study is the determination of the maximum tolerated dose (MTD) of Vorinostat (V), given in combination with fixed doses of Doxorubicin (D), Bortezomib (B) and Dexamethasone (D).
Secondary objectives are:
Assessment of safety and tolerability of VBDD; efficacy data of VBDD.
详细描述
A first cohort of three patients will be treated at the starting dose level of Vorinostat 100 mg/d, on day 1-4, 8-11, and 15-18 in combination with BDD.
The dose level of Vorinostat will be escalated in each new cohort:
if no dose limiting toxicity (DLT) has been observed in the previous dose level in 3 patient, the second cohort of 3 new patients will be treated with Vorinostat 200 mg/d and the third cohort will be given Vorinostat with 300 mg/d.
Bortezomib will be administered intravenously (i.v.) 1.3mg/m2 d1, 8, 15. Doxorubicin will be administered i.v. with a total dose of 18 mg/m2 per cycle (9 mg/m2, d1 and 8).
Dexamethasone will be administered per os (p.o.) with 40mg (first cycle) and 20mg (all other subsequent cycles) on d1, 8, 15, 22.
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
- •Patients with refractory or relapsed MM after at least first-line chemotherapy (CTx) or PBSCT (autologous and allogeneic SCT). All lines of relapse are eligible.
- •Adequate BM function
- •Adequate hepatic and renal function (AST and ALT ≤2.5 times ULN, Bilirubin ≤1.5 times ULN, eGFR >20 ml/min)
排除标准
- •Patient has had prior treatment with Vorinostat or HDAC inhibitors
- •Patients with severe hepatic impairment or acute diffuse infiltrative pulmonary and pericardial disease
- •Patient has preexisting NCI CTC ≥grade 3 neuropathy
- •Patient with known CNS MM-involvement and/or MM-related/induced meningitis
研究组 & 干预措施
1
Vorinostat. To determine the MTD, dose escalation for Vorinostat will be conducted following the "3 + 3 design The first cohort of 3 patients will be given 100mg/d on days 1-4, 8-11, 15-18. The second cohort of 3 new patients will be treated with Vorinostat 200mg/d. The third cohort will be given Vorinostat 300mg/d. Cycles will be repeated every 28 days. Maximum treatment cycles: 6. Bortezomib will be administered intravenously (i.v.) 1.3mg/m2 BSA an days 1, 8, 15.
Doxorubicin will be administered i.v. with a total dose of 18mg/m2 BSA per cycle (9mg/m2 BSA, d1 and 8).
Dexamethasone will be administered per os (p.o.) with 40mg (first cycle) or 20mg (all other cycles) on d1, 8, 15, and 22.
干预措施: Vorinostat (Drug)
1
Vorinostat. To determine the MTD, dose escalation for Vorinostat will be conducted following the "3 + 3 design The first cohort of 3 patients will be given 100mg/d on days 1-4, 8-11, 15-18. The second cohort of 3 new patients will be treated with Vorinostat 200mg/d. The third cohort will be given Vorinostat 300mg/d. Cycles will be repeated every 28 days. Maximum treatment cycles: 6. Bortezomib will be administered intravenously (i.v.) 1.3mg/m2 BSA an days 1, 8, 15.
Doxorubicin will be administered i.v. with a total dose of 18mg/m2 BSA per cycle (9mg/m2 BSA, d1 and 8).
Dexamethasone will be administered per os (p.o.) with 40mg (first cycle) or 20mg (all other cycles) on d1, 8, 15, and 22.
干预措施: Bortezomib (Drug)
1
Vorinostat. To determine the MTD, dose escalation for Vorinostat will be conducted following the "3 + 3 design The first cohort of 3 patients will be given 100mg/d on days 1-4, 8-11, 15-18. The second cohort of 3 new patients will be treated with Vorinostat 200mg/d. The third cohort will be given Vorinostat 300mg/d. Cycles will be repeated every 28 days. Maximum treatment cycles: 6. Bortezomib will be administered intravenously (i.v.) 1.3mg/m2 BSA an days 1, 8, 15.
Doxorubicin will be administered i.v. with a total dose of 18mg/m2 BSA per cycle (9mg/m2 BSA, d1 and 8).
Dexamethasone will be administered per os (p.o.) with 40mg (first cycle) or 20mg (all other cycles) on d1, 8, 15, and 22.
干预措施: Doxorubicin (Drug)
1
Vorinostat. To determine the MTD, dose escalation for Vorinostat will be conducted following the "3 + 3 design The first cohort of 3 patients will be given 100mg/d on days 1-4, 8-11, 15-18. The second cohort of 3 new patients will be treated with Vorinostat 200mg/d. The third cohort will be given Vorinostat 300mg/d. Cycles will be repeated every 28 days. Maximum treatment cycles: 6. Bortezomib will be administered intravenously (i.v.) 1.3mg/m2 BSA an days 1, 8, 15.
Doxorubicin will be administered i.v. with a total dose of 18mg/m2 BSA per cycle (9mg/m2 BSA, d1 and 8).
Dexamethasone will be administered per os (p.o.) with 40mg (first cycle) or 20mg (all other cycles) on d1, 8, 15, and 22.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Maximal Tolerated Dose (MTD)
时间窗: 28 days (within first treatment cycle)
The Maximal Tolerated Dose (MTD) is estimated as the highest dose at which less than two DLTs in 6 patients are observed in the first cycle. MTD estimation is based on the phase I part of the trial. However, the number of DLT's in the first cycle of the phase II patients will be inspected and discussed as well. The primary target variable is the occurrence of any dose-limiting toxicity (DLT) in MM patients during the first 28 days of treatment.
次要结局
- Duration of Response(up to one year after inclusion of the last patient)
- Response(up to 1 year after inclusion of the last patient)
- Quality of Life(during screening period (within 28 days) before start of treatment and at EOT (whether after the completion of the anticipated 6 cycles of chemotherapy or at an earlier time point if patient has to stop treatment because of clinical reasons))
- Overall survival (OS)(up to 1 year after inclusion of the last patient)
- Rates of Adverse Events (AE),Serious Adverse Events and AEs leading to permanent treatment discontinuation(9 months)
- Progression-free survival (PFS)(up to 1 year after inclusion of the last patient)
研究者
Monika Engelhardt
Prof. Dr. med.
University Hospital Freiburg