An Open-label Phase 2 Study of Intravenous Bortezomib and Oral Panobinostat (LBH589) in Adult Patients With Relapsed/Refractory Peripheral T-cell Lymphoma or NK/T-cell Lymphoma After Failure of Conventional Chemotherapy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 25
- 试验地点
- 5
- 主要终点
- Objective Response Rate
研究概览
简要总结
The purpose of this study is to determine whether intravenous Bortezomib combined with oral Panobinostat (LBH589) are effective in treating adult patients with relapsed/refractory peripheral T-cell lymphoma or NK/T-cell lymphoma after the failure of conventional chemotherapy.
详细描述
Peripheral T-cell lymphoma (PTCL) and NK/T-cell lymphoma are uncommon diseases that are prevalent in Asia. They are associated with poor prognosis when treated with conventional chemotherapeutic regimes. Their long term disease-free survivals are dismal with only 10-30% of patients surviving long term. More intensive regimens including high dose chemotherapy with autologous stem cell transplant have been tried as primary induction treatment, but have not been shown to be beneficial. Given the rarity of PTCL and NK/T-cell lymphoma, much of the literature consists of studies with small sample size and anecdotal case reports. Therefore, no consensus exists on the best therapeutic strategy for either newly diagnosed or relapsed disease. The failure of conventional chemotherapy in this regard suggests that novel therapies including epigenetic approaches and proteasome inhibition should be explored.
Preclinical data of bortezomib and histone deacetylase inhibitors (HDIs) in T-cell and NK/T-cell lymphoma cell lines are encouraging. Bortezomib and HDIs have also separately demonstrated activity in T and NK/T-cell lymphomas in phase II studies, leading to their separate developments in phase III studies. Demonstration of synergism in these 2 agents, in part due to their dependence on overlapping pathways, suggests that they should be explored as a combination, especially when treating a disease with a very unfavourable outcome. The purpose of this phase II study is to assess the efficacy of orally-administered panobinostat, a potent class I/II pan-deacetylase inhibitor with intravenous bortezomib in this patient population.
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
- 21 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed PTCL NOS, angioimmunoblastic T-cell lymphoma, extranodal NK/T-cell lymphoma nasal type, enteropathy- type T-cell lymphoma, hepatosplenic T-cell lymphoma, ALCL (ALK-1 negative), or patients with ALK 1 expressing ALCL (ALK-1 positive) who have relapsed disease after ASCT
- •Age ≥21 years
- •Written informed consent
- •Progressive disease following at least one systemic therapy or refractory to at least one prior systemic therapy
- •Measurable disease according to the IWC criteria and/or measurable bone marrow disease by flow cytometry or morphology
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •Absolute neutrophil count of ≥1000 × 10(9)cells/L
- •Serum potassium ≥3.8 mmol/L and magnesium ≥0.85 mmol/L (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria)
- •Negative urine or serum pregnancy test on females of childbearing potential
- •All females of childbearing potential and males must use an effective barrier method of contraception during the treatment period and for at least 1 month thereafter.
排除标准
- •Chemotherapy or immunotherapy within 3 weeks of study entry
- •Concomitant use of any other anti-cancer therapy
- •Concomitant use of any other investigational agent
- •Any known cardiac abnormalities such as:
- •Congenital long QT syndrome;
- •QTcF interval >480 milliseconds (msec);
- •A myocardial infarction within 12 months of study entry;
- •Other significant ECG abnormalities including 2nd atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate < 50 beats/ min).
- •An ECG recorded at screening showing significant ST depression (ST depression of ≥2 mm, measured from isoelectric line to the ST segment at a point 60 msec at the end of the QRS complex). If in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
- •Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction <40% by MUGA scan or <50% by echocardiogram and/or MRI;
- •A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD);
- •Hypertrophic cardiomyopathy or restrictive cardiomyopathy from prior treatment or other causes (if in doubt, see ejection fraction criteria above);
- •Any cardiac arrhythmia requiring anti-arrhythmic medication;
- •Serum potassium <3.8 mmol/L or serum magnesium <0.85 mmol/L (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria)
- •Concomitant use of drugs that may cause a prolongation of the QTcF
- •Concomitant use of CYP3A4 inhibitors
- •Impaired liver, renal or other organ function not caused by lymphoma, which will interfere with the treatment schedule
- •Concomitant use of warfarin due to a potential drug interaction
- •Clinically significant active infection
- •Known infection with human immunodeficiency virus (HIV)
- •Patient has known clinically active hepatitis B or C
- •Previous extensive radiotherapy involving ≥30% of bone marrow (e.g., whole pelvis, half spine), excluding patients who have had total body irradiation as part of a conditioning regimen for stem cell transplant
- •Major surgery within 2 weeks of study entry
- •Peripheral neuropathy or neuropathic pain of Grade 2 or worse
- •Platelet count <50 × 109 cells/L or platelet count <30 × 109 cells/L if bone marrow disease involvement is documented
- •Serum creatinine >2.0 × ULN
- •Patients who are pregnant or breast-feeding
- •Patient has known hypersensitivity to any components of bortezomib (such as boron, mannitol), or panobinostat
研究组 & 干预措施
panobinostat and bortezomib
Oral Panobinostat and intravenous bortezomib
干预措施: panobinostat and bortezomib (Drug)
结局指标
主要结局
Objective Response Rate
时间窗: 1 year
次要结局
- Time to response, Duration of response, Progression-free survival, Overall survival, Safety and tolerability, Changes in disease-related symptoms and ECOG performance status.(1 year)