Phase I Trial of Carfilzomib (PR-171) in Combination With Vorinostat (SAHA) in Patients With Relapsed/Refractory B-Cell Lymphomas
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Number of Participants who experience Adverse Events as a Measure of Safety and Tolerability
研究概览
简要总结
This will be a phase I study of carfilzomib in combination with vorinostat in patients with relapsed/refractory B-cell lymphomas. Combination therapy with proteosome inhibitor PR-171 and HDAC inhibitors is highly synergistic in primary DLBCL cells, and both classes of drugs can also synergize powerfully to induce cell death in bortezomib-resistant cells. The purpose of this study is to see if vorinostat can combine with carfilzomib and to safely find the recommended phase II dose.
详细描述
Study Drugs:
Vorinostat, a class I/II pan-histone deacetylase inhibitor (HDACI), was the first approved agent og this class on the basis of activity in refractory cutaneous T-cell Lymphoma. Lethal mechanisms include anti-apoptotic protein down-regulation, up-regulation of proapoptotic proteins, induction of ROS, death receptor up-regulation, and disruption of chaperone function and DNA-repair proteins.
Carfilzomib, is a irreversible proteasome inhibitor of the epoxyketone class that exhibits a high level of selectivity for the proteosome. This agent induced a dose- and time-dependent inhibition of proliferation, ultimately leading to apoptosis.
Study Drug Administration:
If you are found to be eligible to take part in this study:
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
- •Histologically confirmed B-cell lymphomas, excluding CLL (Chronic Lymphocytic Leukemia), that is recurrent or refractory after at least one prior therapy and for which no other potentially curative therapy is available.
- •Age ≥ 18 years
- •ECOG Performance Status (PS) ≤ 2
- •Laboratory parameters
- •if SLL, lymphocyte count < 5,000/µL
- •Absolute neutrophil count ≥ 1000/µL
- •Platelets ≥ 75,000/µL
- •Creatinine ≤ 1.5x upper limit of normal or calculated creatinine clearance > 40mL/min
- •AST, ALT ≤ 2.5 x upper limit of normal (ULN)
- •Bilirubin ≤ 2.0 mg/mL
- •Serum potassium ≥ 3.5 mEq/L and serum magnesium ≥ 1.7 mEq/dL (electrolytes may be corrected with supplementation).
- •PT < 1.5 x ULN and PTT < 1.2 x ULN (unless receiving therapeutic anticoagulation).
- •Patient is, in investigator's opinion, willing and able to comply with the protocol requirements and offers written informed consent.
- •Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control ( i.e., oral injectable hormonal methods; barrier methods such as intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence)for the duration of the study.
- •Male subject agrees to use an acceptable method for contraception for the duration of study.
排除标准
- •History of brain metastasis including leptomeningeal metastasis.
- •Chemotherapy of radiotherapy within 3 weeks prior to entering the study.
- •Prior histone deacetylase inhibitor as cancer treatment.
- •Concurrent treatment with other investigational agents or cancer treatment.
- •Unable to take oral medications.
- •Active ischemic heart disease or congestive heart failure. If there is suspicion of cardiac disease, left ventricular ejection fraction (LVEF) must be ≥ 45%, otherwise study to evaluate EF is not required.
- •Persistent blood pressure (BP) of ≥ 160/95 (three separate readings on different days).
- •History of allergic reactions attributed to compounds of similar chemical or biological composition to carfilzomib and vorinostat.
- •Known clinical significant infection including infection with human immunodeficiency virus (HIV), or active hepatitis B or C, requiring treatment.
- •Serious medical or psychiatric illness likely to interfere with patient participation.
- •Pregnant or nursing. Confirmation that a woman is not pregnant must be established by a negative serum pregnancy test result obtained at screening.
- •Pregnancy testing is not required for post-menopausal or surgically sterilized women.
- •No prior allogeneic stem cell transplant.
- •Patients scheduled for any type of stem cell transplant within 4 weeks of treatment.
- •Patients who have valproic acid for epilepsy can enroll, provided that they stopped drug at least 30 days prior to enrollment and they will be on a stable, effective dose of an alternative anti-seizure medication.
研究组 & 干预措施
Vorinostat + Carfilzomib
干预措施: Vorinostat (Drug)
结局指标
主要结局
Number of Participants who experience Adverse Events as a Measure of Safety and Tolerability
时间窗: From date of study entry until the 30 days after the last dose of study treatment.
Determine the recommended phase II doses for the combination of carfilzomib and vorinostat in patients with relapsed or refractory B cell lymphoma.
次要结局
- Number of Participants who Respond to Treatment(From the date of completion of first cycle of treatment until the date of best response to treatment, as determined by restaging scans)
研究者
Jonathan Friedberg
Professor
University of Rochester