HDAC Inhibitor Valproic Acid as an Effective Therapy for Chronic Lymphocytic Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Best clinical response as defined by NCIWG criteria for CLL
研究概览
简要总结
OBJECTIVES
To investigate:
- the mechanism of Valproic Acid (VPA)-induced apoptosis in B-CLL
- the ability of VPA in combination with standard chemotherapy or new antitumor agents to induce a synergistic antitumor effect in chronic lymphocytic leukemia (CLL) cells
- the clinical efficacy of VPA in previously treated CLL patients.
This will be an example of a translational research study where the results of our laboratory studies will be applied to a clinical trial in the CLL clinic at CancerCare Manitoba.
详细描述
All participants will be treated with valproic acid (VPA) at a starting dose of 15 mg/kg/day orally in divided doses. This dose produces a VPA plasma level of 346-693 μM and is the recommended starting dose for patients with seizure disorder. Each week a pre-dose serum VPA level will be determined by immunoassay and the daily dose increased by 5 mg/kg/d to ensure a predose level > 1mM. Once the target dose has been achieved serum VPA levels will be determined on a monthly basis to ensure a pre dose level >1mM.
After completing 28 days of therapy participants will be examined and have lab work drawn (CBC with differential, electrolytes, BUN, creatinine, total protein, albumin, calcium, LDH, total and direct bilirubin, ALT/AST, and β2-microglobulin. Females of child bearing age will undergo a pregnancy test prior to each 28 day cycle). For participants identified as having stable or progressive disease (National Cancer Institute Criteria), Fludarabine (Flu) therapy will be added to VPA on a 28 day cycle. Oral Flu will be administered at a dose of 40 mg/m2/day on days 1-3 of a 28 day cycle in addition to VPA as described above. Dose adjustments for Flu will be based on creatinine clearance. All participants receiving fludarabine will receive irradiated blood products and pneumocystis carnii prophylaxis.
Treatment will be continued with VPA ± Flu to a maximum of six 28 day cycles. Therapy will be discontinued prior to six 28 day cycles if: a) the participant requests discontinuation, b) if the participant is unable to comply with the protocol, c) the medical care team thinks a change of therapy would be in the best interest of the participant, d) there is evidence of progressive disease after two cycles of VPA + Flu, e) if the participant experiences unacceptable toxicity attributable to the study drugs such as ≥3 non-hematological toxicity or prolonged grade 4 hematological toxicity (NCI common toxicity criteria, Table 5 of the protocol), f) if the AST/ALT increase to > 6x the upper limit of normal or g) the participant becomes pregnant.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Active CLL (as defined by the National Cancer Institute Working Group)
- •Patients must have received at least one prior therapy for CLL and have been treated with a nucleoside analogue.
- •Recruitment will be limited to those with an ECOG performance status of 2 or less.
排除标准
- •Patients who are pregnant or breastfeeding
- •Patients with a history of autoimmune cytopenias
- •Patients with platelets < 50 x 109/L or an absolute neutrophil count < 1.5X109/L
- •Patients with hepatic disease or an AST/ALT 6x above the upper limit of normal
- •Patients with a calculated creatinine clearance < 30 ml/min using the Cockroft and Gault formula
- •Patients with a history of pancreatitis
- •Patients who are receiving drugs that affect VPA protein binding or metabolism
- •Patients with active infection, HIV or active viral hepatitis
- •Patients with active secondary malignancy or who have central nervous system involvement with CLL
- •Patients diagnosed with more an aggressive lymphoproliferative disorder such as Richter's transformation
研究组 & 干预措施
1
干预措施: Valproic acid & fludarabine (Drug)
结局指标
主要结局
Best clinical response as defined by NCIWG criteria for CLL
时间窗: 6 months after commencing therapy
次要结局
- Effect of treatment on histone acetylation status; hematological toxicity (graded according to NCIWG criteria for CLL) and nonhematological toxicity (graded according to NCI common toxicity criteria)(throughout therapy)