Phase 1 Trial of Flavopiridol in Combination With Lenalidomide in Patients With Relapsed or Refractory B-Cell CLL/SLL
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 39
- 试验地点
- 1
- 主要终点
- MTD of lenalidomide when combined with alvocidib, defined as the maximum dose level with fewer than 2 of 6 patients experiencing dose limiting toxicity (DLT)
研究概览
简要总结
This phase I trial studies the side effects and best dose of lenalidomide when given together with alvocidib in treating patients with relapsed or refractory B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Lenalidomide may stop the growth of leukemia or lymphoma by blocking blood flow to the cancer. Alvocidib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide together with alvocidib may kill more cancer cells.
详细描述
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of flavopiridol (alvocidib) in combination with lenalidomide in patients with relapsed or refractory B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
II. To define the specific toxicities and the dose limiting toxicity (DLT) of flavopiridol in combination with lenalidomide in the treatment of patients with relapsed or refractory CLL/SLL.
SECONDARY OBJECTIVES:
I. To assess preliminary efficacy of flavopiridol combined with lenalidomide in patients with relapsed/refractory CLL/SLL to justify future, rigorous phase II studies of the combination in CLL.
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 CLL/SLL according to World Health Organization (WHO) criteria, or B-cell prolymphocytic leukemia (B-PLL) arising from CLL with at least one of the following indications for treatment:
- •Progressive disease or marked splenomegaly and/or lymphadenopathy
- •Anemia (hemoglobin < 11 mg/dL) or thrombocytopenia (platelets < 100,000/mm^3)
- •Unexplained weight loss exceeding 10% of body weight over the preceding 6 months
- •National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v 4.0) grade 2 or 3 fatigue
- •Fevers > 100.5 or night sweats for greater than 2 weeks without evidence of infection
- •Progressive lymphocytosis, with an increase exceeding 50% over a 2 month period or a doubling time of less than 6 months
- •Must have at least one prior therapy that includes either fludarabine (or equivalent nucleoside analogue) or an alternative regimen if a contra-indication to fludarabine exists (i.e., autoimmune hemolytic anemia); prior therapy with flavopiridol is not permitted; prior lenalidomide is permitted provided that it has been > 6 months since the last lenalidomide dose
- •Eastern Cooperative Oncology Group (ECOG) performance status =< (Karnofsky >= 60%)
- •White blood cell count =< 150,000/mm^3
- •Absolute neutrophil count >= 1,000/mm^3
- •Platelets >= 30,000/mm^3
- •Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 X institutional ULN
- •Creatinine =< 1.5 mg/dL OR creatinine clearance >= 60 ml/min
- •Recovery to =< grade 1 from all toxicities associated with prior therapy
- •Not pregnant or breast-feeding; woman of child bearing potential should have a negative pregnancy test (serum beta-human chorionic gonadotropin [HCG]) within 7-14 days of starting cycle 1 of treatment; woman of child bearing potential should have a negative pregnancy test (serum beta-HCG) within 10-14 days of starting cycle 2, the start of lenalidomide treatment (i.e. days 14-18 of cycle 1), and an additional test within 24 hours of starting cycle 2 treatment
- •Patient must agree to use adequate contraception for 4 weeks prior to the start of lenalidomide and up to 28 days following the last dose of lenalidomide to avoid risk of pregnancy
- •Women of child-bearing potential will be required to use two methods of birth control; one "highly effective method" and one "additional effective method" as defined below:
- •Highly effective methods
- •Intrauterine device
- •Hormonal (oral contraceptive, implants)
- •Tubal ligation
- •Partner's vasectomy
- •Abstinence
- •Alternative effective methods
- •Latex condoms
- •Diaphragm
- •Cervical cap
- •Men must agree to use latex condoms
- •Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days and again within 24 hours prior to starting cycle 1 of lenalidomide; further, they must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy; all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure
- •Patients must agree not to donate blood, semen, sperm/ova during the course of taking lenalidomide and for 28 days after stopping lenalidomide treatment
- •Patients must have the ability to understand and the willingness to sign a written informed consent document
- •Patients who are glucose-6-phosphate dehydrogenase (G6PD) deficient are not eligible for this study
- •Only human immunodeficiency virus (HIV)-positive patients meeting all of the following criteria may be enrolled on this trial:
- •Cluster of differentiation (CD) 4 count > 500/mm^3
- •Not receiving highly active anti-retroviral therapy (HAART) or anti-HIV viral therapy
- •HIV viral load < 10,000 HIV messenger ribonucleic acid (mRNA) copies/mm^3
- •No history of acquired immune deficiency syndrome (AIDS)-defining illness
排除标准
- •Patients may not be receiving any other investigational agents
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated on this study
研究组 & 干预措施
Treatment (alvocidib, lenalidomide)
Patients receive alvocidib IV over 4.5 hours on days 1, 8, and 15 in course 1 followed by a week of rest. Beginning in course 2 and all subsequent courses, patients receive lenalidomide PO QD on days 1-21 and alvocidib IV over 4.5 hours on days 3, 10, and 17. Treatment repeats every 35 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alvocidib Hydrochloride (Drug)
Treatment (alvocidib, lenalidomide)
Patients receive alvocidib IV over 4.5 hours on days 1, 8, and 15 in course 1 followed by a week of rest. Beginning in course 2 and all subsequent courses, patients receive lenalidomide PO QD on days 1-21 and alvocidib IV over 4.5 hours on days 3, 10, and 17. Treatment repeats every 35 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Lenalidomide (Drug)
Treatment (alvocidib, lenalidomide)
Patients receive alvocidib IV over 4.5 hours on days 1, 8, and 15 in course 1 followed by a week of rest. Beginning in course 2 and all subsequent courses, patients receive lenalidomide PO QD on days 1-21 and alvocidib IV over 4.5 hours on days 3, 10, and 17. Treatment repeats every 35 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Treatment (alvocidib, lenalidomide)
Patients receive alvocidib IV over 4.5 hours on days 1, 8, and 15 in course 1 followed by a week of rest. Beginning in course 2 and all subsequent courses, patients receive lenalidomide PO QD on days 1-21 and alvocidib IV over 4.5 hours on days 3, 10, and 17. Treatment repeats every 35 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
结局指标
主要结局
MTD of lenalidomide when combined with alvocidib, defined as the maximum dose level with fewer than 2 of 6 patients experiencing dose limiting toxicity (DLT)
时间窗: Up to day 70
Incidence of DLT in patients treated with alvocidib and lenalidomide graded according to NCI CTCAE version 4.0
时间窗: Up to day 70
Toxicities classified as DLT during course 1 will not be considered DLT for the combination of lenalidomide and flavopiridol, but will result in patient removal from the study.
次要结局
- Plasma IL-6 and selected cytokine levels(Up to 5 years)
- B-cell activation as assessed by surface antigen (CD40, CD80, CD86, HLA-DR, and CD95) expression(Up to 5 years)
- Intracellular pharmacodynamic targets including STAT3, Mcl-1, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)(Up to 5 years)
- Response assessed by National Cancer Institute-Sponsored Working Group guidelines(Up to 5 years)
- Presence of minimal residual disease(Up to 5 years)
- Pharmacokinetic parameters of alvocidib and lenalidomide alone and in combination in plasma samples(Baseline, day 1 of course 1, and on days 2-3 of course 2)
- Progression-free survival (PFS)(Time from start of treatment to time of progression, assessed up to 5 years)
- Toxicity graded according to NCI CTCAE version 4.0(Up to 5 years)