A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide
研究概览
简要总结
The purpose of this study is to assess pharmacokinetic and pharmacodynamic characteristics of oral lenalidomide monotherapy administered to patients with Low- or Intermediate-1-risk Myelodysplastic Syndrome (MDS).
研究设计
- 研究类型
- Interventional
- 干预模型
- Parallel
- 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
- •Must understand and voluntarily sign an informed consent form.
- •Age ≥18 years at the time of signing the informed consent form.
- •Must be able to adhere to the study visit schedule and other protocol requirements.
- •Documented diagnosis of MDS that meets International Prognostic Scoring System (IPSS) criteria for Low- to Intermediate-1-risk disease.
- •Must have a diagnosis of low- or intermediate- risk MDS without a del 5q chromosomal abnormality (patients taking 15 mg starting dose only).
- •Must be able to provide adequate bone marrow (BM) aspirate and biopsy specimens for histopathological analysis and standard cytogenetic analysis during the screening procedure.
- •Red blood cell (RBC) transfusion-dependent anemia defined as having received ≥4 transfusions of RBCs within 56 days of randomization or symptomatic anemia (hemoglobin < 9.0 g/dl).
- •Failed prior treatment with recombinant human erythropoietin (rhu-EPO) (≥ 30,000 U/week x 6) or serum erythropoietin (EPO) concentration ≥500 mU/ml (hemoglobin < 9.0 g/dl).
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or
- •Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse 1) for at least 28 days before starting study drug; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. The two methods of reliable contraception must include one highly effective method (i.e. intrauterine device [IUD], hormonal [birth control pills, injections, or implants], tubal ligation, partner's vasectomy) and one additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of contraceptive methods, if needed.
排除标准
- •Pregnant or lactating females.
- •Prior therapy with lenalidomide.
- •Proliferative white blood cell (WBC) ≥12,000/µL) chronic myelomonocytic leukemia (CMML).
- •MDS secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases.
- •Any of the following lab abnormalities:
- •Absolute neutrophil count (ANC) <500 cells/µL (0.5 x 10^9/L)
- •Platelet count <50,000/µL (50 x 10^9/L)
- •Serum creatinine > upper limit of normal (ULN)
- •Serum glutamic oxaloacetic transaminase/aspartate transaminase (SGOT/AST) or serum glutamic pyruvic transaminase/alanine transaminase (SGPT/ALT) >2.0 x ULN
- •Serum total bilirubin >2.0 mg/dL (34 µmol/L)
- •Prior ≥grade-2 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) allergic reaction to thalidomide.
- •Prior desquamating (blistering) rash while taking thalidomide.
- •Patients with ≥grade-2 neuropathy.
- •Clinically significant anemia due to factors such as iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis or gastrointestinal bleeding.
- •Use of cytotoxic chemotherapeutic agents, erythropoietin, or experimental agents (agents that are not commercially available) for the treatment of MDS within 28 days of the first day of study drug treatment.
- •Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥3 years.
- •Any serious medical condition or psychiatric illness that will prevent the patient from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study.
- •Known human immunodeficiency virus (HIV-1) positivity.
研究组 & 干预措施
10 mg Lenalidomide
Participants in the Pharmacokinetic Phase received a single 10 mg oral dose of lenalidomide on Day -7. During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.
During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.
干预措施: Lenalidomide (Drug)
10 mg Lenalidomide
Participants in the Pharmacokinetic Phase received a single 10 mg oral dose of lenalidomide on Day -7. During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.
During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.
干预措施: Recombinant human erythropoietin (Drug)
15 mg Lenalidomide Non-del 5q
Following the enrollment of the first 25 patients into the Monotherapy Phase, a second group of 15 patients with low- or intermediate-1-risk MDS not associated with a del 5q (non-del 5q) cytogenetic abnormality were enrolled to receive 15 mg of lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.
干预措施: Lenalidomide (Drug)
15 mg Lenalidomide Non-del 5q
Following the enrollment of the first 25 patients into the Monotherapy Phase, a second group of 15 patients with low- or intermediate-1-risk MDS not associated with a del 5q (non-del 5q) cytogenetic abnormality were enrolled to receive 15 mg of lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.
干预措施: Recombinant human erythropoietin (Drug)
结局指标
主要结局
Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide
时间窗: On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose.
Area under the plasma concentration-time curve from Time 0 to 5 hours postdose for lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days, calculated using the log-linear trapezoidal method.
PK Phase: Area-under-the Concentration-time Curve (AUC0-24) for Lenalidomide
时间窗: On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours post-dose.
Area under the plasma concentration-time curve from Time 0 to 24 hours post-dose for lenalidomide after a single dose, calculated using the log-linear trapezoidal method.
次要结局
- PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax)(On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose.)
- Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax)(On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose.)
- PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose(On Day -7 at predose and over the intervals of 0-5, 5-8, 8-12, and 12-24 hours postdose.)
- Marrow-infiltrating Lymphocyte (MIL) Number and Cytolytic Activity(Pre-Study and Week 16)
- Time to Grade 4 Neutropenia or Thrombocytopenia(From the date of first dose until 30 days after the last dose (up to 1218 days))
- Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level(Assessed every 28 days until study discontinuation (up to 1218 days))
- Change From Baseline in Bone Marrow Cellularity and Correlation With Grade 4 Myelosuppression(Baseline and Week 16)
- PK Phase: Terminal Half-life (t1/2)(On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose.)
- Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose(On Day 14, at predose and over the interval of 0-5 hours postdose.)
- Percentage of Participants With a Erythroid Response Across All Phases(Assessed every 28 days until study discontinuation (up to 1218 days).)