A Phase I Open-label, 2-period Study to Evaluate the Influence of Multiple Oral Doses of Rifampin on the Single Dose Pharmacokinetics of Romidepsin in Subjects With Advanced Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Celgene
- 入组人数
- 14
- 试验地点
- 3
- 主要终点
- Area Under the Plasma Concentration Time-curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t)of Romidepsin
研究概览
简要总结
The purpose of this study is to evaluate the effect and safety of multiple doses of rifampin on the pharmacokinetics of romidepsin after a single intravenous (IV) infusion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 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
- •Males and females 18 years of age or older at the time of signing the informed consent document.
- •Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.
- •Able to adhere to the study visit schedule and other protocol requirements.
- •Must have diagnosis of advanced malignancy and must have failed other available therapies considered standard of care for their disease.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Negative urine or serum pregnancy test on females of childbearing potential; and
- •All females of childbearing potential must use an effective barrier method of contraception (either an intrauterine contraceptive device [IUCD] or double barrier method using condoms or a diaphragm plus spermicide) during the treatment period and for at least 1 month thereafter. Male subjects should use a barrier method of contraception during the treatment period and for at least 3 months thereafter. Female subjects should avoid the use of estrogen-containing contraceptives, since romidepsin may reduce the effectiveness of estrogen-containing contraceptives. An in vitro binding assay determined that romidepsin competes with β-estradiol for binding to estrogen receptors.
排除标准
- •Any significant medical condition or psychiatric illness that would prevent the subject from participating in the study.
- •Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
- •Subjects with significant gastrointestinal disease that may impair drug absorption, such as subjects with a history of Cohn's disease, colectomy, gastrectomy, celiac disease, or other diseases with known malabsorption.
- •Serum potassium < 3.8 mmol/L or serum magnesium < 0.85 mmol/L (magnesium converts to 2.1 mg/dl or 1.7 mEq/L) (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria).
- •Concomitant use of drugs that may cause a significant prolongation of the corrected measurement of the time between the start of the cardiac Q wave and the end of the T wave (QTc).
- •Concomitant use of Cytochrome P 450 3A4 (CYP3A4) strong inhibitors within 1 week of trial medications.
- •Concomitant use of CYP3A4 strong inducers within 2 weeks of trial medications.
- •Concomitant use of therapeutic warfarin due to a potential drug interaction. Use of a low dose of warfarin or another anticoagulant to maintain patency of venous access port and cannulas is permitted.
- •Clinically significant active infection.
- •Known infection with Human Immunodeficiency Virus (HIV), hepatitis B, or hepatitis C.
- •Inadequate bone marrow or other organ function as evidenced by:
- •Hemoglobin < 9 g/dL (transfusions and/or erythropoietin are permitted);
- •Absolute neutrophil count (ANC) ≤ 1.0 * 10^9 cells/L [subjects with neutropenia (ANC 1-1.5) as a function of their disease may be supported with granulocyte-colony stimulating factor (G-CSF)];
- •Platelet count < 100 * 10^9 cells/L or platelet count < 75 * 10^9 cells/L if bone marrow disease involvement is documented;
- •Total bilirubin > 1.5 * upper limit of normal (ULN) or > 2.0 * ULN in the presence of demonstrable liver metastases;
- •Serum aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) > 1.5 * ULN or > 2.0 * ULN in the presence of demonstrable liver metastases; or
- •Serum creatinine > 2.0 * ULN;
- •Prior chemotherapy treatment within 3 weeks prior to the first day of romidepsin treatment (6 weeks for nitrosoureas) or prior treatment with an investigational agent within 4 weeks prior to the first day of romidepsin treatment.
- •Prior radiotherapy within 4 weeks prior to the first day of treatment. Subjects who have not fully recovered or whose acute toxicity related to prior radiotherapy has not returned to baseline are ineligible.
- •Major surgery within 2 weeks of study entry (day 1).
- •Concomitant use of any other anti-cancer therapy.
- •Concomitant use of any investigational agent.
- •Prior exposure to romidepsin (other histone deacetylase [HDAC] inhibitors are allowed).
- •Any known cardiac abnormalities, such as:
- •Congenital long measure of the time between the start of the Q wave and the end of the T wave (QT) syndrome;
- •Mean QTc formula (QTcF) interval > 450 msec;
- •A myocardial infarction within 12 months of study entry;
- •A history of coronary artery disease (CAD), e.g., angina Canadian Class II-IV. A stress imaging study should be performed for any subject whose cardiac status is uncertain. If abnormal, an angiography should be completed to define whether or not CAD is present.
- •An electrocardiogram (ECG) recorded at screening showing evidence of cardiac ischemia (ST depression of ≥ 2 mm, measured from isoelectric line to ST segment). A stress imaging study should be performed for any subject whose cardiac status is uncertain. If abnormal, an angiography should be completed to define whether or not CAD is present.
- •Congestive Heart Failure (CHF) that meets the New York Heart Association (NYHA) Class II to IV definitions (see Appendix F) and/or ejection fraction < 40% by multi gated acquisition (MUGA) scan or < 50% by echocardiogram and/or magnetic resonance imaging (MRI);
- •A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD);
- •Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes (if in doubt, see ejection fraction criteria above);
- •Uncontrolled hypertension, i.e., blood pressure (BP) of ≥ 160/95; or
- •Any cardiac arrhythmia requiring anti-arrhythmic medication.
- •Subjects who are pregnant or breast-feeding.
研究组 & 干预措施
Romidepsin and rifampin
Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8.
Rifampin 600 mg oral once daily on Days 4-8
干预措施: Romidepsin (Drug)
Romidepsin and rifampin
Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8.
Rifampin 600 mg oral once daily on Days 4-8
干预措施: Rifampin (Drug)
结局指标
主要结局
Area Under the Plasma Concentration Time-curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t)of Romidepsin
时间窗: Days 1 and 8; at 0 (pre-dose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.
AUC0-t: area under the plasma concentration time-curve from Time 0 to the time of the last quantifiable concentration (Ct), calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing.
Time to Maximum Observed Plasma Concentration (Tmax)
时间窗: Days 1 and 8; at 0 (predose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.
Time to maximum observed plasma concentration (Tmax) was obtained directly from the observed concentration versus time data.
Apparent Total Volume of Distribution (Vz).
时间窗: Days 1 and 8; at 0 (predose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.
Apparent total volume of distribution (Vz) was calculated as \[(CL)/λz\] for Romidepsin and co-administered with Rifampin.
Area Under the Plasma Concentration Time-curve From Time Zero Extrapolated to Infinity (AUC0-∞).
时间窗: Days 1 and 8; at 0 (predose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.
AUC0-∞: area under the plasma concentration time-curve from Time 0 extrapolated to infinity, calculated as \[AUCt + Ct/λz\]. λz is the apparent terminal rate constant. No AUC extrapolation was performed with unreliable λz. If the percentage of AUC extrapolated is ≥ 25%, AUC0-∞ will not be reported.
Maximum Observed Plasma Concentration (Cmax)of Romidepsin
时间窗: Days 1 and 8; at 0 (predose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.
Maximum observed plasma concentration (Cmax)was obtained directly from the observed concentration versus time data.
Estimate of the Terminal Elimination Half-life in Plasma (t1/2)
时间窗: Days 1 and 8; at 0 (predose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.
The terminal elimination half-life (t1/2) in plasma, was calculated as \[(ln 2)/λz\]. This was only calculated when a reliable estimate for λz could be obtained.
Area Under the Plasma Concentration Time-curve From Time 0 to 24-hour (AUC0-24) for Romidepsin
时间窗: Day 1 and Day 8; at 0 (predose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.
Individual and mean romidepsin plasma concentrations by treatment and scheduled time data were collected. AUC0-24: area under the plasma concentration time-curve from Time 0 to 24 hours, calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing.
Clearance (CL): Apparent Total Plasma Clearance.
时间窗: Days 1 and 8; at 0 (predose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.
The apparent total plasma clearance (CL) was calculated as \[Dose/AUC0-∞\] for Romidepsin alone and co-administered with rifampin plasma concentrations.
次要结局
- Summary of Participants With Treatment Emergent Adverse Events (TEAEs)(Day 1 up to Day 36 (28 days after the last treatment))