A Phase I Open-label, 2-period Study to Evaluate the Influence of Multiple Oral Doses of Ketoconazole 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
- 15
- 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 ketoconazole 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 ketoconazole
Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8.
Ketoconazole 400 mg oral once daily on Days 4-8
干预措施: Romidepsin (Drug)
Romidepsin and ketoconazole
Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8.
Ketoconazole 400 mg oral once daily on Days 4-8
干预措施: Ketoconazole (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. For AUC0-t, an analysis of variance (ANOVA) model was used to estimate the ratio of geometric means and its 90% CI between romidepsin alone and romidepsin in the presence to ketoconazole.
Time to Maximum Observed Plasma Concentration (Tmax)
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.
Tmax: time to maximum observed Tmax, 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.
Vz: apparent total volume of distribution, calculated as \[(CL)/λz\].
Area Under the Plasma Concentration Time-curve From Time 0 to 24-hour (AUC 0-24)
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
AUC 0-24: 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; for AUC 0-24 an analysis of variance (ANOVA) model was used to estimate the ratio of geometric means and its 90% confidence interval (CI) between romidepsin alone and romidepsin in the presence of ketoconazole
Area Under the Plasma Concentration Time-curve From Time 0 Extrapolated to Infinity (AUC0-∞)
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-∞: area under the plasma concentration time-curve from Time 0 extrapolated to infinity, calculated as \[AUCt + Ct/λz\].
Maximum Observed Plasma Concentration (Cmax)
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.
Cmax: maximum observed plasma concentration, obtained directly from the observed concentration versus time data; for Cmax, an analysis of variance (ANOVA) model was used to estimate the ratio of geometric means and its 90% confidence interval (CI) between romidepsin alone and romidepsin in the presence of ketoconazole
Apparent Total Plasma Clearance (CL)
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.
Apparent total plasma clearance, (CL) calculated as \[Dose/AUC 0-∞\].
Estimate of the Terminal Elimination Half-life in Plasma (t1/2)
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.
Terminal elimination half-life (t1/2) in plasma, was calculated as \[(ln 2)/λz\]
次要结局
- Summary of Participants With Treatment Emergent Adverse Events (TEAEs)(Day 1 up to Day 36 (28 days after last treatment))