NCT01638533已完成1 期
A Phase 1 and Pharmacokinetic Single Agent Study of Romidepsin in Patients With, Lymphomas, Chronic Lymphocytic Leukemia, and Select Solid Tumors and Varying Degrees of Liver Dysfunction
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 12
- 主要终点
- Pharmacokinetic (PK) profile of romidepsin in patients with varying degrees of hepatic dysfunction using liquid chromatography-electrospray ionization tandem mass spectrometric method
研究概览
简要总结
This phase I trial studies the side effects and best dose of romidepsin in treating patients with lymphoma, chronic lymphocytic leukemia, or solid tumors with liver dysfunction. Romidepsin may stop the growth of cancer cells by entering the cancer cells and by blocking the activity of proteins that are important for the cancer's growth and survival.
详细描述
PRIMARY OBJECTIVES:
I. To establish the safety and tolerability of romidepsin given on days 1, 8, and 15 of a 28 day cycle to patients with varying degrees of liver dysfunction (mild, moderate and severe).
II. To establish the maximum tolerated dose (MTD) and appropriate dosing recommendations for romidepsin in such patients.
III. To characterize the pharmacokinetics (PK) of romidepsin in patients with varying degrees of liver dysfunction.
SECONDARY OBJECTIVES:
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
- •Patients must have histologically or cytologically confirmed (at original diagnosis or subsequent recurrence or progression) lymphoma, chronic lymphocytic lymphoma (CLL) or solid tumor; patients with lymphoma or CLL must have radiologically or clinically evaluable disease, and be refractory to standard therapy as defined by relapse within 6 months of last treatment (see note below); patients with solid tumors must have radiologically or clinically evaluable disease that is metastatic, unresectable, progressive, or recurrent, and for which standard curative measures do not exist or are no longer effective
- •Patients with a liver mass, raised alpha-fetoprotein level (>= 500 ng/mL) and positive serology for hepatitis, consistent with a diagnosis of hepatocellular carcinoma will be eligible without the need for pathologic confirmation of the diagnosis
- •Patients with prostate cancer, renal cell cancer, neuroendocrine tumors, lung cancer, colorectal cancers, soft tissue sarcomas, glioma and thyroid cancer are excluded in the normal and mild cohorts due to a lack of efficacy in these tumor types in phase 2 studies; patients with breast, pancreatic, bladder, head and neck cancers, as well as melanoma and other malignancies are eligible
- •Note: patients with prostate cancer, renal cell cancer, lung cancer, colorectal cancers, soft tissue sarcomas, glioma and thyroid cancer are allowed to enroll in the moderate and severe cohorts provided the patients:
- •Sign a separate consent form which outlines the lack of efficacy observed in prior studies
- •Are consented to the study by a protocol-specified designee who is not their longitudinal oncologist; patients with neuroendocrine tumors are still excluded from the moderate and severe cohorts
- •Note: as romidepsin is approved for patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) or cutaneous T cell lymphoma (CTCL), these patients would be eligible WITHOUT the requirement of having 'relapsed within 6 months of last treatment'
- •Life expectancy of > 3 months
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- •Hemoglobin >= 9 g/dL (transfusions and/or erythropoietin are permitted)
- •Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- •Platelets >= 100 x 10^9/L (or platelet count >= 30 x 10^9 cells/L in patients with lymphoma or CLL if bone marrow disease involvement is documented)
- •Creatinine =< twice upper limit institutional normal
- •Patients with abnormal liver function will be eligible and will be grouped according to the criteria below
- •Group A (normal hepatic function)
- •Bilirubin =< upper limit of normal (ULN) and aspartate aminotransferase (AST) =< ULN
- •Group B (mild hepatic dysfunction)
- •B1: bilirubin =< ULN and AST > ULN
- •B2: bilirubin > ULN but =< 1.5 x ULN and any AST
- •Group C (moderate hepatic dysfunction)
- •Bilirubin > 1.5 x ULN to =< 3 x ULN and any AST
- •Group D (severe hepatic dysfunction)
- •Bilirubin > 3 x ULN and up to investigators discretion and any AST
- •Patients with active hemolysis should be excluded; no distinction will be made between liver dysfunction due to metastases and liver dysfunction due to other causes; registration laboratory investigations will be used to assign a patient to a hepatic function group; liver function tests should be repeated within 24 hours prior to starting initial therapy and may result in the patients' group assignment being altered if different to registration test results
- •Patients with brain metastases who require corticosteroids or non-enzyme inducing anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to enrollment; patients with known brain metastases should have completed brain irradiation (whole brain or gamma knife) more than 4 weeks before starting the protocol; patients on enzyme inducing anticonvulsants are not eligible; note that patients should have had their steroids tapered to low dose (i.e. < 1.5 mg of dexamethasone/day) due to the potential for higher dexamethasone doses to induce CYP3A4
- •Patients with biliary obstruction for which a stent has been placed are eligible, provided the shunt has been in place for at least 10 days prior to the first dose of romidepsin and the liver function has stabilized; two measurements at least 2 days apart that put the patient in the same hepatic dysfunction stratum will be accepted as evidence of stable hepatic function; there should be no evidence of biliary sepsis
- •Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or PK of romidepsin will be determined following review of their case by the site principal investigator
- •Patients treated with any of the medications prohibited must discontinue their use at least 7 days prior to the first dose of romidepsin; certain other agents that interact with the CYP3A4 system may be used with caution
- •Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; note: since romidepsin binds to the estrogen receptor, the effectiveness of estrogen containing contraceptives may be reduced
- •Human immunodeficiency virus (HIV)-positive patients who are not receiving: agents with the potential for PK interactions with romidepsin or hepatotoxic antiretrovirals (nucleoside reverse-transcriptase inhibitors [NRTIs]: abacavir, didanosine, emtricitabine, lamivudine, stavudine, and zidovudine), dual protease inhibitor (PI)-based regimens except low-dose boosting with ritonavir, atazanavir, indinavir, maraviroc, and nevirapine may be eligible; additionally, the HIV-positive patients should have a cluster of differentiation (CD)4 count > 250/mm^3; if the specific cause of hepatic dysfunction is unknown, the patient should be worked up for other viral causes of hepatitis and their eligibility determined after consultation with the principal investigator
- •Patients who have received prior romidepsin use are eligible
- •Ability to understand and the willingness to sign a written informed consent document
排除标准
- •Patients who have had (prior to entering the study): major surgery and biologic/antibody therapies (including immunotherapies) are not permitted within 4 weeks of romidepsin administration; anti-cancer therapy including chemotherapy, radiotherapy, hormonal (with the exception of hormones for thyroid conditions), and other investigational agents will not be allowed within 14 days or five (5) half-lives (whichever is longer) prior to the first dose of romidepsin (6 weeks for nitrosoureas or mitomycin C); additionally, participants must have recovered to less than grade 2 clinically significant adverse effect(s)/toxicity(ies) of the previous therapy, with the exception of alopecia, unless approved by the principal investigator
- •Patients with prostate cancer, renal cell cancer, neuroendocrine tumors, lung cancer, colorectal cancers, soft tissue sarcomas, glioma, and thyroid cancer are excluded in the normal and mild cohorts due to a lack of efficacy in these tumor types in phase 2 studies; patients with prostate cancer, renal cell cancer, lung cancer, colorectal cancers, soft tissue sarcomas, glioma and thyroid cancer are allowed to enroll in the moderate and severe cohorts only; patients with neuroendocrine tumors are still excluded from the moderate and severe cohorts
- •Patients may not be receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to romidepsin, including cyclic tetrapeptide compounds
- •Concurrent medications associated with a known risk of corrected QT interval (QTc) prolongation and/or Torsades de Pointes are not allowed within 2 weeks of initiation of study treatment; those medications listed as a possible risk for causing QTc prolongation and Torsades de Pointes will be allowed, although if an alternative medication can be substituted, that would be preferable; granisetron is an acceptable antiemetic on this study, but if a patient must take ondansetron, they may NOT take any other concomitant agents which might impact their QTc
- •Thiazolidinedione agents such as rosiglitazone and pioglitazone are not permitted
- •Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
- •Patients with current evidence of significant cardiovascular disease (New York Heart Association class III or IV cardiac disease), symptomatic congestive heart failure, dilated/hypertrophic or restrictive cardiomyopathy, myocardial infarction (within the past 6 months), unstable angina, unstable arrhythmia or a need for anti-arrhythmic therapy (use of medications for rate control for atrial fibrillation is allowed such as calcium channel blockers and beta-blockers, if stable medication for at least last month prior to initiation of romidepsin treatment and medication not listed as causing Torsades de Pointes), or evidence of acute ischemia on electrocardiogram (ECG); marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval > 450 msec*; long QT syndrome; the required use of concomitant medication that may cause Torsades de Pointes or may cause a significant prolongation of the QTc
- •Note: due to difficulties assessing QTc in patients with heart block, they may be eligible if deemed safe by a cardiologist; if a patient must take ondansetron as their antiemetic, their QTc may NOT be over 450 (no exception for patients with heart block)
- •Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with this drug
- •Warfarin is not permitted
研究组 & 干预措施
Treatment (romidepsin)
Experimental
Patients receive romidepsin IV over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Treatment (romidepsin)
Experimental
Patients receive romidepsin IV over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Romidepsin (Drug)
结局指标
主要结局
Pharmacokinetic (PK) profile of romidepsin in patients with varying degrees of hepatic dysfunction using liquid chromatography-electrospray ionization tandem mass spectrometric method
时间窗: 0, 1, 2, 3, 4, 4.25, 4.5, 5, 6, 8, 10, 24, and 48 hours after initiation of the infusion on day 1
Pharmacokinetic variables will be tabulated and descriptive statistics calculated for each function group. Geometric means and coefficients of variation will be presented for maximum concentration and area under the curve for each group.
Maximum tolerated dose of romidepsin in groups of patients with varying degree of hepatic dysfunction according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0
时间窗: 28 days
Analyses will be descriptive in nature. The observed toxicities will be characterized by dose level within each category of liver dysfunction (mild, moderate, severe, and liver transplant). These results will be summarized in relation to what is known about romidepsin in a population without liver dysfunction (as defined in this protocol).
Dose-limiting toxicity of romidepsin in groups of patients with varying degree of hepatic dysfunction according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0
时间窗: 28 days
In order to define levels of hepatic impairment at which dose modifications of romidepsin are required, data will be combined across hepatic dysfunction groups to evaluate the association between toxicity, dose, and liver assay level(s). The outcome variable, drug tolerance and dose-limiting toxicities will be modeled as function of dose and liver assay using multivariate linear regression. Higher order terms of the predictor variables and interactions will be included if there is evidence of non-linear and/or non-additive associations.
次要结局
- Child-Pugh classification of hepatic dysfunction(Baseline)
- Antitumor activity assessed using Response Evaluation Criteria in Solid Tumors and the International Workshop Lymphoma Response Criteria(Up to 30 days)
研究者
研究点 (12)
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