NCT02423057已完成1 期
Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients With Advanced Solid Tumors
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
- 27
- 试验地点
- 1
- 主要终点
- To determine the safety, tolerability, and MTD of oral TdCyd administered daily for 5 days a week for 2 weeks, with one week off, q 21-day cycles
研究概览
简要总结
Background:
- Genes are made up of DNA and are the instruction book for cells. When people have cancer, some of the genes that might have slowed the growth of tumor cells were turned off. Researchers think a drug called TdCyd might help to turn these genes back on. This may slow the growth of tumors in people with cancer.
Objectives:
- To test the safety of TdCyd and to find out how it works. Also, to find out the dose of the drug that can be safely given to humans.
Eligibility:
- Adults 18 years and older who have advanced cancer that has progressed after standard treatment, or for which no effective therapy exists.
Design:
- Participants will take TdCyd by mouth. The drug is given in 21-day cycles. TdCyd is taken once a day during week 1 for 5 days. Then for 2 days participants do not take the drug. Then they take it for 5 days during week 2. No TdCyd is taken during week 3.
- Participants will keep a diary of their study drug doses.
- Participants will have tests about every 3 weeks to see how the study drugs are affecting their body. They will have blood and urine tests, a medical history, and physical exams. They may have computed tomography (CT) scans to measure their tumors. They may have an electrocardiogram, which measures the heart electrical activity.
- If participants develop any side effects, they may be asked to visit more often.
- Participants will stay in the study as long as they are tolerating TdCyd and their tumors are either stable or getting better. One month after stopping the drug, they will have a follow-up phone call.
详细描述
Background:
- Methylation-mediated silencing of genes is an epigenetic mechanism implicated in carcinogenesis; agents that inhibit this mechanism are of clinical interest because of their potential to re-activate silenced tumor suppressor genes. Two DNA hypomethylating nucleosides, 5-azacytidine (azacytidine) and 5-aza-2'-deoxycytidine (decitabine) have been approved by the FDA for the treatment of patients with myelodysplastic syndromes and certain leukemias.
- The nucleoside analog 4'-thio-2'-deoxycytidine (TdCyd) is incorporated into DNA where it engages the active site of DNA methyltransferase I (DNMT1), a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes. DNMT1 can become trapped in a covalent complex with DNA, thus depleting free enzyme and inhibiting the normal maintenance methylation of CpG sites, resulting in reactivation of tumor suppressor genes.
- Data generated at Southern Research Institute and the NCI suggest a correlation between TdCyd activity in solid tumor xenograft models and decreased levels of DNMT1.
- TdCyd offers an improvement over current DNA methyltransferase inhibitors by virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity; treatment with TdCyd is anticipated to result in the inhibition of tumor growth due to DNMT1 depletion at oral doses that are well tolerated in extended dosing schedules.
- Two patients on dose levels 6 and 7 developed Pneumocystis jiroveci pneumonia (PJP) so all patients will be administered PJP prophylaxis.
Primary Objective:
-To establish the safety, tolerability, and MTD of oral TdCyd administered daily for 5 days a week for 2 weeks, with one week off, q 21-day cycles, to patients with refractory solid tumors
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 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Patients must have histologically documented solid tumors whose disease has progressed on standard therapy or for which there is no available standard therapy.
- •Patients must have measurable or evaluable disease.
- •Age greater than or equal to 18 years of age.
- •ECOG performance status less than or equal to
- •Life expectancy > 3 months.
- •Patients must have normal organ and marrow function as defined below:
- •absolute neutrophil count greater than or equal to 1,500/mcL
- •platelets greater than or equal to 100,000/mcL
- •total bilirubin less than or equal to 1.5 times institutional upper limit of normal
- •AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of normal
- •creatinine less than or equal to 1.5 times institutional upper limit of normal
- •e. creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above 1.5 times institutional normal
- •Because nucleoside analogs are known to be teratogenic, women of child-bearing potential and men must agree to use two forms of contraception (hormonal or barrier method of birth control; abstinence; sterilization) prior to study entry, for the duration of study participation, and for 3 months after completing study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use two forms of contraception prior to the study, for the duration of study participation, and for 3 months after completion of administration of TdCyd.
- •Patients must have completed any chemotherapy, radiation therapy, or biologic therapy greater than or equal to 4 weeks or 5 half-lives (whichever is shorter) (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in a phase 0 or equivalent study and be greater than or equal to 2 weeks since any prior palliative radiation or cyberknife therapy. Patients must have recovered to grade 1 from prior toxicity or adverse events. Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment prior to study entry may continue this treatment.
- •Ability to understand and the willingness to sign a written informed consent document.
- •Willingness to provide blood and urine samples for research purposes.
- •Ability to swallow pills/capsules.
排除标准
- •Patients who are receiving any other investigational agents.
- •Pregnant women and women who are breastfeeding are excluded from this study.
- •Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to active or uncontrolled infection, immune deficiencies, known HIV infection requiring protease inhibitor therapy, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for greater than or equal to 1 month after treatment of the brain metastases. Patients should not be on anti-seizure medications. These patients may be enrolled at the discretion of the Principal Investigator.
- •Malabsorption syndrome or other conditions that would interfere with intestinal absorption.
- •INCLUSION OF WOMEN AND MINORITIES:
- •Both men and women of all races and ethnic groups are eligible for this trial.
研究组 & 干预措施
1
Experimental
TdCyd will be administered orally once a day for 5 days of each week for 2 weeks, with one week off, in 21-day cycles
干预措施: TdCyd (Drug)
结局指标
主要结局
To determine the safety, tolerability, and MTD of oral TdCyd administered daily for 5 days a week for 2 weeks, with one week off, q 21-day cycles
时间窗: Cycle 1
To determine the safety, tolerability, and MTD of oral TdCyd administered daily for 5 days a week for 2 weeks, with one week off, q 21-day cycles
次要结局
- To document preliminary evidence of TdCyd activity(Cycle 1 and 2)
研究者
研究点 (1)
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