Phase I Evaluation of Adjuvant Oral Decitabine and Tetrahydrouridine With or Without Celecoxib in Patients Undergoing Pulmonary Metastasectomy
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Table of toxicities including type, severity, time of onset, time of resolution and probable association with study regimen
研究概览
简要总结
Background:
Most patients who have surgery for cancer that has metastasized (spread) to the lungs later get more metastases that cannot be treated with surgery or chemotherapy. The drug resistance may be due to DNA changes in cancer cells that activate some genes and turn others off. Researchers want to test a combination of drugs for people with metasteses. Decitabine (DAC) may reverse the DNA changes. Tetrahydrouridine (THU) makes DAC last longer. Celecoxib may slow the progression of cancer.
Objectives:
To determine a safe dose of DAC and THU by mouth. To see if DAC-THU with or without celecoxib reactivates genes in lung metastases.
Eligibility:
Adults 18 years and older, with cancer in both lungs that can be treated with surgery.
Design:
Participants will be screened with:
Blood, lung, and heart tests
Scans
Tests for viruses
Pregnancy test
Participants will have blood and stool tests.
They will have surgery to remove metasteses in 1 lung.
About 3 weeks later, they will have lung scans. If the disease is not back, participants will get DAC and THU with or without celecoxib, by mouth for 6 weeks.
Participants will have more scans. If the disease is not worse, they will continue the study drugs for 4 more weeks.
Participants will have more scans and heart and lung tests. They will have surgery to remove metasteses from the other lung.
Participants will have weekly blood and urine tests, plus several blood draws the first 2 days of taking the drugs.
Participants will have exams and blood tests before each surgery.
Participants will have follow-up visits 1 and 3 months after the second surgery.
详细描述
Background:
- Whereas malignancies of diverse histologies express a variety of cancer testis antigens (CTAs), immune responses to these antigens appear uncommon in cancer patients, possibly due to low-level, heterogeneous antigen expression, as well as immunosuppressive regulatory T cells.
- In published studies we have demonstrated induction of NY-ESO-1 and MAGE-A3 in cancer cells of various histologies but not normal respiratory epithelial cells or fibroblasts following exposure to the DNA demethylating agent, Decitabine (DAC); up-regulation of these CTAs facilitated CTL-mediated lysis of tumor cells. We have also demonstrated eradication of pulmonary metastases in immunocompetent mice following systemic treatment with DAC and subsequent adoptive transfer of CTL recognizing the murine CTA, P1A. In a phase 1 trial, we demonstrated up-regulation of NY-ESO-1 and MAGE-A3 as well as reactivation of p16 in thoracic malignancies following intravenous 72hr DAC infusions. Chronic administration schedules are necessary for optimal gene induction in solid cancers.
- Additional studies using murine tumor models suggest that DNA demethylating agents may enhance the activity of immune checkpoint inhibitors not only by upregulating antigen presentation, but by inhibiting activity of myeloid derived suppressor cells (MDSC).
- Presently, there is no information regarding gene modulation and antitumor activity of oral epigenetic therapy in patients with solid tumors.
- In this study, the optimal frequency/dose of DAC-THU administration will be established in patients with bilateral pulmonary metastases, then an additional cohort of patients will receive DAC-THU together with celecoxib to inhibit activity of immunosuppressive Treg and myeloid derived suppressor cells. Correlative experiments will be performed to ascertain if oral epigenetic therapy modulates gene expression in pulmonary metastases and enhances antitumor immunity to these neoplasms.
- This trial is intended to establish the rationale and conditions for the use of oral DAC-THU +/- celecoxib in combination with immune checkpoint inhibitors or adoptive immunotherapy regimens targeting CTAs in patients with thoracic malignancies.
Objectives:
-To determine the pharmacokinetics, toxicities and maximum tolerated dose of oral DAC and THU with or without celecoxib in patients undergoing resection of pulmonary metastases
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Dose escalation cohort
dose escalation cohort
干预措施: decitabine (DAC) (Drug)
Dose escalation cohort
dose escalation cohort
干预措施: Tetrahydrouridine (THU) (Drug)
Expansion cohort
expansion cohort at MTD
干预措施: decitabine (DAC) (Drug)
Expansion cohort
expansion cohort at MTD
干预措施: Tetrahydrouridine (THU) (Drug)
expansion cohort with celecoxib
expansion cohort at MTD with celecoxib
干预措施: decitabine (DAC) (Drug)
expansion cohort with celecoxib
expansion cohort at MTD with celecoxib
干预措施: Tetrahydrouridine (THU) (Drug)
expansion cohort with celecoxib
expansion cohort at MTD with celecoxib
干预措施: Celecoxib (Drug)
结局指标
主要结局
Table of toxicities including type, severity, time of onset, time of resolution and probable association with study regimen
时间窗: 30 days after treatment initiation
Maximum tolerated dose
时间窗: 4 weeks after the start of study therapy
次要结局
未报告次要终点