Phase I/II Evaluation of Oral Decitabine/Tetrahydrouridine as Epigenetic Priming for Pembrolizumab Immune Checkpoint Blockade in Inoperable Locally Advanced or Metastatic Non-Small Cell Lung Cancers, Esophageal Carcinomas, or Pleural Mesotheliomas
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of Decitabine
研究概览
简要总结
Background:
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Lung cancer is the leading cause of cancer-related death in the United States. Most people with lung cancer are already in the advanced stages of the disease by the time they see a doctor. Researchers want to see if combining an approved drug with two new drugs can help.
Objective:
To study if tetrahydrouridine-decitabine (THU-DAC) with pembrolizumab is safe and effective in people with non-small cell lung cancer that cannot be removed by surgery.
Eligibility:
People 18 years and older who have NSCLC that cannot be removed by surgery
Design:
Participants will be screened with
- Medical history
- Physical exam
- Blood and urine tests
- Tests of heart and lung function
They may have a small tumor sample taken (biopsy). They may have tumor scans.
Before starting treatment, participants will repeat the screening tests. They will also give a stool sample.
The study will be done in 3-week cycles for up to 6 cycles.
- Participants will take the 2 study drugs by mouth 3-5 days a week.
- Participants will get pembrolizumab in a vein for 30 minutes 1 day each cycle.
Participants will keep a study medication diary.
During cycle 1, participants will have blood taken multiple times on days 1 and 2.
Every 3 cycles, participants will repeat screening tests.
Participants will have a mandatory tumor biopsy.
When they finish treatment, participants will have a physical exam and blood tests.
详细描述
Background:
- Non-small cell lung cancers (NSCLC) esophageal cancer (EsC) and malignant pleural mesotheliomas (MPM) account for approximately 185,000 deaths annually in the United States, with over two thirds of patients presenting with advanced, incurable disease. 1st-line platinum-based chemotherapy for advanced NSCLC, esophageal cancer (ESCs) or malignant pleural mesothelioma (MPM) produces transient responses at best, with most patients succumbing to disease within 12-16 months following diagnosis.
- Recent randomized clinical trials have demonstrated response rates approximating 20% in unselected patients with advanced NSCLC or EsC, and nearly 45% in patients with tumors exhibiting high level expression of programmed death ligand 1 (PD-L1) following administration of pembrolizumab, a humanized monoclonal anti-Programmed cell death protein 1 (PD-1) antibody.
- Approximately 17% of unselected MPM patients have exhibited objective responses following administration of pembrolizumab or other PD-1 inhibitors.
- Preclinical studies have demonstrated that epigenetic drugs such as deoxyribonucleic acid (DNA) demethylating agents and histone deacetylase (HDAC) inhibitors can prime cancer cells and tumor microenvironments thereby enhancing efficacy of immune checkpoint inhibitors.
- Although a potent DNA demethylating agent, Decitabine has poor bioavailability and inconsistent distribution in solid tumors due to rapid inactivation by cytidine deaminase (CDA) which is present in high levels in many organs.
- Recent studies in rodents and nonhuman primates, as well as a Phase 1 clinical trial (NCT#01685515) in patients with sickle cell disease have demonstrated that oral tetrahydrouridine (THU), an inhibitor of CDA, significantly enhances bioavailability/solid-tissue-distribution of low dose oral Decitabine (DAC), thereby enhancing systemic DNA demethylation with acceptable toxicities.
- Preliminary results of recent clinical trial suggest that oral DAC-THU can increase the frequency and magnitude of responses to immune checkpoint inhibitors in lung cancer patients with low or absent intra-tumoral PD-L1 expression.
- These data support further evaluation of oral DAC-THU in combination with immune checkpoint inhibitors for therapy of thoracic malignancies.
Objectives:
Phase I
-To define pharmacokinetics, toxicities and maximum tolerated dose of oral DAC-THU in combination with pembrolizumab in patients with inoperable, or unresectable locally advanced or metastatic NSCLC, EsC, or MPM.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
2/Dose Expansion
Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at the dose established in Arm 1
干预措施: Tetrahydrouridine (THU) (Drug)
1/Dose Escalation
Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at escalating doses
干预措施: Decitabine (DAC) (Drug)
1/Dose Escalation
Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at escalating doses
干预措施: Tetrahydrouridine (THU) (Drug)
1/Dose Escalation
Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at escalating doses
干预措施: Pembrolizumab (Drug)
2/Dose Expansion
Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at the dose established in Arm 1
干预措施: Decitabine (DAC) (Drug)
2/Dose Expansion
Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at the dose established in Arm 1
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Decitabine
时间窗: Within the first 6 weeks (two cycles)
Maximum Tolerated Dose (MTD) is the maximum dose at which fewer than one-third of participants experience dose limiting toxicity (DLT) within the first 6 weeks (two cycles) of decitabine and tetrahydrouridine therapy. If one of three patients at any given dose level experiences DLT, up to three additional patients will be treated at this dose level. If only one of six patients exhibit DLT, subsequent patients will be enrolled into the next higher dose level. As soon as two patients at any given dose level develop DLT, no additional patients will be entered at that level. Subsequent patients will be accrued into the preceding dose level; if DLT is observed in less than two of six patients treated at this lower level, this dose will represent maximum tolerated dose (MTD). A DLT is any Grade 3 or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.
Overall Response Rate
时间窗: Every 10 weeks (± 1 week) until disease progression or unacceptable toxicity or off study criteria is met. Longest participant on study 11 months.
Overall response rate was measured using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 to determine if the combination of decitabine and tetrahydrouridine is associated with a response rate which exceeds that of Pembrolizumab alone in participants who have programmed death-ligand 1 (PD-L1) expression of at least 50% and those who do not. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.
Maximum Tolerated Dose (MTD) of Tetrahydrouridine
时间窗: Within the first 6 weeks (two cycles)
Maximum Tolerated Dose (MTD) is the maximum dose at which fewer than one-third of participants experience dose limiting toxicity (DLT) within the first 6 weeks (two cycles) of decitabine and tetrahydrouridine therapy. If one of three patients at any given dose level experiences DLT, up to three additional patients will be treated at this dose level. If only one of six patients exhibit DLT, subsequent patients will be enrolled into the next higher dose level. As soon as two patients at any given dose level develop DLT, no additional patients will be entered at that level. Subsequent patients will be accrued into the preceding dose level; if DLT is observed in less than two of six patients treated at this lower level, this dose will represent maximum tolerated dose (MTD). A DLT is any Grade 3 or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.
次要结局
- Changes in Gene, Endogenous Retroviral (ERV), Micro Ribonucleic Acid (RNA) Expressions, Deoxyribonucleic Acid (DNA) Methylation Signatures and Tumor Microenvironment(Baseline and post-treatment after one course of therapy (Week 10 +/- one week))
- Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC)(Baseline and post-treatment after one course of therapy (Week 10 +/- one week))
- Changes in Circulating Tumor Cells (CTCs)(Baseline and post-treatment after one course of therapy (Week 10 +/- one week))
- Percent Viable Tumor Cells(Baseline and post-treatment after one course of therapy (Week 10 +/- one week))
研究者
David Schrump, M.D.
Principal Investigator
National Cancer Institute (NCI)