A Phase I Study of Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 19
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of LMB-100 With Tofacitinib
研究概览
简要总结
Background:
The protein mesothelin is found on many kinds of tumors. The drug LMB-100 targets cancer cells that make this protein. Researchers want to see if LMB-100 combined with another drug can help people with these tumors.
Objective:
To find a safe dose of LMB-100 plus tofacitinib in people with pancreatic cancer, bile-duct cancer, and other solid tumors that make mesothelin.
Eligibility:
People ages 18 and older with pancreatic cancer, bile-duct cancer, or any other solid tumor with mesothelin that worsened after treatment or they could not receive standard treatment
Design:
Participants will be screened with:
- Medical history
- Tumor tissue sample. If they do not have a sample, they will have a biopsy.
- Physical exam
- Blood and heart tests
- Scans and x-rays: They may have a dye injected for the scans.
Participants will take the drugs in up to three 21-day cycles. They will take tofacitinib by mouth twice a day on days 1-10 of each cycle. They will have LMB-100 injected into the blood on days 4, 6, and 8 of every cycle. Patients that do not have a medi-port may need to have a central vein access line placed.
Participants will take other drugs on the days they receive LMB-100.
Participants will repeat screening tests during the study. They may have a biopsy at the start of the first 2 cycles.
If participants must stop the study, they will have a safety visit 3-6 weeks after their last dose of the study drug. Some participants may then have visits every 6 weeks.
After treatment, participants will be contacted about once a year. They will be asked about their cancer.
详细描述
Background:
- Pancreatic cancer is the fourth most common cause of cancer death in the United States, claiming more than 40,000 lives each year.
- Incidence nearly equals mortality with just 6% of participants living five years beyond their diagnosis. Most patients are diagnosed at an advanced stage, but even patients with early-stage disease have a long-term survival of less than 20%.
- Cholangiocarcinoma is a rare disease and just 3,000 patients are diagnosed with the extrahepatic form yearly. The median overall survival of patients with advanced disease receiving standard of care treatment is less than 1 year.
- Expression of mesothelin (MSLN) in pancreatic ductal adenocarcinoma (PDA) has been examined in several published studies and ranges from 86 to 100%. Similar incidence of expression has been observed in extrahepatic cholangiocarcinoma.
- In addition to pancreatobiliary tumors, many other solid tumor types also express MSLN such as mesothelioma, colorectal, lung adenocarcinomas, epithelial ovarian, gastric and triple negative breast cancers, as well as some tumors of squamous cell origin.
- LMB-100 and a closely related immunotoxin also targeting MSLN have been studied in previous Phase 1 clinical studies for mesothelioma and pancreatic cancer.
- Results from these studies showed that almost all patients formed anti-drug-antibodies (ADAs) that neutralized subsequent injection of the product making it ineffective.
- Tofacitinib is an oral Janus Kinase-1 and -3 (JAK) inhibitor approved by the FDA for the treatment of rheumatoid arthritis and ulcerative colitis.
- Pre-clinical studies have shown that tofacitinib can prevent the formation of ADAs against an immunotoxin closely related to LMB-100
- Co-administration of tofacitinib with immunotoxin increased immunotoxin serum half- life in mice and enhanced anti-tumor efficacy
- This clinical trial will investigate whether co-administration of tofacitinib with LMB- 100 can prevent or delay the formation of ADAs and thus allow patients to receive additional effective cycles of LMB-100.
Objectives:
- The primary objective of the dose escalation phase of this study is to assess the safety and tolerability of LMB-100 given in combination with tofacitinib to patients with pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma and other mesothelin-positive solid tumors
- The primary objective of the expansion phase of this study is to determine whether co-administration of tofacitinib delays formation of neutralizing anti-LMB-100 ADAs through cycle 2 of treatment (as measured by LMB-100 serum drug levels) in patients with pancreatobiliary cancers.
Eligibility:
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 —（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
1. Dose escalation
LMB-100 at escalating doses plus tofacitinib
干预措施: LMB-100 (Drug)
1. Dose escalation
LMB-100 at escalating doses plus tofacitinib
干预措施: Tofacitinib (Drug)
1. Dose escalation
LMB-100 at escalating doses plus tofacitinib
干预措施: Mesothelin Expression (Device)
2. Dose expansion
LMB-100 at optimal dose plus tofacitinib
干预措施: LMB-100 (Drug)
2. Dose expansion
LMB-100 at optimal dose plus tofacitinib
干预措施: Tofacitinib (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of LMB-100 With Tofacitinib
时间窗: First cycle of treatment (21 days)
MTD is defined as the maximum dose at which less than 33% of participants experience a dose-limiting toxicity (defined as any events occurring within the first cycle of treatment (21 days) such as any death not clearly due to the underlying disease or extraneous causes).
Percentage of Participants With Pancreatobiliary Cancer and LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 Who Received LMB-100 at Maximum Tolerated Dose
时间窗: Plasma LMB-100 levels during Cycle 2 treatment (each cycle = 21 days)
This measure assessed how many participants have LMB-100 plasma drug levels higher than threshold (600 ng/mL) during Cycle 2 pharmacokinetics (PK) measurements, a sign of effective prevention of anti-LMB-100 antibodies. The validated enzyme-linked immunosorbent assay (ELISA) test was used to measure plasma LMB-100 concentration. Below 600ng/mL is considered a bad outcome and above 600ng/mL is considered a good outcome.
Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Treated in the Dose Escalation Group
时间窗: Throughout study treatment until 30 days post-completion, approximately 13 weeks
Grade 1-5 adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 observed in participants with pancreatic cancer. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant. Grade 4 is life-threatening consequences. Grade 5 is death related to adverse events.
次要结局
- Percentage of Participants With LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 in Dose Escalation(Plasma LMB-100 levels during Cycle 2 of treatment (each cycle = 21 days))
- Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100(Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days))
- Percentage of Participants Without Delayed Formation of Neutralizing Anti-LMB-100 Anti-drug Antibodies (ADAs)(Plasma LMB-100 levels during Cycle 3 treatment (each cycle = 21 days))
- Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) of LMB-100(Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days))
- Plasma Half-Life (T1/2) of LMB-100(Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days))
- Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Who Have Pancreatobiliary Cancer(Throughout study treatment until 30 days post-completion, approximately 13 weeks.)
研究者
Christine Alewine, M.D.
Principla Investigator
National Cancer Institute (NCI)