A Phase Ib/II Study of Mesothelin-Targeted Immunotoxin LMB-100 Alone or in Combination With Nab-Paclitaxel in Participants With Previously Treated Metastatic and/ or Locally Advanced Pancreatic Ductal Adenocarcinoma and Mesothelin Expressing Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Objective Response (OR) (Partial Responses + Complete Responses) in Phase 2 Subjects of Short Infusion LMB-100+ Nab-paclitaxel
研究概览
简要总结
Background:
LMB-100 is a man-made protein designed to kill cancer cells. LMB-100 targets a cancer marker called mesothelin. Mesothelin is found on the surface of many different tumors, including pancreatic cancer, but is made by a very small number of normal tissues. Other cancers that make mesothelin include mesothelioma, cholangiocarcinoma, thymic carcinoma, ovarian, lung, gastric, endometrial, cervical, and ampullary cancers. After binding to the mesothelin on tumors, LMB-100 can attack and kill cancer cells. Researchers want to see how well it works when given with and without nab-paclitaxel, a drug which treats pancreatic cancer.
Objectives:
Arm A- To find a safe dose of LMB-100 with a fixed standard dose of nab-paclitaxel in people with advanced pancreatic cancer. To see how well the combination of the two drugs reduce tumor size.
Arm B- To find a safe dose of LMB-100 when it is given as a continuous infusion over several days.
Eligibility:
Arm A- Adults age 18 and older with advanced pancreatic cancer that has worsened after anti-cancer therapy.
Arm B- Adults age 18 and older with advanced pancreatic cancer, mesothelioma or other solid tumor that makes mesothelin that has worsened after anti-cancer therapy
Design:
Participants will be screened with medical history and physical exam. They will give blood, urine, and tissue samples. They will have scans and x-rays.
During each 21-day cycle:
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For Arm A
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Participants will get LMB-100 by an intravenous (IV) catheter on days 1, 3, and 5. This is a tube inserted in a vein, usually in the arm.
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Participants will get nab-paclitaxel by IV on days 1 and 8.
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For Arm B
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Participants will get LMB-100 by an IV catheter as a continuous infusion beginning on day 1 and continuing for 2-4 days
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Some participants will also get nab-paclitaxel by IV on days 1 and 8.
All participants will get this combination for up to 2 cycles or until their disease worsens or they have intolerable side effects.
Participants will have blood and urine tests and scans throughout the study.
Participants will have a safety follow-up visit 3-6 weeks after treatment ends. If their disease remains stable or improves, they will be scanned every 6 weeks until their disease gets worse. Even if their disease gets worse, they or their doctor will be called to talk about their cancer status....
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%.
- Mesothelin is specifically a marker of adenocarcinoma in the human disease and is not expressed in preceding pre-malignant stages of tumor development
- Expression of mesothelin in pancreatic ductal adenocarcinoma (PDA) has been examined in several published studies and ranges from 86 to 100%
- Recombinant immunotoxins (RITs) are antibody-based therapeutics that carry a toxin payload. RITs that target mesothelin contain a genetically engineered variant of Pseudomonas exotoxin A (PE) in which the native cell-binding domain of PE is replaced by the mesothelin-binding antibody fragment. SS1P was the first mesothelin-targeted RIT tested in patients.
- LMB-100 contains a newly engineered PE fragment that has improved activity against most pancreatic cancer cell lines in vitro, and is also much less toxic than SS1P in preclinical models. The new PE contains modifications specifically designed to reduce immunogenicity of the molecule.
- Pre-administration of paclitaxel with SS1P was demonstrated to increase the amount of immunotoxin internalized by tumor cells and to reduce levels of shed mesothelin in the intra-tumoral environment so that more immunotoxin could bind tumor cells. The effect is even more pronounced with NAB-paclitaxel in a pancreatic cancer model.
- Initial clinical testing of LMB-100 was performed by Roche in a multi-center international first in human trial (NCT02317419). The agent was well tolerated and appeared to have decreased immunogenicity compared to SS1P based on preliminary results.
- In initial and subsequent clinical testing, LMB-100 was found to have half-life of approximately 60 mins. This is shorter then that measured for previous RITs used in the clinical setting.
Primary Objectives:
- Arm A1 (Phase I, short infusion):
--To determine the maximum tolerated dose of short infusion LMB-100 in combination nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer
- Arm B1(Continuous infusion single agent lead-in):
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
Arm A1, Dose Level 1 (Phase 1, short infusion) 100µg/kg LMB-100
Arm A1, Dose Level 1, Phase I Short Infusion 100µg/kg LMB-100 +125mg/m^2 nab-paclitaxel
Dose level 1 (DL1) Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving short infusion LMB-100+nabpaclitaxel
干预措施: LMB-100 (Drug)
Arm A1, Dose Level 1 (Phase 1, short infusion) 100µg/kg LMB-100
Arm A1, Dose Level 1, Phase I Short Infusion 100µg/kg LMB-100 +125mg/m^2 nab-paclitaxel
Dose level 1 (DL1) Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving short infusion LMB-100+nabpaclitaxel
干预措施: Nab-Paclitaxel (Drug)
Arm A1, Dose Level-1 (Phase 1, short infusion) 65µg/kg LMB-100
Arm A1, DL-1, Ph I Short Infusion 65µg/kg LMB-100 +125mg/m^2 nab-paclitaxel
干预措施: LMB-100 (Drug)
Arm A1, Dose Level-1 (Phase 1, short infusion) 65µg/kg LMB-100
Arm A1, DL-1, Ph I Short Infusion 65µg/kg LMB-100 +125mg/m^2 nab-paclitaxel
干预措施: Nab-Paclitaxel (Drug)
Arm A2 (Phase 2, short infusion) 65µg/kg LMB-100
Arm A2, Phase 2 Short Infusion 65µg/kg LMB-100 +125mg/m^2 nab-paclitaxel
Efficacy determination in patients with pancreatic cancer receiving short infusion LMB-100 + nabpaclitaxel
干预措施: LMB-100 (Drug)
Arm A2 (Phase 2, short infusion) 65µg/kg LMB-100
Arm A2, Phase 2 Short Infusion 65µg/kg LMB-100 +125mg/m^2 nab-paclitaxel
Efficacy determination in patients with pancreatic cancer receiving short infusion LMB-100 + nabpaclitaxel
干预措施: Nab-Paclitaxel (Drug)
Arm B1, Dose Level 2 Phase I (Continuous infusion single agent lead-in)
Arm B1, DL2, 48-hr Continuous Infusion Single Agent Lead-in 100µg/kg/day LMB-100 Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving continuous infusion LMB-100 as single agent
干预措施: LMB-100 (Drug)
Arm B1, Dose Level 2 Phase I (Continuous infusion single agent lead-in)
Arm B1, DL2, 48-hr Continuous Infusion Single Agent Lead-in 100µg/kg/day LMB-100 Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving continuous infusion LMB-100 as single agent
干预措施: Mesothelin Expression (Device)
Arm B1, Dose Level 1 Phase I (Continuous infusion single agent lead-in)
Arm B1, DL1, 48-hr Continuous Infusion Single Agent Lead-in 65µg/kg/day LMB-100
干预措施: LMB-100 (Drug)
Arm B1, Dose Level 1 Phase I (Continuous infusion single agent lead-in)
Arm B1, DL1, 48-hr Continuous Infusion Single Agent Lead-in 65µg/kg/day LMB-100
干预措施: Mesothelin Expression (Device)
Arm B1, Dose Level 3R Phase I (Continuous infusion single agent lead-in)
Arm B1, DL3R, 24-hr Continuous Infusion Single Agent Lead-in 100µg/kg LMB-100
干预措施: LMB-100 (Drug)
Arm B1, Dose Level 3R Phase I (Continuous infusion single agent lead-in)
Arm B1, DL3R, 24-hr Continuous Infusion Single Agent Lead-in 100µg/kg LMB-100
干预措施: Mesothelin Expression (Device)
Arm B2 Phase I (continuous infusion combination therapy)
Subjects with pancreatic cancer receiving continuous infusion LMB-100 combination therapy
干预措施: LMB-100 (Drug)
Arm B2 Phase I (continuous infusion combination therapy)
Subjects with pancreatic cancer receiving continuous infusion LMB-100 combination therapy
干预措施: Nab-Paclitaxel (Drug)
结局指标
主要结局
Objective Response (OR) (Partial Responses + Complete Responses) in Phase 2 Subjects of Short Infusion LMB-100+ Nab-paclitaxel
时间窗: Approximately 6 weeks after the start of treatment and continuing every 6 weeks until progression or start of a new treatment, up to 1 year
OR is defined as partial responses + complete response in participants in the phase 2 Arm A portion of the study assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response is a disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters
Maximum Tolerated Dose (MTD) of Short Infusion LMB-100 + Nab Paclitaxel
时间窗: 21 days after LMB-100 is administered (end of cycle 1)
MTD is defined as the highest dose tolerated without exceeding a pre-set number of adverse events in Phase 1, Arm A.
Maximum Tolerated Dose (MTD) of Continuous Infusion LMB-100
时间窗: 21 days after LMB-100 is administered (end of cycle 1)
MTD is defined as the highest dose tolerated without exceeding a pre-set number of adverse events in Phase 1, 1 Arm B, single agent lead-in
次要结局
- Overall Survival (OS)(Time from treatment initiation to death, up to 1-2 years.)
- Progression Free Survival (PFS)(Time from treatment initiation to disease progression or death, an average of 1 year.)
- Proportion of Participants Disease Control Rate (DCR) at End of Treatment (EOT)(up to 3 months)
- Number of Participants With an Objective Response (OR) (Partial Responses + Complete Responses) in Phase 1 Arm A1(Approximately 6 weeks after the start of treatment and continuing every 6 weeks until progression or start of a new treatment up to 1 year.)
- Number of Participants With an Objective Response (OR) (Partial Response + Complete Response) in Phase 1, Arm B(Approximately 6 weeks after the start of treatment and continuing every 6 weeks until progression or start of a new treatment up to 1 year.)
- Number of Participants With Adverse Events Attributed to LMB-100(Date treatment consent signed to date off study, approx. 11 mos, 8 days for A1DL1; 20 mos, 9 days for A1DL-1; 10 mos, 17 days for A2; 2 mos, 16 days for B1DL1; 14 mos, 30 days for B1DL2; 5 mos, 1 day for B2; and 4 mos, 15 days for B1DL3R.)
- Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).(Date treatment consent signed to date off study, approx. 11 mos, 8 days for A1DL1; 20 mos, 9 days for A1DL-1; 10 mos, 17 days for A2; 2 mos, 16 days for B1DL1; 14 mos, 30 days for B1DL2; 5 mos, 1 day for B2; and 4 mos, 15 days for B1DL3R.)
研究者
Christine Alewine, M.D.
Principal Investigator
National Cancer Institute (NCI)