A Phase I Study of the Mesothelin-Targeted Immunotoxin LMB-100 With or Without Nab-Paclitaxel (Abraxane) in Patients With Malignant Mesothelioma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Recommended Phase 2 Dose (RP2D) of LMB100 + Nab-paclitaxel
研究概览
简要总结
Background:
LMB-100 is a man-made protein. It is attracted to the mesothelin protein. This is found in many tumors, including mesothelioma. But it is found in only a very small number of normal tissues. After binding to mesothelin on tumors, LMB-100 attacks and kills cancer cells. Researchers want to test LMB-100 in people with advanced mesothelioma.
Objective:
To find a safe dose and anti-tumor activity of LMB-100 for people with advanced mesothelioma.
Eligibility:
Adults ages 18 and older with:
Advanced pleural or peritoneal mesothelioma that has not responded to platinum-based
therapy
Adequate organ function
Design:
Participants will be screened with:
Samples of tumor tissue or tumor fluid. These can be new or from a previous procedure.
Medical history
Physical exam
Blood, urine, and heart tests
Chest x-rays
Computed tomography (CT) or magnetic resonance imaging (MRI) scans
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans
Participants will get LMB-100 on days 1, 3, and 5 of each 21-day cycle. It will be given through an intravenous (IV) catheter, a tube inserted in an arm vein. They will get standard medicines before each infusion to help prevent side effects. Each infusion lasts about 30 minutes. They will be monitored for up to 2 hours after.
During each cycle, participants will repeat the screening tests.
Participants will get the study drug for up to 4 cycles or until their disease worsens or they have intolerable side effects.
About 4-6 weeks after their last infusion, participants will have a follow-up visit. They will repeat the study tests.
Participants will have follow-up scans every 6 weeks until their disease gets worse.
Participants will be called about once a year to see how they are doing.
详细描述
Background:
- Although mesothelioma patients with a limited tumor burden may benefit from surgical resection, most patients have advanced disease at diagnosis and are not candidates for cytoreductive surgery.
- For mesothelioma patients who are not eligible for curative surgery, the median survival with supportive care alone is 6 months whereas with the current standard treatment, a combination of cisplatin and pemetrexed, the median survival is 12 months.
- Mesothelin, a tumor differentiation antigen, is expressed in over 95% of epitheloid mesothelioma. Mesothelin is a suitable candidate for targeted therapy due to its very limited expression in normal human tissue and its high expression in several tumors including mesothelioma.
- LMB-100 is a novel recombinant anti-mesothelin immunotoxin developed for the treatment of patients with solid tumors that express mesothelin. Mesothelin is targeted by linking a humanized fragment of the anti-mesothelin Fab to a de-immunized Pseudomonas exotoxin (PE).
- The clinical use of first generation immunotoxins such as SS1P was hampered mainly by their high immunogenicity. LMB-100 is a next generation PE-fusion protein that has been protein-engineered to maximally reduce its immunogenicity. LMB-100 has shown broad activity against different mesothelin expressing cancer cell lines and tumor xenograft models.
Objectives: Phase 1
To identify the recommended phase 2 dose (RP2D) of LMB-100 in patients with treatment refractory advanced epithelioid or biphasic mesothelioma and evaluate potential efficacy of the identified RP2D.
-Phase 2
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
A1/LMB-100 dose escalation (closed)
De-escalating doses of LMB-100 in up to 18 subjects
干预措施: LMB-100 (Drug)
A2/LMB-100 dose expansion (closed)
Fixed dose of LMB-100 as determined in Arm A1 in up to 16 subjects
干预措施: LMB-100 (Drug)
B1/LMB-100+ nab- paclitaxel dose escalation
De-escalating doses of LMB-100 + fixed dose of nab-paclitaxel in up to 12 subjects
干预措施: LMB-100 (Drug)
B1/LMB-100+ nab- paclitaxel dose escalation
De-escalating doses of LMB-100 + fixed dose of nab-paclitaxel in up to 12 subjects
干预措施: nab-paclitaxel (Drug)
B2/LMB-100+ nab- paclitaxel dose expansion
Fixed dose of LMB-100 as determined in Arm B1 + fixed dose of nab-paclitaxel in up to 16 subjects
干预措施: LMB-100 (Drug)
B2/LMB-100+ nab- paclitaxel dose expansion
Fixed dose of LMB-100 as determined in Arm B1 + fixed dose of nab-paclitaxel in up to 16 subjects
干预措施: nab-paclitaxel (Drug)
结局指标
主要结局
Recommended Phase 2 Dose (RP2D) of LMB100 + Nab-paclitaxel
时间窗: 3 weeks after initial dose
Highest administered dose of LMB-100 + nab-paclitaxel at which no more than 1 of 6 participants experiences a dose limiting toxicity (DLT). A DLT is any of the following events attributed to LMB-100 and occurring within 21 days after the first dose of LMB-100 such as Grade 4 neutropenia, Grade 3 and 4 febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia associated with bleeding episodes. Grade ≥ 3 non-hematological toxicity with the exception of alopecia (any grade), Grade 3 nausea and vomiting without appropriate treatment, Grade 3 diarrhea lasting for ≤ 2 days with no fever or dehydration.
次要结局
- Number of Grade 3-5 Adverse Events Possibly, Probably, and/or Definitely Related to the LMB-100 +/- Nab-Paclitaxel(30 days after treatment)
- Median Progression Free Survival (PFS)(At progression, up to 3.6 months)
- Number of Participants at Recommended Phase 2 Dose (RP2D) With Partial or Complete Response by the Response Evaluation Criteria in Solid Tumors (RECIST)(End of treatment, an average of 57.6 days)
- Median Overall Survival (OS)(At death, up to 60.8 months)
- Number of Participants With LMB-100 Maximum Observed Serum Concentration (Cmax) of >100ng/mL(Cycle 1 and Cycle 2 (each cycle is 21 days), approximately 42 days)
- Number of Participants With Anti-drug Antibodies (ADAs) Formation to LMB-100(Cycle 1 and Cycle 2 (each cycle is 21 days), approximately 42 days)
- Duration of Response (DOR)(time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented by computed tomography (CT) scans performed every 6 weeks.)
研究者
Raffit Hassan, M.D.
Principal Investigator
National Cancer Institute (NCI)