A Pilot/ Phase 2 Study of Pentostatin Plus Cyclophosphamide Immune Depletion to Decrease Immunogenicity of SS1P in Patients With Mesothelioma, Lung Cancer or Pancreatic Cancer

Background:
Malignant mesothelioma is a form of cancer that develops on the protective lining that covers the body's internal organs. It most often occurs on the lining of the lungs and chest wall or the lining of the abdomen. There is no known cure for malignant mesothelioma, so researchers are searching for new ways to treat it.
Mesothelin is a protein that is found in mesothelioma and other types of cancer cells. An experimental cancer drug called SS1P is designed to attack cells that have mesothelin while leaving healthy cells alone. Researchers want to test how effective SS1P is when it is given with pentostatin and cyclophosphamide. These drugs help suppress the immune system and may make the SS1P more effective.
Objectives:
- To study the effectiveness of SS1P plus two drugs that suppress the immune system to treat malignant mesothelioma.
Eligibility:
- Individuals at least 18 years of age who have malignant mesothelioma in the chest or abdomen.
Design:
Participants will be screened with a physical exam, medical history, and blood tests. They will also have imaging studies.
The first treatment cycle will last 30 days. Up to three 21-day cycles of treatment will follow.
In the first cycle, participants will have pentostatin on days 1, 5, and 9. They will have cyclophosphamide on days 1 through 12. They will have SS1P on days 10, 12, and 14.
On the next three cycles, participants will have pentostatin on day 1.They will have cyclophosphamide on days 1 through 4. They will have SS1P on days 2, 4, and 6.
Participants will have frequent blood tests and other studies. They will receive all four cycles of treatment as long as there are no severe side effects.
Participants will have regular followup visits as directed by the study doctors.

开始日期2011-05-11

申办/合作机构

National Cancer Institute

NCT01051934

/ Completed临床1期IIT

A Phase I Trial of SS1 (dsFv) PE38 With Paclitaxel, Carboplatin, and Bevacizumab in Subjects With Unresectable Non-Small Cell Lung Adenocarcinoma

Background:
Advanced cases of non-small-cell lung carcinoma (NSCLC) usually are not successfully treated with standard therapies. Even treatments that attempt to specifically target NSCLC cells have not proved effective.
Researchers are interested in determining whether a combination of the chemotherapy drugs SS1 (dsFv) PE38, paclitaxel, carboplatin, and bevacizumab may be effective in shrinking the size of NSCLC tumors. Three of the drugs (paclitaxel, carboplatin, and bevacizumab) are commercially available, while the other is a drug that is currently being tested to determine its usefulness in cancer treatment. This study will help to determine if the combination of all four drugs is more effective and as safe, safer, or less safe than other drug combinations given to treat NSCLC.
Objectives:
- To determine a safe and tolerable dose for the combination of SS1 (dsFv) PE38 with paclitaxel, carboplatin, and bevacizumab in patients with advanced mesothelin-expressing lung adenocarcinoma.
Eligibility:
Age > 18 years of age
Newly diagnosed advanced non-small-cell lung carcinoma
No prior chemotherapy for lung cancer
Individuals at least 18 years of age who have advanced non-small-cell lung carcinoma that has not responded to standard treatments.
Design:
The study will last for two 21-day cycles of treatment for the four-drug combination, with additional treatment cycles of carboplatin, paclitaxel, and bevacizumab.
Two to three weeks prior to the study, participants will be screened with a full medical history and physical exam, bone marrow biopsy (we do not do bone marrow biopsies) (if one has not been performed in the last 6 months), computed tomography (CT) or ultrasound scan, tumor measurements, and other tests as required by the researchers. Participants will provide blood and urine samples at this time as well.
During the study, participants will receive SS1 (dsFv) PE38, carboplatin, paclitaxel, and bevacizumab for a maximum of two cycles. On Day 15 of the first cycle, participants will provide a blood sample to be tested to see if SS1 (dsFv) PE38 is being effective. If the tests show that SS1 (dsFv) PE38 is not effective, participants will not receive another dose of it, but will continue to receive paclitaxel, carboplatin, and bevacizumab for the second cycle.
After the first two cycles, participants will continue to receive carboplatin, paclitaxel, and bevacizumab every 3 weeks for up t...

开始日期2009-12-29

申办/合作机构

National Cancer Institute

NCT01445392

/ Terminated临床1期IIT

A Phase 1, Single Center, Dose-Escalation Study of SS1(dsFv)PE38 Administered Concurrently With Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Epithelial Pleural Mesothelioma

Background:
Standard therapy for mesothelioma is a combination of the drugs pemetrexed and cisplatin. However, the benefits of this treatment are limited, and in most treated patients the disease continues to worsen.
SS1(dsFV)PE38 is a genetically engineered drug. It contains an antibody that binds to a certain protein on mesothelioma cells and a toxin (type of poison) made from a product of a bacterium called Pseudomonas aeruginosa. It is hoped that the antibody will attach to the cancer cells, allowing the toxin to enter and kill the cells.
Objectives:
To find out if SS1(dsFV)PE38, together with pemetrexed and cisplatin is safe and tolerable in patients with mesothelioma.
To determine the maximum tolerated dose of SS1(dsFV)PE38 (the highest dose that does not cause unacceptable side effects).
To see if SS1(dsFV)PE38 given with pemetrexed and cisplatin has any effect on patients tumors.
To learn how the body breaks down SS1(dsFV)PE38.
Eligibility:
Patients 18 years of age and older with epithelial pleural mesothelioma whose disease cannot be cured with surgery, and have not had prior treatment with chemotherapy.
Design:
Treatment with pemetrexed, cisplatin and SS1(dsFV)PE38 in two 21-day cycles as follows:
Day 1 - Intravenous (through a vein) infusions of pemetrexed and cisplatin.
Days 1 and 2 - Intravenous solution to prevent dehydration that might occur with SS1(dsFV)PE38.
Days 1, 3 and 5 Intravenous infusion of SS1(dsFV)PE38. Small groups (3 to 6) of patients are given SS1(dsFV)PE38 at a certain dose level. If the first group experiences no significant side effects, the next group a higher dose. This continues in succeeding groups until the maximum tolerated study dose (highest dose that patients can be given safely) is determined.
Continuing standard treatment with additional cycles of pemetrexed and cisplatin.
Evaluations during the treatment period:
Physical examination, including vital signs and body weight checks, and pregnancy test for women who can become pregnant.
Questions about medications and side effects.
Blood and urine tests.
Disease evaluation with CT, chest X-ray, and possibly PET scans, lung function tests, pulse oximetry, performance of daily activities and quality-of-life questionnaires.
Post-treatment evaluations:
Clinic visits at months 1, 3, 6, 12, 15, 18 and 21 for physical examination and disease assessment.
End-of-study visit for blood tests, vital signs and weight measurements, disease assessment, electrocardiogram, pregnancy test for women who can become pregnant

开始日期2007-11-14

申办/合作机构

National Cancer Institute

100 项与 CAT-5001 相关的临床结果

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100 项与 CAT-5001 相关的转化医学

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100 项与 CAT-5001 相关的专利（医药）

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项与 CAT-5001 相关的文献（医药）

2022-11-29·Proceedings of the National Academy of Sciences of the United States of America1区 · 综合性期刊

Anti-mesothelin immunotoxin induces mesothelioma eradication, anti-tumor immunity, and the development of tertiary lymphoid structures

1区 · 综合性期刊

Article

作者: Pastan, Ira ; Liu, Xiufen ; Liu, Wenlong ; Tai, Chin-Hsien

LMB-100 is a recombinant immunotoxin composed of a Fab linked to a toxin. It kills cells expressing human mesothelin (hMSLN), which is highly expressed on the surface of mesothelioma and many other cancer cells. Clinically, we observed some patients had delayed responses to an anti-hMSLN immunotoxin treatment, suggesting the induction of anti-tumor immunity. We aimed to develop a mouse model to investigate whether immunotoxin alone can induce anti-tumor immunity and to study the mechanism of this immunity. An immunocompetent transgenic mouse was used to grow mouse mesothelioma AB1 cells expressing hMSLN in the peritoneal cavity. Mice were treated with LMB-100, and mice with complete responses (CRs) were rechallenged with tumor cells to determine whether anti-tumor immunity developed. Changes in gene expression profiles were evaluated by Nanostring, and changes in cytokines and chemokines were checked by protein arrays. The distribution of various immune cells was assessed by immunohistochemistry. Our results show that the mice with tumor reached CRs and developed anti-tumor immunity after LMB-100 treatment alone. The primary response requires CD8 + T cells, CD4 + T cells, and B cells. Transcriptional profiling shows that LMB-100 treatment reshapes the tumor immune microenvironment by upregulating chemotaxis signals. LMB-100 treatment upregulates genes associated with tertiary lymphoid structures (TLS) development and induces TLS formation in tumors. In sum, immunotoxin-mediated cell death induces anti-tumor immunity and the development of TLS, which provides insights into how immunotoxins cause tumor regressions.

2021-06-01·International journal of pharmaceutics2区 · 医学

Preclinical evaluation of a novel anti-mesothelin immunotoxin based on a single domain antibody as the targeting ligand

2区 · 医学

Article

作者: Ding, Yu ; Li, Wenjing ; Jing, Zhe ; Hong, Zhangyong ; Xu, Keyuan ; Li, Qiyu ; Wang, Xi ; Xing, Yutong

Pancreatic cancer, as one of the most aggressive and lethal malignancies in the world, is lack of effective treatment. Constructing immunotoxin molecules to target the mesothelin (MSLN) receptor is a potential therapeutic strategy for pancreatic cancer and other related malignant tumors, with some molecules being tested in clinical trials. However, currently, there are still some limitations in its applications, such as the difficulty of the preparation of drug molecules, the limited effectiveness of drugs, and the inadequacy of drug safety and immunogenicity. In this study, we constructed a novel type of anti-MSLN immunotoxin, A1-PE24X7, in which a single domain antibody (sdAb) molecule was used as the target ligand and an improved PE24X7 toxin with reduced off-target toxicity and immunogenicity was used as the effector. Unlike conventional immunotoxins, the designed A1-PE24X7 could be easily expressed in the E. coli system in the form of a soluble protein with a good yield (15--20 mg/L), avoiding the complex process of denaturation and refolding of inclusion bodies, and it can be conveniently stored in PBS solution for more than 7 days at 4 °C, showing high storage stability. Cell-based experiments showed that A1-PE24X7 entered MSLN-expressing tumor cells in a receptor-mediated manner and killed these cells with an EC₅₀ in the low nanomolar range (0.13 nM against NCI-N87 cells and 0.79 nM against AsPC-1 cells) and it showed ideal selectivity for the MSLN receptor (>100 nM against receptor negative PC3 cells). In animal-based experiments, A1-PE24X7 had tumor enrichment ability in relation to MSLN-positive tumors and showed strong tumor killing and inhibition in mouse models of pancreatic cancer and gastric cancer. Five injections of 3.0 mg/kg A1-PE24X7 significantly reduced the tumor volume of gastric NCI-N87 cancer and also significantly inhibited the growth of pancreatic AsPC-1 cancer. In addition, the maximum tolerable dosage (MSD) of A1-PE24X7 to mice was higher than 15 mg/kg, showing that A1-PE24X7 has a relatively broad therapeutic window. These preclinical results indicate that this strategy has good potential for application to the treatment of pancreatic cancer and other tumors with high MSLN expression.

2020-11-15·Cancer1区 · 医学

Phase 1 study of the immunotoxin LMB‐100 in patients with mesothelioma and other solid tumors expressing mesothelin

1区 · 医学

Article

作者: Méresse Naegelen, Valérie ; Soria, Jean‐Charles ; Alewine, Christine ; Hassan, Raffit ; Niederfellner, Gerhard ; Gomez‐Roca, Carlos ; Peer, Cody J. ; Bahleda, Rastilav ; Italiano, Antoine ; Figg, William D. ; Siu, Lillian L. ; Steinberg, Seth M. ; Delord, Jean‐Pierre ; Pastan, Ira ; Lassen, Ulrik ; Spreafico, Anna ; Thomas, Anish ; Mian, Idrees

Background:

LMB‐100 is an antibody‐toxin conjugate with an antimesothelin Fab linked to a 24‐kilodalton portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of the current first‐in‐human phase 1 study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin.

Methods:

Cohorts of 1 to 7 patients received intravenous LMB‐100 at 7 dose levels from 40 µg/kg to 250 µg/kg intravenously on days 1, 3, and 5 of a 21‐day cycle.

Results:

Of the 25 patients accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer, and 2 patients had gastric cancer. Dose‐limiting toxicities occurred in 2 of 4 patients treated at a dose of 250 µg/kg (capillary leak syndrome) and in 3 of 7 patients treated at a dose of 170 µg/kg (creatinine increase). The MTD of LMB‐100 was 140 µg/kg. Of the 10 patients with mesothelioma who were treated at doses of 170 µg/kg or 140 µg/kg, 8 had stable disease and 2 developed progressive disease. Peak LMB‐100 plasma concentrations were dose‐dependent during cycle 1. The development of antidrug antibodies decreased LMB‐100 blood levels in 8 of 21 patients (38%) who received cycle 2 and 9 of 11 patients (81.8%) who received cycle 3.

Conclusions:

The MTD for single‐agent LMB‐100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first‐generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB‐100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB‐100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer.

Lay Summary:

Mesothelin, a cell surface antigen, is an attractive target for cancer therapy given its limited expression in normal human tissues and high expression in many human cancers. LMB‐100 is a recombinant antimesothelin immunotoxin consisting of a humanized antimesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A.In the current study, the authors determined the safety, maximum tolerated dose, and pharmacokinetics of LMB‐100, as well as the generation of antidrug antibodies.Ongoing phase 2 clinical trials are evaluating the combination of LMB‐100 plus pembrolizumab in patients with treatment‐refractory mesothelioma and non–small cell lung cancer.

100 项与 CAT-5001 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
肺腺癌	临床2期	美国	National Cancer Institute	2011-05-11
晚期肺腺癌	临床2期	美国	National Cancer Institute	2011-05-11
腹膜恶性间皮瘤	临床2期	美国	National Cancer Institute	2011-05-11
恶性胸膜间皮瘤	临床2期	美国	National Cancer Institute	2011-05-11
胰腺腺癌	临床2期	美国	National Cancer Institute	2011-05-11
间皮瘤	临床2期	-	阿斯利康制药有限公司	-
卵巢癌	临床2期	-	阿斯利康制药有限公司	-
卵巢癌	临床2期	-	National Cancer Institute	-
胰腺癌	临床2期	-	阿斯利康制药有限公司	-
不可切除的非小细胞肺癌	临床1期	美国	National Cancer Institute	2009-12-29

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


WCLC2013	N/A	间皮瘤	11	Pentostatin (P)	衊餘憲蓋製簾觸簾齋繭(願繭獵夢醖製築鑰顧積) = 簾膚鏇繭顧構鬱築膚膚膚構構夢糧簾願網範齋 (願鹹範膚糧遞構襯選觸, +) 更多	-	2013-10-29
WCLC2013	N/A	间皮瘤	11	Cyclophosphamide (C)	衊餘憲蓋製簾觸簾齋繭(願繭獵夢醖製築鑰顧積) = 築鹽襯願窪鬱窪鹽簾窪膚構構夢糧簾願網範齋 (願鹹範膚糧遞構襯選觸, +) 更多	-	2013-10-29
ASCO2011	N/A	恶性胸膜间皮瘤	-	SS1P with pemetrexed and cisplatin	範膚鬱窪鏇鏇製衊夢繭(繭膚窪鏇鏇鏇鑰淵繭蓋) = 淵憲網簾淵鹹鹽衊鏇鬱艱願淵壓築觸網繭餘鏇 (鬱鏇簾夢獵網壓醖製製 )	积极	2011-05-20
ASCO2007	临床1期	间皮瘤 \| 胰腺癌	34	SS1P	網鹹築衊廠構鏇簾構網(衊構膚醖膚選齋鑰觸願) = 鬱鑰膚憲餘衊壓餘選築膚廠醖蓋餘遞夢壓壓簾 (獵獵鏇顧艱獵鹹鏇獵夢 ) 更多	-	2007-06-20