Phase 1 study of the immunotoxin LMB-100 in patients with mesothelioma and other solid tumors expressing mesothelin.
Phase 1 study of the immunotoxin LMB-100 in patients with mesothelioma and other solid tumors expressing mesothelin.
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免疫毒素LMB-100在间皮瘤和表达间皮素的其他实体瘤患者中的I期研究。
DOI：
10.1002/cncr.33145
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发表时间：
2020-11-15
期刊：
影响因子：
6.2
通讯作者：
Pastan I
中科院分区：
文献类型：
--
作者：
Hassan R;Alewine C;Mian I;Spreafico A;Siu LL;Gomez-Roca C;Delord JP;Italiano A;Lassen U;Soria JC;Bahleda R;Thomas A;Steinberg SM;Peer CJ;Figg WD;Niederfellner G;Méresse Naegelen V;Pastan I
LMB-100 is an antibody-toxin conjugate with an anti-mesothelin Fab linked to a 24 kDa portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of this first-in-human Phase I study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin. Cohorts of 1–7 patients received intravenous LMB-100 at 7 dose levels from 40 to 250 mcg/kg intravenously on days 1, 3 and 5 of a 21-day cycle. Of 25 subjects accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer and 2 had gastric cancer. Dose limiting toxicity (DLT) occurred in 2 of 4 treated at 250 mcg/kg (capillary leak syndrome) and 3 of 7 treated at 170 mcg/kg (creatinine increase). The MTD of LMB-100 was 140 mcg/kg. Of 10 mesothelioma patients treated at 170 or 140 mcg/kg, 8 had stable disease and 2 progressive disease. Peak LMB-100 plasma concentrations were dose-dependent during cycle 1. Development of anti-drug antibodies (ADAs) decreased LMB-100 blood levels in 8 of 21 (38%) patients who received cycle 2 and 9 of 11 patients (81.8%) receiving cycle 3. The MTD for single agent LMB-100 is 140 mcg/kg given on a QOD x 3 schedule. Although less immunogenic than the first generation anti-mesothelin immunotoxin SS1P, the majority of patients developed ADAs after 2 cycles and LMB-100 has limited anti-tumor efficacy as a single agent. Phase II studies of LMB-100 plus pembrolizumab are ongoing for patients with mesothelioma and lung cancer. Mesothelin, a cell surface antigen is an attractive target for cancer therapy, given its limited expression on normal human tissues and high expression in many human cancers. LMB-100 is a recombinant anti-mesothelin immunotoxin consisting of a humanized anti-mesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A (PE). In this study, the authors have determined the safety, maximum tolerated dose and pharmacokinetics of LMB-100, as well as the generation of anti-drug antibodies. Ongoing phase II clinical trials are evaluating the combination of LMB-100 plus pembrolizumab in patients with treatment refractory mesothelioma and non-small cell lung cancer. Mesothelin targeting immunotoxin LMB-100 is well tolerated with manageable adverse effects. Based on anti-tumor efficacy seen in preclinical studies, the combination of LMB-100 plus pembrolizumab is currently being evaluated in the clinic.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
DOI：
10.1093/jnci/djp079
发表时间：
2009-05-20
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Le Tourneau C;Lee JJ;Siu LL
通讯作者：
Siu LL
影响因子：
17.1
作者：
Jiang Q;Ghafoor A;Mian I;Rathkey D;Thomas A;Alewine C;Sengupta M;Ahlman MA;Zhang J;Morrow B;Steinberg SM;Pastan I;Hassan R
通讯作者：
Hassan R
影响因子：
45.3
作者：
Hassan, Raffit;Thomas, Anish;Pastan, Ira
通讯作者：
Pastan, Ira
DOI：
10.1097/pai.0000000000000292
发表时间：
2016-04
期刊：
Applied immunohistochemistry & molecular morphology : AIMM
影响因子：
--
作者：
Illei PB;Alewine C;Zahurak M;Cowan ML;Montgomery E;Hassan R;Xiang L;Pastan I;Kelly RJ
通讯作者：
Kelly RJ