Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma

Abstract

Purpose: LMB-100 is a recombinant immunotoxin (iTox) consisting of a mesothelin-binding Fab for targeting and a modified Pseudomonas exotoxin A payload. Preclinical studies showed that combining taxanes with iTox results in synergistic antitumor activity. The objectives of this phase I/II study were to determine the MTD of LMB-100 when administered with nanoalbumin bound (nab)-paclitaxel to patients with previously treated advanced pancreatic adenocarcinoma and to assess the objective response rate. Patients and Methods: Patients (n = 20) received fixed-dose nab-paclitaxel (125 mg/m2 on days 1 and 8) with LMB-100 (65 or 100 μg/kg on days 1, 3, and 5) in 21-day cycles for 1–3 cycles. Results: Fourteen patients were treated on the dose escalation and an additional six in the phase II expansion. MTD of 65 μg/kg was established for the combination. Dose-limiting toxicity resulting from capillary leak syndrome (CLS) was seen in two of five patients treated at 100 μg/kg and one of six evaluable phase I patients receiving the MTD. Severity of CLS was associated with increases in apoptotic circulating endothelial cells. LMB-100 exposure was unaffected by anti-LMB-100 antibody formation in five of 13 patients during cycle 2. Seven of 17 evaluable patients experienced >50% decrease in CA 19-9, including three with previous exposure to nab-paclitaxel. One patient developed an objective partial response. Patients with biomarker responses had higher tumor mesothelin expression. Conclusions: Although clinical activity was observed, the combination was not well tolerated and alternative drug combinations with LMB-100 will be pursued.

Immunogenicity of Immunotoxins Containing Pseudomonas Exotoxin A: Causes, Consequences, and Mitigation

“…None of the patients received a third cycle of therapy due to toxicity of the nab-pactaxel. However, post treatment ADA monitoring showed that 9/10 of the patients evaluated were ADA positive; most of them with a very high OD signal ( 25 ).…”

“…LMB-100 is a PE-based RIT engineered for decreased immunogenicity ( Figure 1F ). To study the impact of ADAs on LMB-100 levels, we analyzed immunogenicity and pharmacokinetic date from a clinical trial treating Pancreatic Ductal Adenocarcinoma with LMB-100 and nab-paclitaxel ( 25 ). Anti LMB-100 ADA were monitored using ultrasensitive methods to triage ADA positive and negative responses (screening assay).…”

“… Impact of ADA on maximal concentration of LMB-100 (C max ) in blood of patients. C max and ADA measurements were performed as described in ( 25 ). C max and ADA results were obtained from ( 25 ).…”

Immunotoxin Screening System: A Rapid and Direct Approach to Obtain Functional Antibodies with Internalization Capacities

“…In addition to the current FDA-approved therapeutics, multiple toxin-mediated modalities targeting solid tumors are presently in the clinical trials. These modalities include cintredekin besudotox (IL13-PE38QQR) for glioblastoma [ 28 ], oportuzumab monatox (VB4-845) for urothelial carcinoma [ 29 ], naptumomab estafenatox for renal cell carcinoma [ 30 ], and LMB-100 for advanced pancreatic adenocarcinoma [ 31 ]. At the preclinical level, ITs have been developed and modified to target activated macrophages [ 32 ], murine noradrenergic neurons in the locus ceruleus [ 33 ], and human immunodeficiency virus (HIV)-infected cells [ 34 ].…”

Development of Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer: An Update

“…In some PE-based immunotoxin clinical trials, there have been adverse effects reported following treatment. Cardiac arrythmias, pneumonitis, hemolytic uremic syndrome, elevated liver enzymes and sepsis are some of the more severe side effects associated with immunotoxin treatment [73][74][75]. Other ribosomal inhibitor domains are also being explored in these current clinical trials.…”