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

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 anti-tumor activity. The objectives of this phase I/II study were to determine the maximum tolerated dose (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 & 8) with LMB-100 (65 or 100 mcg/kg on Days 1, 3 & 5) in 21-day cycles for 1-3 cycles. Results: Fourteen patients were treated on the dose-escalation and an additional 6 in the phase II expansion. MTD of 65 mcg/kg was established for the combination. Dose-limiting toxicity (DLT) resulting from capillary leak syndrome (CLS) was seen in 2 of 5 patients treated at 100 mcg/kg and 1 of 6 evaluable phase I patients receiving the MTD. Severity of CLS was associated with increases in apoptotic circulating endothelial cells (CECs). LMB-100 exposure was unaffected by anti-LMB-100 antibody formation in 5 of 13 patients during cycle 2. Seven of 17 evaluable patients experienced >50% decrease in CA 19-9, including 3 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.