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

Clin Cancer Res. 2020 Feb 15;26(4):828-836. doi: 10.1158/1078-0432.CCR-19-2586. Epub 2019 Dec 2.

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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Albumins / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Drug Administration Schedule
  • Female
  • GPI-Linked Proteins / antagonists & inhibitors
  • Humans
  • Immunoconjugates / administration & dosage
  • Male
  • Maximum Tolerated Dose
  • Mesothelin
  • Middle Aged
  • Molecular Targeted Therapy
  • Paclitaxel / administration & dosage
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology

Substances

  • 130-nm albumin-bound paclitaxel
  • Albumins
  • GPI-Linked Proteins
  • Immunoconjugates
  • LMB-100
  • Mesothelin
  • Paclitaxel