Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125

Cancer. 2014 Nov 1;120(21):3311-9. doi: 10.1002/cncr.28875. Epub 2014 Jul 2.

Abstract

Background: The primary objective of this study was to determine the safety and maximum tolerated dose (MTD) of the antimesothelin immunotoxin SS1(dsFv)PE38 (SS1P) (a recombinant antimesothelin immunotoxin consisting of a murine antimesothelin variable antibody fragment [Fv] linked to PE38, a truncated portion of Pseudomonas exotoxin A) in combination with pemetrexed and cisplatin in chemotherapy-naive patients with advanced malignant pleural mesothelioma (MPM). Secondary objectives included tumor response, SS1P pharmacokinetics, and serum biomarkers of response.

Methods: Chemotherapy-naive patients with stage III or IV, unresectable, epithelial or biphasic MPM and normal organ functions were eligible. Pemetrexed (500 mg/m(2) on day 1) and cisplatin (75 mg/m(2) on day 1) were administered every 3 weeks for up to 6 cycles with escalating doses of SS1P administered intravenously on days 1, 3, and 5 during cycles 1 and 2. Tumor response was evaluated every 6 weeks.

Results: Twenty-four patients received SS1P at 4 dose levels from 25 to 55 mcg/kg. Grade 3 fatigue was dose-limiting in 1 patient at 55 mcg/kg. The MTD of SS1P was established as 45 mcg/kg. Other grade 3 toxicities associated with SS1P included hypoalbuminemia (21%), back pain (13%), and hypotension (8%). Of 20 evaluable patients, 12 (60%) had a partial response, 3 had stable disease, and 5 had progressive disease. Of 13 patients who received the MTD, 10 (77%) had a partial response, 1 had stable disease, and 2 had progressive disease. Objective radiologic responses were associated with significant decreases in serum mesothelin (P=.0030), megakaryocyte potentiating factor (P=.0005), and cancer antigen 125 (P < .0001).

Conclusions: SS1P given with pemetrexed and cisplatin is safe and well tolerated and exhibits significant antitumor activity in patients with unresectable, advanced pleural mesothelioma. Serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125 levels correlated with objective tumor responses.

Keywords: SS1P; immunotoxin; mesothelin; pleural mesothelioma.

Publication types

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

MeSH terms

  • ADP Ribose Transferases
  • Aged
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / blood
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Bacterial Toxins
  • CA-125 Antigen / blood
  • Cisplatin / administration & dosage
  • Exotoxins
  • Female
  • GPI-Linked Proteins / administration & dosage
  • GPI-Linked Proteins / blood
  • Glutamates / administration & dosage*
  • Guanine / administration & dosage
  • Guanine / analogs & derivatives*
  • Humans
  • Lung Neoplasms / blood
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Male
  • Maximum Tolerated Dose
  • Mesothelioma / blood
  • Mesothelioma / drug therapy*
  • Mesothelioma / pathology
  • Middle Aged
  • Neoplasm Staging
  • Pemetrexed
  • Pleural Neoplasms / blood
  • Pleural Neoplasms / drug therapy*
  • Pleural Neoplasms / pathology
  • Virulence Factors

Substances

  • Antibodies, Monoclonal
  • Bacterial Toxins
  • CA-125 Antigen
  • Exotoxins
  • GPI-Linked Proteins
  • Glutamates
  • SS1(dsFv)PE38
  • Virulence Factors
  • Pemetrexed
  • Guanine
  • ADP Ribose Transferases
  • toxA protein, Pseudomonas aeruginosa
  • mesothelin
  • Cisplatin

Supplementary concepts

  • Mesothelioma, Malignant