A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma

Invest New Drugs. 2020 Apr;38(2):457-467. doi: 10.1007/s10637-019-00783-7. Epub 2019 May 7.

Abstract

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.

Keywords: Combination therapy; FGF; Ligand trap; Mesothelioma; Phase 1.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Cisplatin / administration & dosage*
  • Cisplatin / adverse effects
  • Female
  • Fibroblast Growth Factor 2 / metabolism
  • Humans
  • Immunoglobulin G / administration & dosage*
  • Immunoglobulin G / adverse effects
  • Ligands
  • Male
  • Mesothelioma, Malignant / drug therapy*
  • Mesothelioma, Malignant / metabolism
  • Middle Aged
  • Oncogene Proteins, Fusion / administration & dosage*
  • Oncogene Proteins, Fusion / adverse effects
  • Oncogene Proteins, Fusion / pharmacokinetics
  • Pemetrexed / administration & dosage*
  • Pemetrexed / adverse effects
  • Receptor, Fibroblast Growth Factor, Type 1 / administration & dosage*
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Immunoglobulin G
  • Ligands
  • Oncogene Proteins, Fusion
  • Pemetrexed
  • Fibroblast Growth Factor 2
  • FP-1039
  • Receptor, Fibroblast Growth Factor, Type 1
  • Cisplatin