A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma

J Neurooncol. 2020 Jan;146(1):79-89. doi: 10.1007/s11060-019-03337-2. Epub 2019 Nov 27.

Abstract

Purpose: To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D) for combined INC280 and buparlisib in patients with recurrent glioblastoma with homozygous phosphatase and tensin homolog (PTEN) deletion, mutation or protein loss.

Methods: This multicenter, open-label, Phase Ib/II study included adult patients with glioblastoma with mesenchymal-epithelial transcription factor (c-Met) amplification. In Phase Ib, patients received INC280 as capsules or tablets in combination with buparlisib. In Phase II, patients received INC280 only. Response was assessed centrally using Response Assessment in Neuro-Oncology response criteria for high-grade gliomas. All adverse events (AEs) were recorded and graded.

Results: 33 patients entered Phase Ib, 32 with altered PTEN. RP2D was not declared due to potential drug-drug interactions, which may have resulted in lack of efficacy; thus, Phase II, including 10 patients, was continued with INC280 monotherapy only. Best response was stable disease in 30% of patients. In the selected patient population, enrollment was halted due to limited activity with INC280 monotherapy. In Phase Ib, the most common treatment-related AEs were fatigue (36.4%), nausea (30.3%) and increased alanine aminotransferase (30.3%). MTD was identified at INC280 Tab 300 mg twice daily + buparlisib 80 mg once daily. In Phase II, the most common AEs were headache (40.0%), constipation (30.0%), fatigue (30.0%) and increased lipase (30.0%).

Conclusion: The combination of INC280/buparlisib resulted in no clear activity in patients with recurrent PTEN-deficient glioblastoma. More stringent molecular selection strategies might produce better outcomes.

Trial registration: NCT01870726.

Keywords: Buparlisib; Capmatinib; Glioblastoma; INC280; PTEN; c-Met.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aminopyridines / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Female
  • Follow-Up Studies
  • Glioblastoma / drug therapy*
  • Glioblastoma / genetics
  • Glioblastoma / pathology
  • Humans
  • Imidazoles / administration & dosage
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Morpholines / administration & dosage
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • PTEN Phosphohydrolase / genetics
  • Prognosis
  • Proto-Oncogene Proteins c-met / genetics
  • Tissue Distribution
  • Triazines / administration & dosage

Substances

  • Aminopyridines
  • Imidazoles
  • Morpholines
  • NVP-BKM120
  • Triazines
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • capmatinib

Associated data

  • ClinicalTrials.gov/NCT01870726