Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer

Invest New Drugs. 2015 Apr;33(2):357-70. doi: 10.1007/s10637-014-0192-4. Epub 2014 Dec 23.

Abstract

Purpose Transforming growth factor-beta (TGF-β) signaling plays a key role in epithelial-mesenchymal transition (EMT) of tumors, including malignant glioma. Small molecule inhibitors (SMI) blocking TGF-β signaling reverse EMT and arrest tumor progression. Several SMIs were developed, but currently only LY2157299 monohydrate (galunisertib) was advanced to clinical investigation. Design The first-in-human dose study had three parts (Part A, dose escalation, n = 39; Part B, safety combination with lomustine, n = 26; Part C, relative bioavailability study, n = 14). Results A preclinical pharmacokinetic/pharmacodynamic (PK/PD) model predicted a therapeutic window up to 300 mg/day and was confirmed in Part A after continuous PK/PD. PK was not affected by co-medications such as enzyme-inducing anti-epileptic drugs or proton pump inhibitors. Changes in pSMAD2 levels in peripheral blood mononuclear cells were associated with exposure indicating target-related pharmacological activity of galunisertib. Twelve (12/79; 15%) patients with refractory/relapsed malignant glioma had durable stable disease (SD) for 6 or more cycles, partial responses (PR), or complete responses (CR). These patients with clinical benefit had high plasma baseline levels of MDC/CCL22 and low protein expression of pSMAD2 in their tumors. Of the 5 patients with IDH1/2 mutation, 4 patients had a clinical benefit as defined by CR/PR and SD ≥6 cycles. Galunisertib had a favorable toxicity profile and no cardiac adverse events. Conclusion Based on the PK, PD, and biomarker evaluations, the intermittent administration of galunisertib at 300 mg/day is safe for future clinical investigation.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins
  • Adult
  • Aged
  • Anticonvulsants / pharmacology
  • Area Under Curve
  • Blood Cell Count
  • Chemokine CCL22
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Lomustine
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Proton Pump Inhibitors / pharmacology
  • Pyrazoles
  • Quinolines
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Smad2 Protein / biosynthesis
  • Tumor Suppressor Proteins

Substances

  • Anticonvulsants
  • Chemokine CCL22
  • Proton Pump Inhibitors
  • Pyrazoles
  • Quinolines
  • Receptors, Transforming Growth Factor beta
  • Smad2 Protein
  • Tumor Suppressor Proteins
  • LY-2157299
  • Lomustine
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • ADAM Proteins
  • ADAM11 protein, human