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

Jordi Rodón, Michael Carducci, Juan M. Sepulveda-Sánchez, Analía Azaro, Emiliano Calvo, Joan Seoane, Irene Braña, Elisabet Sicart, Ivelina Gueorguieva, Ann Cleverly, N. Sokalingum Pillay, Durisala Desaiah, Shawn T. Estrem, Luis Paz-Ares, Matthias Holdhoff, Jaishri Blakeley, Michael M. Lahn, Jose Baselga

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)357-370
Number of pages14
JournalInvestigational New Drugs
Volume33
Issue number2
DOIs
StatePublished - Apr 1 2015

Keywords

  • First-in-Human Dose
  • Galunisertib
  • Glioma
  • Pharmacodynamics
  • Pharmacokinetics
  • TGF-β inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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