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 A 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 journalArticle

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

Fingerprint

LY-2157299
Growth Factor Receptors
Transforming Growth Factors
Phosphotransferases
Pharmacokinetics
Biomarkers
Epithelial-Mesenchymal Transition
Neoplasms
Glioma
Transforming Growth Factor beta
Lomustine
Proton Pump Inhibitors
Biological Availability
Blood Cells
Pharmacology
Safety
Mutation

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor i kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. / Rodón, Jordi; Carducci, Michael A; Sepulveda-Sánchez, Juan M.; Azaro, Analía; Calvo, Emiliano; Seoane, Joan; Braña, Irene; Sicart, Elisabet; Gueorguieva, Ivelina; Cleverly, Ann; Pillay, N. Sokalingum; Desaiah, Durisala; Estrem, Shawn T.; Paz-Ares, Luis; Holdhoff, Matthias; Blakeley, Jaishri; Lahn, Michael M.; Baselga, Jose.

In: Investigational New Drugs, Vol. 33, No. 2, 01.04.2015, p. 357-370.

Research output: Contribution to journalArticle

Rodón, J, Carducci, MA, Sepulveda-Sánchez, JM, Azaro, A, Calvo, E, Seoane, J, Braña, I, Sicart, E, Gueorguieva, I, Cleverly, A, Pillay, NS, Desaiah, D, Estrem, ST, Paz-Ares, L, Holdhoff, M, Blakeley, J, Lahn, MM & Baselga, J 2015, 'Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor i kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer', Investigational New Drugs, vol. 33, no. 2, pp. 357-370. https://doi.org/10.1007/s10637-014-0192-4
Rodón, Jordi ; Carducci, Michael A ; Sepulveda-Sánchez, Juan M. ; Azaro, Analía ; Calvo, Emiliano ; Seoane, Joan ; Braña, Irene ; Sicart, Elisabet ; Gueorguieva, Ivelina ; Cleverly, Ann ; Pillay, N. Sokalingum ; Desaiah, Durisala ; Estrem, Shawn T. ; Paz-Ares, Luis ; Holdhoff, Matthias ; Blakeley, Jaishri ; Lahn, Michael M. ; Baselga, Jose. / Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor i kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. In: Investigational New Drugs. 2015 ; Vol. 33, No. 2. pp. 357-370.
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AU - Sepulveda-Sánchez, Juan M.

AU - Azaro, Analía

AU - Calvo, Emiliano

AU - Seoane, Joan

AU - Braña, Irene

AU - Sicart, Elisabet

AU - Gueorguieva, Ivelina

AU - Cleverly, Ann

AU - Pillay, N. Sokalingum

AU - Desaiah, Durisala

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AU - Paz-Ares, Luis

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N2 - 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.

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