Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer
Adult
Male
0301 basic medicine
Maximum Tolerated Dose
Enzyme-Linked Immunosorbent Assay
Protein Serine-Threonine Kinases
Drug Administration Schedule
03 medical and health sciences
Lomustine
Phase I Studies
Neoplasms
Humans
Pharmacology (medical)
Drug Interactions
Aged
Pharmacology
Chemokine CCL22
Dose-Response Relationship, Drug
Middle Aged
Blood Cell Count
3. Good health
ADAM Proteins
Oncology
Area Under Curve
Leukocytes, Mononuclear
Anticonvulsants
Female
DOI:
10.1007/s10637-014-0192-4
Publication Date:
2014-12-22T02:10:28Z
AUTHORS (18)
ABSTRACT
SummaryPurpose 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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CITATIONS (87)
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