Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors.

Abstract

PURPOSE:

Inhibition of transforming growth factor-beta receptor I (TGF-beta RI)-mediated signaling pathways blocks tumor growth and metastases in nonclinical studies. Galunisertib (LY2157299), a small molecule inhibitor of TGF-beta RI serine/threonine kinase, had antitumor effects with acceptable safety/tolerability in a first-in-human dose (FHD) study conducted mainly in Caucasian patients with glioma. In this nonrandomized, open-label, dose-escalation study, we assessed safety/tolerability, pharmacokinetics (PK), and tumor response in Japanese patients.

METHODS:

Patients with advanced and/or metastatic disease refractory were assigned sequentially to Cohort-1 (80 mg) or Cohort-2 (150 mg) of galunisertib, administered twice daily and treated using 2-week on, 2-week off treatment cycles. Dose escalation was guided by predefined PK criteria and dose-limiting toxicities (DLT). Safety assessments included treatment-emergent adverse events (TEAEs) and cardiac safety (ultrasound cardiography/Doppler imaging, electrocardiogram, chest computed tomography, and cardiotoxicity serum biomarkers).

RESULTS:

Twelve patients (Cohort-1, n = 3; Cohort-2, n = 9) were enrolled and the most common types of cancer were pancreatic (n = 5) and lung cancer (n = 3). Seven patients (Cohort-1, n = 2; Cohort-2, n = 5) experienced possibly galunisertib-related TEAEs. The most frequent related TEAEs were brain natriuretic peptide increased (n = 2), leukopenia (n = 2), and rash (n = 2). No cardiovascular toxicities or other DLTs were reported. PK profile of galunisertib was consistent with the FHD study. Maximum plasma concentration was reached within 2 h post-dose, and the mean elimination half-life was 9 h.

CONCLUSIONS:

Galunisertib had an acceptable tolerability and safety profile in Japanese patients with advanced cancers. CLINICATRIALS.GOV.

IDENTIFIER:

NCT01722825.

• Authors: Yutaka Fujiwara, Hiroshi Nokihara, Yasuhide Yamada, Noboru Yamamoto, Kuniko Sunami, Hirofumi Utsumi, Hiroya Asou, Osamu TakahashI, Ken Ogasawara, Ivelina Gueorguieva, Tomohide Tamura
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 76 Issue 6 Pg. 1143-52 (Dec 2015) ISSN: 1432-0843 [Electronic] Germany
• PMID: 26526984 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrazoles
• Quinolines
• Receptors, Transforming Growth Factor beta
• LY-2157299
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I

Topics

• Adult
• Aged
• Area Under Curve
• Asian People
• Constipation (chemically induced)
• Dose-Response Relationship, Drug
• Exanthema (chemically induced)
• Female
• Humans
• Japan
• Male
• Metabolic Clearance Rate
• Middle Aged
• Neoplasms (drug therapy, ethnology, pathology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Pyrazoles (adverse effects, pharmacokinetics, therapeutic use)
• Quinolines (adverse effects, pharmacokinetics, therapeutic use)
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors)
• Sleep Initiation and Maintenance Disorders (chemically induced)
• Treatment Outcome