TY - JOUR
T1 - Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors
AU - Weiss, Glen J.
AU - Jameson, Gayle
AU - Von Hoff, Daniel D.
AU - Valsasina, Barbara
AU - Davite, Cristina
AU - Di Giulio, Claudia
AU - Fiorentini, Francesco
AU - Alzani, Rachele
AU - Carpinelli, Patrizia
AU - Di Sanzo, Alessandro
AU - Galvani, Arturo
AU - Isacchi, Antonella
AU - Ramanathan, Ramesh K.
N1 - Publisher Copyright:
© 2017, Springer Science+Business Media, LLC.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Methods This was a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors. A treatment cycle comprised 5 days of oral administration followed by 16 days of rest, for a total of 21 days (3-week cycle). Results Nineteen of 21 enrolled patients with confirmed metastatic disease received study medication. No DLTs occurred at the first 3 dose levels (6, 12, and 24 mg/m2/day). At the subsequent dose level (48 mg/m2/day), 2 of 3 patients developed DLTs. An intermediate level of 36 mg/m2/day was therefore investigated. Four patients were treated and two DLTs were observed. After further cohort expansion, the MTD and recommended phase II dose (RP2D) were determined to be 24 mg/m2/day. Disease stabilization, observed in several patients, was the best treatment response observed. Hematological toxicity (mostly thrombocytopenia and neutropenia) was the major DLT. Systemic exposure to NMS-1286937 increased with dose and was comparable between two cycles of treatment following oral administration of the drug. Conclusions This study successfully identified the MTD and DLTs for NMS-1286937 and characterized its safety profile.
AB - Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Methods This was a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors. A treatment cycle comprised 5 days of oral administration followed by 16 days of rest, for a total of 21 days (3-week cycle). Results Nineteen of 21 enrolled patients with confirmed metastatic disease received study medication. No DLTs occurred at the first 3 dose levels (6, 12, and 24 mg/m2/day). At the subsequent dose level (48 mg/m2/day), 2 of 3 patients developed DLTs. An intermediate level of 36 mg/m2/day was therefore investigated. Four patients were treated and two DLTs were observed. After further cohort expansion, the MTD and recommended phase II dose (RP2D) were determined to be 24 mg/m2/day. Disease stabilization, observed in several patients, was the best treatment response observed. Hematological toxicity (mostly thrombocytopenia and neutropenia) was the major DLT. Systemic exposure to NMS-1286937 increased with dose and was comparable between two cycles of treatment following oral administration of the drug. Conclusions This study successfully identified the MTD and DLTs for NMS-1286937 and characterized its safety profile.
KW - Advanced/metastatic solid tumors
KW - Clinical trial
KW - Phase I
KW - Polo-like kinase 1
UR - http://www.scopus.com/inward/record.url?scp=85025090837&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85025090837&partnerID=8YFLogxK
U2 - 10.1007/s10637-017-0491-7
DO - 10.1007/s10637-017-0491-7
M3 - Article
C2 - 28726132
AN - SCOPUS:85025090837
SN - 0167-6997
VL - 36
SP - 85
EP - 95
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 1
ER -