Bendell, Johanna C., Bischoff, Helge G., Hwang, Jimmy, Reinhardt, Hans Christian, Zander, Thomas, Wang, Xuejing, Hynes, Scott, Pitou, Celine, Campbell, Robert, Iversen, Philip, Farrington, Daphne L., Bell-McGuinn, Katherine and Thomas, Michael (2020). A phase 1 dose-escalation study of checkpoint kinase 1 (CHK1) inhibitor prexasertib in combination with p38 mitogen-activated protein kinase (p38 MAPK) inhibitor ralimetinib in patients with advanced or metastatic cancer. Invest. New Drugs, 38 (4). S. 1145 - 1156. DORDRECHT: SPRINGER. ISSN 1573-0646

Full text not available from this repository.

Abstract

Purpose The primary objective was to determine the recommended Phase 2 dose (RP2D) of checkpoint kinase 1 inhibitor, prexasertib, in combination with the p38 mitogen-activated protein kinase inhibitor, ralimetinib, which may be safely administered to patients with advanced cancer. Methods This Phase 1, nonrandomized, open-label, dose-escalation study of prexasertib+ralimetinib included patients with advanced and/or metastatic cancer, followed by a planned cohort expansion in patients with colorectal or non-small-cell lung cancer with KRAS and/or BRAF mutations. Intravenous prexasertib was administered at 60 mg/m(2) (days 1 and 15 of a 28-day cycle), together with oral ralimetinib every 12 h (days 1 to 14 at 100 mg [Cohort 1, n = 3] or 200 mg [Cohort 2, n = 6]). Dose escalations for each agent were planned using a model-based 3 + 3 escalation paradigm. Safety was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0X. Tumor response was determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results Nine patients were treated; 3 experienced dose-limiting toxicities, all in Cohort 2, prohibiting further dose escalation. The most common >= Grade 3 adverse event was neutrophil count decreased; other reported >= Grade 3 hematological toxicities included febrile neutropenia and anemia. The pharmacokinetics of prexasertib+ralimetinib was comparable to the monotherapy population profile for each agent. One patient achieved a best overall response of stable disease (for 2 cycles); there were no complete/partial responses. Conclusions This study did not achieve its primary objective of establishing an RP2D of combination prexasertib + ralimetinib that could be safely administered to patients with advanced cancer.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bendell, Johanna C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bischoff, Helge G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hwang, JimmyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, XuejingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hynes, ScottUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pitou, CelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iversen, PhilipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Farrington, Daphne L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bell-McGuinn, KatherineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-127904
DOI: 10.1007/s10637-019-00873-6
Journal or Publication Title: Invest. New Drugs
Volume: 38
Number: 4
Page Range: S. 1145 - 1156
Date: 2020
Publisher: SPRINGER
Place of Publication: DORDRECHT
ISSN: 1573-0646
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LY2228820 DIMESYLATE; CELL-CYCLE; DNA; REPLICATION; CRITERIAMultiple languages
Oncology; Pharmacology & PharmacyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12790

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item