Reference Detail

Ref Type

Journal Article

PMID

(31707688)

Authors

Bendell JC, Bischoff HG, Hwang J, Reinhardt HC, Zander T, Wang X, Hynes S, Pitou C, Campbell R, Iversen P, Farrington DL, Bell-McGuinn K, Thomas M

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	38	4	2020 Aug	1145-1155	Invest New Drugs

URL

Abstract Text

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/m2 (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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Ralimetinib	Ralimetinib	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Ralimetinib		LY2228820\|LY-2228820\|LY 2228820	p38-alpha Inhibitor 1	Ralimetinib (LY2228820) is a selective ATP competitive inhibitor of p38 MAPK alpha (MAPK14) and beta (MAPK11), which inhibits tumor growth (PMID: 26581242, PMID: 24356814, PMID: 31791552, PMID: 31707688).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References