Reference Detail

Ref Type

Journal Article

PMID

(28097385)

Authors

Infante JR, Patnaik A, Verschraegen CF, Olszanski AJ, Shaheen M, Burris HA, Tolcher AW, Papadopoulos KP, Beeram M, Hynes SM, Leohr J, Lin AB, Li LQ, McGlothlin A, Farrington DL, Westin EH, Cohen RB

Title

Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer chemotherapy and pharmacology	79	2	2017 Feb	315-326	Cancer Chemother Pharmacol

URL

Abstract Text

This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor.Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125-16 mg/m2/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels.One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/m2/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies.On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/m2/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/m2/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle.

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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
Litronesib	Litronesib	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Litronesib		LY2523355\|KF89617		Litronesib (LY2523355) is a selective inhibitor of Kif11 that induces mitotic arrest and apoptosis in tumor cells (PMID: 26304237, PMID: 28097385).

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