Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer.
Cancer Chemother Pharmacol
; 79(2): 315-326, 2017 Feb.
Article
em En
| MEDLINE
| ID: mdl-28097385
ABSTRACT
PURPOSE:
This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor.METHODS:
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.RESULTS:
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.CONCLUSIONS:
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Tiadiazóis
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Cinesinas
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Neoplasias
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article