Phase I dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours.
Eur J Cancer
; 50(17): 2897-904, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25262379
ABSTRACT
BACKGROUND:
Orally administered SNX-5422, a novel, selective prodrug of the Heat shock protein 90 (Hsp90) inhibitor SNX-2112, was investigated in two sequential phase I studies to determine the safety, maximum tolerated doses (MTDs) and pharmacokinetic profile of SNX-5422.METHODS:
Using a dose-escalation design, 3-6 adults with advanced solid tumours received SNX-5422 every-other-day (QOD) or once-daily (QD) 3weeks on/1week off or QD continuously, with disease assessments every 8 weeks. Single-dose and steady-state pharmacokinetic parameters of SNX-2112 were determined.RESULTS:
In total, 56 patients were enrolled QOD 3 weeks on/1 week off, n=36; QD 3weeks on/1 week off, n=17; QD continuous, n=3. Doses ranged from 4 to 133mg/m(2) QOD and 50 to 89 mg/m(2) QD. The MTDs were defined as 100mg/m(2) QOD and 67 mg/m(2) QD, respectively, with diarrhoea being dose-limiting on both 3 weeks on/1 week off schedules. Overall, treatment-related adverse events were mainly low grade, including diarrhoea (64%), nausea (39%), fatigue (28%), and vomiting (28%). Reversible grade 1-3 nyctalopia (night blindness) was reported by four patients (dose 50-89mg/m(2) QD; 100mg/m(2) QOD). Exposure was generally linear, though greater than dose-proportional. Of 32 evaluable patients on QOD dosing, there was one durable complete response (prostate cancer), one confirmed (HER2+breast cancer) and one unconfirmed partial response (adrenal gland cancer). Three patients (QOD schedule) had stable disease for ⩾ 6 months.CONCLUSIONS:
The dose and schedule recommended for further study with SNX-5422 is 100mg/m(2) QOD 3 weeks on/1 week off based on improved tolerability and preliminary evidence of clinical activity.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Choque Térmico HSP90
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Neoplasias
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Antineoplásicos
Tipo de estudo:
Clinical_trials
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Eur J Cancer
Ano de publicação:
2014
Tipo de documento:
Article