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) 3 weeks on/1 week 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 3 weeks on/1 week off, n = 17; QD continuous, n = 3. Doses ranged from 4 to 133 mg/m2 QOD and 50 to 89 mg/m2 QD. The MTDs were defined as 100 mg/m2 QOD and 67 mg/m2 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: 50-89 mg/m2 QD; 100 mg/m2 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 100 mg/m2 QOD 3 weeks on/1 week off based on improved tolerability and preliminary evidence of clinical activity.
- Keywords Heat shock protein 90
- Phase I
- Solid tumours
ASJC Scopus subject areas
- Cancer Research