Phase i dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours

Jeffrey R. Infante, Glen J. Weiss, Suzanne Jones, Raoul Tibes, Todd M. Bauer, Johanna C. Bendell, James M. Hinson, Daniel D. Von Hoff, Howard A. Burris, Everardus O. Orlemans, Ramesk K Ramanathan

Research output: Contribution to journalArticle

21 Citations (Scopus)

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) 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.

Original languageEnglish (US)
Pages (from-to)2897-2904
Number of pages8
JournalEuropean Journal of Cancer
Volume50
Issue number17
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

HSP90 Heat-Shock Proteins
Night Blindness
Appointments and Schedules
Maximum Tolerated Dose
Diarrhea
Neoplasms
Pharmacokinetics
Adrenal Gland Neoplasms
Prodrugs
Nausea
Vomiting
Fatigue
Prostatic Neoplasms
Breast Neoplasms
Safety
PF 04929113
SNX 2112

Keywords

  • inhibitor
  • Keywords Heat shock protein 90
  • Phase I
  • SNX-2112
  • SNX-5422
  • Solid tumours

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Phase i dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours. / Infante, Jeffrey R.; Weiss, Glen J.; Jones, Suzanne; Tibes, Raoul; Bauer, Todd M.; Bendell, Johanna C.; Hinson, James M.; Von Hoff, Daniel D.; Burris, Howard A.; Orlemans, Everardus O.; Ramanathan, Ramesk K.

In: European Journal of Cancer, Vol. 50, No. 17, 2014, p. 2897-2904.

Research output: Contribution to journalArticle

Infante, JR, Weiss, GJ, Jones, S, Tibes, R, Bauer, TM, Bendell, JC, Hinson, JM, Von Hoff, DD, Burris, HA, Orlemans, EO & Ramanathan, RK 2014, 'Phase i dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours', European Journal of Cancer, vol. 50, no. 17, pp. 2897-2904. https://doi.org/10.1016/j.ejca.2014.07.017
Infante, Jeffrey R. ; Weiss, Glen J. ; Jones, Suzanne ; Tibes, Raoul ; Bauer, Todd M. ; Bendell, Johanna C. ; Hinson, James M. ; Von Hoff, Daniel D. ; Burris, Howard A. ; Orlemans, Everardus O. ; Ramanathan, Ramesk K. / Phase i dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours. In: European Journal of Cancer. 2014 ; Vol. 50, No. 17. pp. 2897-2904.
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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) 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.",
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T1 - Phase i dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours

AU - Infante, Jeffrey R.

AU - Weiss, Glen J.

AU - Jones, Suzanne

AU - Tibes, Raoul

AU - Bauer, Todd M.

AU - Bendell, Johanna C.

AU - Hinson, James M.

AU - Von Hoff, Daniel D.

AU - Burris, Howard A.

AU - Orlemans, Everardus O.

AU - Ramanathan, Ramesk K

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - inhibitor

KW - Keywords Heat shock protein 90

KW - Phase I

KW - SNX-2112

KW - SNX-5422

KW - Solid tumours

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