Phase I dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor,in patients with refractory solid tumours |
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| Institution: | 1. Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA;2. Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ, USA;3. Unicorn Pharma Consulting, Brentwood, TN, USA;4. Esanex Inc, Indianapolis, IN, USA;1. Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China;2. Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210002, China;1. Institute of Pathology, Charité University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany;2. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany;3. Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany;4. Tissue Bank of the National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany;5. Division of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer 581, 69120 Heidelberg, Germany;6. Institute of Pathology, SLK-Clinics Heilbronn, Am Gesundbrunnen 20-26, 74078 Heilbronn, Germany;1. Department of Gynaecology and Obstetrics, University Ulm, Prittwitzstraße 43, 89075 Ulm, Germany;2. Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Centre, Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 69, 55131 Mainz, Germany;3. Department of economics, Institute for medical biostistics, epidemiology and informatics, University medical centre, Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 69, Mainz, Germany;1. Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA;2. Wolfson Centre for Mathematical Biology, Mathematical Institute, Radcliffe Observatory Quarter, University of Oxford, Woodstock Road, Oxford OX2 6GG, UK;3. Mathematical Sciences, University of Gothenburg and Chalmers University of Technology, 412 96 Gothenburg, Sweden;1. Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany;2. Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;3. Institute of Radiotherapy, University of Cologne, Cologne, Germany;1. Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium;2. Laboratory Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium;3. Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium;4. Gynecology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium;5. Electrical Engineering (ESAT-SISTA), KU Leuven, Herestraat 49, 3000 Leuven, Belgium;6. Multidisciplinary Breast Center, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium;7. General Medical Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium;8. Cardiovascular Sciences, KU Leuven, Herestraat 49, 3000 Leuven, Belgium |
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| Abstract: | BackgroundOrally 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.MethodsUsing 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.ResultsIn 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.ConclusionsThe 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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| Keywords: | Heat shock protein 90 inhibitor Phase I SNX-5422 SNX-2112 Solid tumours |
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