Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors
| العنوان: | Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors |
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| المؤلفون: | Fabienne Hollinger, Kieuhoa T. Vo, Steven G. DuBois, Nicole Nasholm, Janel Long-Boyle, Katherine K. Matthay, Stephen Shiboski, Erin E. Karski, W. Clay Gustafson, Shelly Allen |
| المصدر: | Oncotarget, vol 8, iss 14 Oncotarget |
| بيانات النشر: | Impact Journals, LLC, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Pharmacology, Gastroenterology, 0302 clinical medicine, Antibiotics, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Epidemiology, Child, Stomatitis, Cancer, Pediatric, Antibiotics, Antineoplastic, Antineoplastic, Local, Oncology, 6.1 Pharmaceuticals, 030220 oncology & carcinogenesis, mTOR, Female, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Cyclophosphamide, Oncology and Carcinogenesis, Young Adult, 03 medical and health sciences, topotecan, Refractory, Clinical Research, Internal medicine, medicine, Humans, Sirolimus, business.industry, Evaluation of treatments and therapeutic interventions, medicine.disease, Regimen, Neoplasm Recurrence, 030104 developmental biology, phase 1, Pharmacodynamics, cyclophosphamide, Topotecan, Clinical Research Paper, Neoplasm Recurrence, Local, business |
| الوصف: | // Kieuhoa T. Vo 1 , Erin E. Karski 1 , Nicole M. Nasholm 1 , Shelly Allen 1 , Fabienne Hollinger 1 , W. Clay Gustafson 1 , Janel R. Long-Boyle 2 , Stephen Shiboski 3 , Katherine K. Matthay 1 and Steven G. DuBois 1 1 Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA 2 Department of Clinical Pharmacy, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA 3 Department of Epidemiology and Biostatistics, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA Correspondence to: Kieuhoa T. Vo, email: // Keywords : phase 1, mTOR, sirolimus, topotecan, cyclophosphamide Received : August 23, 2016 Accepted : October 13, 2016 Published : October 25, 2016 Abstract Purpose: To determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population. Materials and Methods: Patients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m 2 /dose) on days 1-21 and oral topotecan (0.8 mg/m 2 /dose) on days 1-14 in 28-day cycles. Sirolimus steady-state plasma trough concentrations of 3-7.9 ng/mL and 8-12.0 ng/mL were evaluated, with dose escalation based on a 3+3 phase 1 design. Biomarkers of angiogenesis were also evaluated. Results: Twenty-one patients were treated (median age 18 years; range 9-30). Dose-limiting toxicities included myelosuppression, ALT elevation, stomatitis, and hypertriglyceridemia. The MTD was sirolimus with trough goal of 8-12.0 ng/mL; cyclophosphamide 25 mg/m 2 /dose; and topotecan 0.8 mg/m 2 /dose. No objective responses were observed. Four patients had prolonged stable disease > 4 cycles (range 4-12). Correlative biomarker analyses demonstrated reductions in thrombospondin-1 ( p =0.043) and soluble vascular endothelial growth factor receptor-2 plasma concentrations at 21 days compared to baseline. Conclusions: The combination of oral sirolimus, topotecan, and cyclophosphamide was well tolerated and biomarker studies demonstrated modulation of angiogenic pathways with this regimen. |
| وصف الملف: | application/pdf |
| تدمد: | 1949-2553 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cb643748933bb90166710c0938477b07Test https://doi.org/10.18632/oncotarget.12904Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cb643748933bb90166710c0938477b07 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19492553 |
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