Vo KT, Karski EE, Nasholm NM, Allen S, Hollinger F, Gustafson WC, Long-Boyle JR, Shiboski S, Matthay KK, and DuBois SG1 from the Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA; the Department of Clinical Pharmacy, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, and the Department of Epidemiology and Biostatistics, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA have just published a new metronomic phase I trial in Oncotarget entitled : Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors. In this article, the athors aimed to o determine the MTD, toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and metronomic cyclophosphamide in a pediatric population.
Patients received :
- daily oral sirolimus
daily oral cyclophosphamide (25-50 mg/m2/dose) on days 1-21
daily oral oral topotecan (0.8 mg/m2/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.
21 patients with relapsed/refractory solid tumors (including CNS) 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/m2/dose;
topotecan 0.8 mg/m2/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. It does not seem to be more efficient that previous more simple metronomic treatment with topotecan-cyclophosphamide
the full textg can be found freely on the oncotarget website=12904&pubmed-linkout=1].