Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors.
Oncotarget
; 8(14): 23851-23861, 2017 Apr 04.
Article
in En
| MEDLINE
| ID: mdl-27793021
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 ANDMETHODS:
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/m2/dose) on days 1-21 and 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.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/m2/dose; and 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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antineoplastic Combined Chemotherapy Protocols
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Neoplasm Recurrence, Local
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Neoplasms
Limits:
Adolescent
/
Adult
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Child
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Female
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Humans
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Male
Language:
En
Journal:
Oncotarget
Year:
2017
Document type:
Article
Affiliation country:
United States
Country of publication:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
/
USA