Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors.
Pediatr Blood Cancer
; 61(1): 128-33, 2014 Jan.
Article
de En
| MEDLINE
| ID: mdl-23956145
ABSTRACT
BACKGROUND:
The combination of vinblastine and mammalian target of rapamycin (mTOR) inhibitor sirolimus inhibits the growth of neuroblastoma xenografts through pro-apoptotic and anti-angiogenic mechanisms. This phase I study aimed to explore the safety and toxicity of this combination in pediatric patients with advanced solid tumors. PROCEDURE Patients ≤21 years of age with recurrent/refractory solid tumors (including CNS) were eligible. Sirolimus was administered daily by mouth or nasogastric (NG) tube, with doses adjusted to achieve a target trough concentration of 10-15 ng/ml, with weekly intravenous vinblastine (dose escalated 4-6 mg/m(2)/dose according to 3 + 3 phase I design).RESULTS:
Fourteen patients were enrolled (median age 8.7 years; range 2.3-19) of whom 12 were evaluable for toxicity and 11 for response. One patient experienced a dose-limiting toxicity (grade 3 mucositis) at the highest vinblastine dose level. Myelosuppression was the most common toxicity. Dose-adjusted sirolimus trough concentrations were significantly lower in patients receiving drug via NG tube (1.50 ± 0.75 ng/ml/mg vs. 2.25 ± 1.07 ng/ml/mg for oral administration). Correlative biomarker analysis demonstrated a significant reduction in serum concentration of soluble vascular endothelial growth factor receptor (sVEGFR2) at 28 days compared to baseline consistent with inhibition of angiogenesis. One patient had a partial response and three had stable disease for more than 3 months.CONCLUSIONS:
The combination of mTOR inhibitor and vinblastine given over an extended continuous schedule is safe, associated with a reduction in circulating angiogenic factor (CAF) VEGFR2 and resulted in clinical responses. Future studies using the intravenously administered mTOR inhibitor temsirolimus are planned.Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protocoles de polychimiothérapie antinéoplasique
/
Tumeurs
Type d'étude:
Clinical_trials
Limites:
Adolescent
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Adult
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Child
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Child, preschool
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Female
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Humans
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Male
Langue:
En
Journal:
Pediatr Blood Cancer
Sujet du journal:
HEMATOLOGIA
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NEOPLASIAS
/
PEDIATRIA
Année:
2014
Type de document:
Article
Pays d'affiliation:
Canada