Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors

• Published in: Pediatric blood & cancer Vol. 61; no. 1; pp. 128 - 133
• Main Authors: Morgenstern, Daniel A., Marzouki, Monia, Bartels, Ute, Irwin, Meredith S., Sholler, Giselle L.S., Gammon, Janet, Yankanah, Rosanna, Wu, Bing, Samson, Yvan, Baruchel, Sylvain
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.01.2014; Wiley Subscription Services, Inc
• Subjects: Adolescent; anti-angiogenesis; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Drug therapy; Female; Hematology; Humans; Male; Maximum Tolerated Dose; mTOR; Neoplasm Recurrence, Local - drug therapy; Neoplasms - drug therapy; Oncology; Pediatrics; Phase I; rapamycin; Receptors, Vascular Endothelial Growth Factor - blood; sirolimus; Sirolimus - administration & dosage; Sirolimus - adverse effects; Sirolimus - pharmacokinetics; Tumors; Vascular Endothelial Growth Factor A - blood; vinblastine; Vinblastine - administration & dosage; Vinblastine - adverse effects; Vinblastine - pharmacokinetics; Young Adult; mTOR; Phase I; vinblastine; anti-angiogenesis; sirolimus; rapamycin
• ISSN: 1545-5009; 1545-5017
• DOI: 10.1002/pbc.24656

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/m2/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. Pediatr Blood Cancer 2014;61:128–133. © 2013 Wiley Periodicals, Inc.