Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors. Issue 1 (17th August 2013)

• Record Type: Journal Article
• 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
• Is Part Of: Pediatric blood & cancer. Volume 61:Issue 1(2014:Jan.)
• Page Start: 128
• Page End: 133
• Publication Date: 2013-08-17
• Subjects: Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Cancer in children -- Periodicals; 618.92
• DOI: 10.1002/pbc.24656
• Languages: English
• ISSNs: 1545-5009

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="pbc24656-sec-0001" sec-type="section"> <title>Background</title> <p>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.</p> </sec> <sec id="pbc24656-sec-0002" sec-type="section"> <title>Procedure</title> <p>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<sup>2</sup>/dose according to 3 + 3 phase I design).</p> </sec> <sec id="pbc24656-sec-0003" sec-type="section"> <title>Results</title> <p>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.</p> </sec> <sec id="pbc24656-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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.</p> </sec> </abstract>