Abstract A48: Phase I study of Everolimus (mTOR inhibitor) in combination with Vandetanib (multikinase inhibitor of EGFR,VEGFR,RET) in children, adolescents, and young adults with advanced solid tumors
Authors: Moonat Hatel Rana , Roxas Michael , Huh Winston W. , Herzog Cynthia E. , Piha-Paul Sarina , Daw Najat C. , Rytting Michael , Mote Estella , Ward Erica N. , Amin Yazan , Meric-Bernstam Funda , Schwartz Cindy L. , Subbiah Vivek 
Published: May 2016

Abstract
Background: Early phase clinical trials are often limited to adults, reducing the opportunity to explore safety and efficacy of new agents in children. Pre-clinical models have shown that combining an mTOR inhibitor (everolimus) with a multikinase VEGFR2 inhibitor (vandetanib) overcomes intrinsic and /or acquired resistance to either agent alone. Since this combination may have activity against pediatric cancer, pediatric patients were eligible for enrollment (NCT01582191).
Methods: We designed a conventional 3+3 Phase I study to determine the safety, maximum tolerated dose (MTD), recommended Phase II dose (RP2D), and dose-limiting toxicities (DLTs) of this combination using oral vandetanib and oral everolimus in pediatric patients with advanced solid tumors. Younger patients were enrolled at the accruing dose level, with BSA-based dose adjustments for smaller children. Tumor responses were assessed using RECIST v1.1.
Results: To date, 15 pediatric patients were enrolled between February 2013 and May 2015. The median age was 18 years (range 8-26 years) and 8 patients (53%) were male. The most common diagnosis was sarcoma (n=9; 5 soft tissue and 4 bone). Seven patients (47%) had 2 or more sites of metastases. One patient was treated at dose level 0 (vandetanib 100 mg daily + everolimus 2.5 mg daily), another at dose level 1 (vandetanib 200 mg daily + everolimus 2.5 mg daily), and 13 patients at dose level 4 (determined to be the MTD, vandetanib 300 mg daily + everolimus 10 mg daily). The most common adverse events observed in patients across different dose levels included G1 rash (n=4); G1 fatigue (n=2); G1-G2 hypertension (n=2); G1-G2 QTc prolongation (n=2); G1-G4 transaminitis (n=4); G1-G4 thrombocytopenia (n=3). Eight patients (53%) were taken off study due to disease progression and one patient (7%) due to drug toxicity. One patient with epithelioid sarcoma had a PR (74% tumor size reduction) and one patient with AKT1 p.E17K mutant pseudopapillary pancreatic tumor had a 15% reduction in tumor size. In addition, two patients with alveolar soft part sarcoma had stable disease with clinical benefit.
Conclusions: The toxicities of the combination of everolimus with vandetanib seen in children are similar to those seen in adults. Evidence of response was noted in heavily pre-treated pediatric patients with refractory solid tumors. Including younger patients in institutional phase I trials provides a mechanism to study new combinations in children.
Note: This abstract was not presented at the conference.
Citation Format: Hatel Rana Moonat, Michael Roxas, Winston W. Huh, Cynthia E. Herzog, Sarina Piha-Paul, Najat C. Daw, Michael Rytting, Estella Mote, Erica N. Ward, Yazan Amin, Funda Meric-Bernstam, Cindy L. Schwartz, Vivek Subbiah. Phase I study of Everolimus (mTOR inhibitor) in combination with Vandetanib (multikinase inhibitor of EGFR,VEGFR,RET) in children, adolescents, and young adults with advanced solid tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A48.