Abstract CT030: STARTRK-NG: A phase 1/1b study of entrectinib in children and adolescents with advanced solid tumors and primary CNS tumors, with or without TRK, ROS1, or ALK fusions
Authors: Desai Ami V. , Brodeur Garrett M. , Foster Jennifer , Shusterman Suzanne , Sabnis Amit J. , Macy Magaret , Wetmore Cynthia , Basu Ellen , Hornby Zachary , Esquibel Vanessa , Maneval Edna Chow , Multani Pratik S. , Fox Elizabeth 
Published: July 2017

Abstract
Background: The STARTRK-NG (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases - Next Generation) trial is a Phase 1/1b dose-escalation and expansion study of entrectinib in pediatric patients with cancer. Entrectinib is a potent oral, CNS-penetrant, inhibitor of the tyrosine kinases TRKA/B/C (encoded by the genes NTRK1/2/3, respectively), ROS1, and ALK with IC50s &lt; 2 nM (biochemical kinase assay). Three adult studies (Phase 1 ALKA-372-001, Phase 1 STARTRK-1, and Phase 2 STARTRK-2) have enrolled hundreds of patients with advanced or metastatic solid tumors harboring TRKA/B/C, ROS1, or ALK molecular alterations, with or without CNS disease. Previously, we reported 400 mg/m2 daily as the adult body surface area (BSA)-based Recommended Phase 2 Dose (RP2D) (Patel et al, ASCO 2015). An objective response rate of 79% was seen in 24 tyrosine kinase inhibitor-naïve patients with TRK, ROS1, or ALK fusions who were treated at doses consistent with the RP2D (Drilon et al, AACR 2016). Gene fusions have been observed in a variety of adult solid tumor types, including non-small cell lung cancer, salivary gland cancers, soft tissue sarcomas and glioneuronal tumors. These fusions have also been found in cancers that affect the pediatric population, such as infantile fibrosarcoma, juvenile breast cancer, mesoblastic nephroma, intrinsic pontine gliomas, acute leukemias and anaplastic lymphoma. In addition, overexpression of TRKB and activating ALK point mutations have been observed in neuroblastoma. Thus, a pan-TRK, ROS1, and ALK inhibitor, like entrectinib, may potentially have broad therapeutic utility in pediatric patients.
Methods: This is a multicenter, dose escalation study in pediatric patients (aged 2-21 years) with relapsed or refractory extracranial solid tumors (Phase 1), with additional expansion cohorts (Phase 1b) in patients with primary brain tumors harboring TRK, ROS1, or ALK molecular alterations inclusive of gene fusions, neuroblastoma, and other non-neuroblastoma, extracranial solid tumors harboring TRK, ROS1, or ALK gene fusions (NCT02650401). During dose escalation, a 3+3 schema will be used to determine the pediatric RP2D of entrectinib with a starting dose of 250 mg/m2 (approximately 60% of the adult BSA-based RP2D), administered orally once daily in repeated 4-week cycles, with concordant pharmacokinetics and pharmacodynamics studies. Up to four dose levels will be evaluated. Dose modifications, if necessary, will follow a protocol-specific dosing nomogram for each dose level. Once the pediatric RP2D is determined, the Phase 1b expansion cohorts will be opened simultaneously, and prospective molecular profiling will be performed to determine eligibility except for patients with neuroblastoma.
Citation Format: Ami V. Desai, Garrett M. Brodeur, Jennifer Foster, Suzanne Shusterman, Amit J. Sabnis, Magaret Macy, Cynthia Wetmore, Ellen Basu, Zachary Hornby, Vanessa Esquibel, Edna Chow Maneval, Pratik S. Multani, Elizabeth Fox. STARTRK-NG: A phase 1/1b study of entrectinib in children and adolescents with advanced solid tumors and primary CNS tumors, with or without TRK, ROS1, or ALK fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT030. doi:10.1158/1538-7445.AM2017-CT030