Abstract LB-174: Translation of preclinical predictive sensitivity of Ewing sarcoma to PARP inhibition: Phase II study of olaparib in adult patients with recurrent/metastatic Ewing sarcoma following failure of prior chemotherapy.
Authors: Choy Edwin , Butrynski James , Harmon David , Morgan Jeffrey , George Suzanne , Wagner Andrew , D'Adamo David , Cote Greg , Rubinstein Yael , Benes Cyril , Haber Daniel , Baselga Jose , Demetri George 
Published: August 2014

Abstract
Based on preclinical biology (1, 2), this translational trial aimed to assess the efficacy and tolerability of the PARP inhibitor, olaparib, in patients with advanced Ewing sarcoma progressing after prior chemotherapy.
In this uncontrolled phase II pilot, adult participants with radiographically measureable disease received 400 mg of olaparib capsules, twice daily, until disease progression or drug intolerance. Tumor measurements were determined by CT or MRI, at 6 and 12 weeks after starting olaparib administration, and then every 8 weeks thereafter. Tumor response determinations were made according to RECIST 1.1, and adverse event determinations were made according to CTCAE, version 4.0. A total of 22 participants were planned to be enrolled using a conventional 2-step phase II study design. If no objective responses were observed after 12 participants had been followed for at least 3 months, further accrual would be stopped.
12 participants were enrolled, and all were evaluable. A single case each of grade 3 anemia and grade 3 thrombocytopenia was observed (see Table One). Otherwise, no significant or unexpected toxicities were observed while participants were receiving study drugs. There were 0 PR/CR, 4 SD (duration 10.9, 11.4, 11.9, and 18.4 wks), and 8 PD as best response. Of the SD, 2 had minor responses (-16.7% and -11.7% by RECIST 1.1). The median time to disease progression was 5.7 weeks. Further enrollment was therefore discontinued.
This study is the first report of a prospective phase II trial to evaluate the safety and efficacy of a PARP inhibitor in patients with Ewing sarcoma. Olaparib tablets were safe and well tolerated when administered to this small cohort at the 400 mg BID dose, although the median duration of dosing was for only 5.7 weeks. However, no significant responses were seen, and the short average interval to disease progression underscores the aggressiveness of this disease. Preclinical modeling supports exquisite in vivo sensitivity of this pathway in combination with chemotherapy, and such a trial of olaparib with temozolomide will begin shortly at our Center.
Toxicity Type # of Patients Grade 1 2 3 4 Anemia 1 0 0 0 0 Blood and lymphatic systems disorders: other 1 1 0 0 0 Fatigue 1 1 0 0 0 Fever 1 1 0 0 0 Pain 2 1 0 1 0 Rash maculo-papular 1 1 0 0 0 Nausea 1 1 1 0 0 Vomiting 1 1 0 0 0 Urinary tract infection 1 1 0 0 0 Platelet count decreased 2 1 1 0 Hypoglycemia 1 1 0 0 0 Metabolism and nutrition disorders: other 1 1 0 0 0 Arthritis 1 1 0 0 0 Musculoskeletal and connective tissue disorder: other 1 1 0 0 0 Dizziness 1 1 0 0 0 Nervous system disorders: other 1 1 1 0 0 Cough 3 3 0 0 0 Postnasal drip 1 1 0 0 0 Respiratory, thoracic and mediastinal disorders: other 1 1 0 0 0 Hypertension 1 1 0 0 0 Total 25 19 3 0 0
Citation Format: Edwin Choy, James Butrynski, David Harmon, Jeffrey Morgan, Suzanne George, Andrew Wagner, David D'Adamo, Greg Cote, Yael Rubinstein, Cyril Benes, Daniel Haber, Jose Baselga, George Demetri. Translation of preclinical predictive sensitivity of Ewing sarcoma to PARP inhibition: Phase II study of olaparib in adult patients with recurrent/metastatic Ewing sarcoma following failure of prior chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-174. doi:10.1158/1538-7445.AM2013-LB-174