Abstract CT135: A pre-surgical window of opportunity study to investigate the biomarker effects of DNA damage response (DDR) agents in patients (pts) with head and neck squamous cell carcinoma (HNSCC)
Authors: Duvvuri Umamaheswar , Dean Emma , Frewer Paul , Berges Alienor , Cheung S. Y. , Stephens Christine , Khan Musaddiq , Hollingsworth Simon J. , Pierce Andrew J. 
Published: August 2018

Abstract
Background: The annual incidence of head and neck cancers is &gt;550,000 cases worldwide and approximately 90% are HNSCC. Treatment for locoregionally advanced (stage III/IV) HNSCC involves primary surgery, radiation and/or chemotherapy. Cancer cells with DDR defects can activate the immune system and immunotherapy (IO) has shown therapeutic benefit in pts with advanced recurrent HNSCC. This study assesses the immunological effects of DDR agents in both tumor tissue and peripheral blood samples to inform optimal combinations with IO therapies. The overall hypothesis is that DDR agents will convert an “immunologically cold” tumor into an “immunologically hot” tumor that is both responsive to IO and improved prognosis.
Objectives: The primary objective is to assess immune activation due to DDR inhibition by monitoring the induction of genes interacting with the immune system and potentially linked to prognosis. The secondary objective is to assess increasing prevalence of tumor infiltrating CD8+ and CD3+ T-cells also linked to prognosis. Exploratory measurements of tumour proliferative and DDR-relevant markers, peripheral T/B/NK and regulatory T cells, key immuno-regulatory cytokines, TCR repertoire, levels of circulating tumour cells and relevant genomic changes in both tumour and circulating tumour DNA will be conducted. Safety and tolerability of the investigational agents is also monitored.
Methods: This ongoing, randomised multi-centre, window of opportunity biomarker study is enrolling patients with newly diagnosed, treatment naïve, HNSCC suitable for surgical resection followed by radiotherapy and/or chemotherapy (NCT03022409). Two oral DDR agents are currently under evaluation as monotherapy: AZD6738 is a potent selective inhibitor of the serine/threonine-specific protein kinase, ataxia telangiectasia and Rad3-related protein (ATR), and olaparib is a poly-ADP ribose polymerase (PARP) inhibitor. Eligible pts are randomised to receive a DDR agent for between 10 to 21 days (D), followed by surgery. After surgery, pts do not receive further investigational treatment and attend a follow-up visit at D31. Tumor tissue is collected pre- (archival diagnostic biopsy) and post-treatment (surgical specimen), and evaluated for changes in key biomarkers related to immune response and DNA damage inhibition. If surgery is scheduled between D11-21 (+3D) following three successive days of DDR agent, an on-treatment biopsy is also required between D10-12. Pts undergo a weekly assessment for adverse events, hematology, biochemistry, and electrocardiogram. Plasma samples are also included to characterise the pharmacokinetics of each agent, relative to any biomarker changes observed. Enrolment commenced in December 2017 and the study is designed to permit the addition of treatment arms, including different combinations, sequences and doses.
Citation Format: Umamaheswar Duvvuri, Emma Dean, Paul Frewer, Alienor Berges, S. Y. Cheung, Christine Stephens, Musaddiq Khan, Simon J. Hollingsworth, Andrew J. Pierce. A pre-surgical window of opportunity study to investigate the biomarker effects of DNA damage response (DDR) agents in patients (pts) with head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT135.