Abstract CT035: A dose escalation trial of the WEE1 inhibitor AZD1775, gemcitabine, and concurrent radiation in locally advanced pancreatic cancer
Authors: Cuneo Kyle C. , Morgan Meredith , Schipper Matthew J. , Maybaum Jonathan , Feng Mary U. , Al-Hawary Mahmoud , Simeone Diane M. , Olson Leah D. , Sahai Vaibhav , Zalupski Mark , Lawrence Theodore S. 
Published: July 2016

Abstract
Background: Gemcitabine based chemoradiation for locally advanced pancreatic cancer (LAPC) is safe and effective, although most patients remain unresectable and freedom from local progression is not ensured. Targeting cell cycle checkpoints may enhance the efficacy of chemoradiation. Tumor cells commonly have an abnormal G1 checkpoint due to mutations in p53 or its pathway making them reliant on the G2 checkpoint to arrest and repair DNA damage after radiation. In our preclinical studies, WEE1 inhibition with AZD1775 abrogates the G2 checkpoint and sensitizes pancreatic cancer cell lines and xenografts to gemcitabine and radiation. Additionally, AZD1775 attenuates homologous recombination and promotes replication stress in cancer cells. Given these preclinical findings, we designed a phase I dose escalation study of the WEE1 inhibitor AZD1775 in combination with gemcitabine and radiation in patients with LAPC (NCT02037230).
Methods: The primary objective of this phase I study is to determine the maximum tolerated dose (MTD) of AZD1775 combined with gemcitabine and radiation in patients with LAPC. Secondary objectives include estimation of the efficacy of this regimen at the target dose and to determine if WEE1 is inhibited by AZD1775 at or below its target dose in surrogate tissues. Protocol therapy consists of the administration of AZD1775 and gemcitabine at an assigned dose level in accordance with a Time-to-Event Continual Reassessment Method (TITE-CRM). Study treatment consists of four 21 day cycles. Gemcitabine is given on day 1 and day 8, and AZD1775 on days 1, 2 and 8, 9 of each cycle. Cycles 2 and 3 are administered with concurrent radiation, 52.5 Gy in 25 daily fractions to gross disease using volumetric modulated arc therapy to spare normal tissues. Following cycle 3, subjects have a 3 week break prior to cycle 4. The MTD will be determined by the development of dose limiting toxicities within the first 105 days of therapy with a target dose limiting toxicity rate of 25%. Tumor assessment using CT or MRI is performed at baseline, 1 month after radiation, and approximately every 3 months afterwards, with response characterized per RECIST. Blood samples obtained at baseline and after cycles 1, 2, and 4 will be used for correlative studies on circulating tumor cells and tumor derived exosomes. Target accrual is 36 patients; to date, 16 patients have been enrolled. Dose Escalation SchemaRadiation (Gy)Gemcitabine(mg/m⁁2)AZD1775 (mg)Level -252.5800100Level -152.51000100Level 052.51000125Level 152.51000150Level 252.51000175
Citation Format: Kyle C. Cuneo, Meredith Morgan, Matthew J. Schipper, Jonathan Maybaum, Mary U. Feng, Mahmoud Al-Hawary, Diane M. Simeone, Leah D. Olson, Vaibhav Sahai, Mark Zalupski, Theodore S. Lawrence. A dose escalation trial of the WEE1 inhibitor AZD1775, gemcitabine, and concurrent radiation in locally advanced pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT035.