Abstract CT235: A dose escalation trial of the Wee1 inhibitor AZD1775, in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer

Abstract

Background: To improve outcome for patients with locally advanced pancreatic, better locoregional and systemic therapies are needed. Our preclinical studies showed that Wee1 inhibition produced selective chemoradiosensitization and chemosensitization in pancreatic cancer. AZD1775 (adavosertib) is an orally available, small molecule inhibitor of the Wee1 kinase. In this study, we built on our preclinical studies to evaluate the safety and efficacy of AZD1775 in combination with gemcitabine and radiation in patients with newly diagnosed locally advanced pancreatic cancer. Patients and Methods: Thirty-four patients previously untreated with locally advanced pancreatic cancer were enrolled with intention to receive four 21-day cycles of gemcitabine (1000 mg/m2 days 1, 8) with AZD1775 (once daily on days 1, 2, 8, 9). Cycles 2 and 3 were administered concurrently with radiation (52.5 Gy in 25 fractions) to the primary tumor and involved lymph nodes using image guided, intensity modulated radiation therapy. AZD1775 was dose escalated using a time-to-event continual reassessment method based off the rate of dose limiting toxicities (DLT) within the first 15 weeks of therapy. Patients with stable or responding disease were offered the option for 4 additional cycles. The primary objective was to determine the maximum tolerated dose of AZD1775 given in conjunction with gemcitabine and radiation. Secondary objectives were to estimate overall and progression free survival and determine pharmacodynamic activity of AZD1775 in surrogate tissues at the recommended phase 2 dose (RP2D). Results: Thirty of the 34 patients enrolled completed the full course of radiation therapy and 26 patients received at least 4 cycles of study therapy. Eight patients experienced a DLT with the most common being anorexia, nausea, or fatigue. The recommended phase 2 dose of AZD1775 was 150 mg per day. Overall survival for all patients on the study was 21.7 months (95% confidence interval 16.7 to 24.7 months) and progression free survival was 9.4 months (95% confidence interval 7.4 to 9.9 months) from the time of enrollment, both of which are superior to our prior results with radiation and gemcitabine alone. No local failures occurred within the first 6 months and the 12 month freedom from local progression rate was 68%. The first site of progression was local in only 3 of the 34 patients. There were 17 distant failures with a median time to distant failure of 9.9 months. Hair follicle biopsies demonstrated evidence of Wee1 inhibition with decreased phospho-CDK1 staining by immunohistochemistry after AZD1775 administration in surrogate tissues at the RP2D. Conclusions: AZD1775 in combination with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue. Although preliminary, the survival seen in our intent to treat study population is 50% above that of our prior studies and warrants further investigation in a randomized trial. Supported by R01 CA138723 Citation Format: Kyle C. Cuneo, Meredith A. Morgan, Mark M. Zalupski, Vaibhav Sahai, Matthew J. Schipper, Jonathan Maybaum, Theodore S. Lawrence. A dose escalation trial of the Wee1 inhibitor AZD1775, in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT235.