Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer

Abstract

Purpose: AZD1775 (adavosertib) is an 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 with locally advanced pancreatic cancer were enrolled with the intention to receive four 21-day cycles of gemcitabine (1,000 mg/m2 days 1 and 8) with AZD1775 (once daily on days 1, 2, 8, and 9). Cycles 2 and 3 were administered concurrently with radiation, and cycles 5 to 8 were optional. AZD1775 was dose escalated using a time-to-event continual reassessment method on the basis of the rate of dose-limiting toxicities within the first 15 weeks of therapy. 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.

Results: The recommended phase II dose of AZD1775 was 150 mg/d. Eight patients (24%) experienced a dose-limiting toxicity, most commonly anorexia, nausea, or fatigue. The median overall survival for all patients was 21.7 months (90% CI, 16.7 to 24.8 months), and the median progression-free survival was 9.4 months (90% CI, 8.0 to 9.9 months). Hair follicle biopsy samples demonstrated evidence of Wee1 inhibition with decreased phosphorylation of cyclin-dependent kinase 1 staining by immunohistochemistry after AZD1775 administration at the recommended phase II dose.

Conclusion: AZD1775 in combination with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue. The overall survival is substantially higher than prior results combining gemcitabine with radiation therapy and warrants additional investigation.

Trial registration: ClinicalTrials.gov NCT02037230.

Figures

FIG 1.

Estimates of dose-limiting toxicity (DLT) rates using the time-to-event continual reassessment method (TITE-CRM) and a two-parameter logistic regression model with 90% CI at each dose level of the Wee1 inhibitor AZD1775. The target DLT rate was 0.30. Dose level 1 (150 mg AZD1775) was determined to be the maximum tolerated dose and recommended phase II dose.

FIG 2.

Overall survival (OS) with 90% CI for all patients enrolled in the trial calculated from the time of study enrollment to the date of death. (*) Indicates censor.

FIG 3.

Progression-free survival (PFS) with 90% CI for all patients enrolled in the trial calculated from the time of study enrollment to the date of progression.

FIG 4.

Pharmacodynamics of AZD1775 in surrogate tissues. Sequential punch biopsy samples of hair-bearing skin were obtained after gemcitabine infusion but before AZD1775 administration and after AZD1775 administration. Immunohistochemistry on paraffin-embedded specimens was performed using anti–phosphorylation of cyclin-dependent kinase 1 (phospho-CDK1) antibody. (A) Representative images of phospho-CDK1 staining of hair follicles before and after AZD1775 in a patient treated in this study. (B) Mean percentage of phospho-CDK1–positive hair follicles with 95% CI before and after AZD1775 for each dose level.