Dr Huffman on the Investigation of Azenosertib Plus Gemcitabine in Advanced Pancreatic Cancer

Brandon Huffman, MD, medical oncologist, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, instructor in medicine, Harvard Medical School, discusses an ongoing phase 2 clinical trial (NCT06015659) evaluating azenosertib (ZN-c3) in combination with gemcitabine for the second-line treatment of patients with locally advanced or metastatic pancreatic cancer who experienced intolerance to or disease progression on or after a platinum-based regimen.

Replication stress could serve as a therapeutic vulnerability in pancreatic cancer, and data from preclinical studies have shown that azenosertib plus gemcitabine increased markers of replication stress and increased DNA damage in pancreatic cancer cell lines, Huffman explains, Huffman notes that azenosertib, a selective inhibitor of WEE1, has shown synergistic cytotoxicity when combined with gemcitabine in these cell lines.

Huffman explains that the single-arm trial's design involves a safety lead-in phase utilizing a 3 + 3 design, where investigators expect to enroll patients to confirm the recommended phase 2 dose. If no more than 1 dose-limiting toxicitiy is observed in 6 patients treated at dose level 1, the study will proceed to stage I enrollment. If 2 or more DLTs are reported in the first 6 patients, does level –1 will be examined before proceeding to stage 1. If more than 2 DLTs occur at dose level –1, investigators will reassess the dosing. In stage I, if at least 6 of 23 patients achieve a progression-free survival (PFS) of at least 6 months, 11 additional patients will be enrolled in stage II.

Efficacy will be evaluated through a Simon two-stage minimax design, and 6-month PFS rate will serve as the trial’s primary end point. Secondary end points include PFS, overall survival, objective response rate, and safety.

Additionally, the study will incorporate pretreatment and on-treatment tumor biopsies to better understand the pharmacodynamics of the combination, Huffman says. Enrollment in the trial is ongoing.