Abstract A127: Targeting replication stress in pancreatic cancer: results of a phase 1b trial of azenosertib and gemcitabine in second line pancreatic cancer after progression on FOLFIRINOX

Abstract

Treatment options for patients with pancreatic ductal adenocarcinoma (PDAC) who have had progressive disease on FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and infusional 5-fluorouracil) are limited, and patients are typically treated with gemcitabine and nab-paclitaxel. Targeting therapeutic vulnerabilities of replication stress in PDAC has been efficacious in preclinical models. We report a phase 1b trial using gemcitabine with the WEE1 inhibitor azenosertib in patients with metastatic PDAC after progression on FOLFIRINOX. This trial assessed the safety and tolerability of gemcitabine combined with azenosertib, while also evaluating preliminary signals of clinical activity. Patients enrolled on this trial had metastatic PDAC, and they developed progressive disease after first-line FOLFIRINOX chemotherapy. To ensure tolerability of the combination, the trial enrolled 12 patients into a safety lead-in at two dose levels in 21 day cycles: Gemcitabine 800 mg/m2 (DL1) or Gemcitabine 600 mg/m2 (DL-1) on days 1 and 8 with azenosertib 150 mg once daily days 1-5, 8-12, 15-19. The study was stopped early for safety and tolerability concerns. Tissue biopsies were collected before treatment and on treatment to explore mechanisms of sensitivity and resistance. Twelve participants enrolled in the safety lead-in and received at least one dose of therapy. Ten participants were DLT-evaluable: 6 enrolled at DL1 and 4 enrolled at DL-1. There were two DLTs in DL1 and two DLTs in DL-1. At DL1, one participant developed grade 3 thrombocytopenia requiring transfusion and received less than 75% of the planned azenosertib dose. The other participant at DL1 developed grade 3 thrombocytopenia and received less than 75% of the planned azenosertib dose. At DL-1, two participants developed grade 3 thrombocytopenia and received less than 75% of the planned azenosertib dose. There were 11 (92%) participants with at least one possibly related TEAE including myelosuppression, gastrointestinal side effects, and limb edema. Seven participants (58%) experienced at least one related grade 3 TEAE. As of the data cut-off of December 31, 2025, all 12 enrolled participants had discontinued study treatment. The estimated 6-month PFS rate was 16.7% (95% CI, 4.7%–59.1%) which did not meet the primary endpoint. The objective response rate (complete plus partial response) was 10%. There was one patient with confirmed partial response who remained on study for 11 months. The combination of azenosertib and gemcitabine was associated with substantial myelosuppression in patients with metastatic PDAC previously treated with FOLFIRINOX, limiting further clinical evaluation of this dosing strategy. Given the known hematologic toxicity profile of gemcitabine in this setting and potential for WEE1 inhibition to enhance chemotherapy-related effects, the observed toxicity likely reflects the effects of the combination in a heavily pretreated population. Despite these limitations, a durable partial response was observed in one patient. Brandon M. Huffman, Haeseong Park, Nadine Jackson, Anuj K. Patel, Kimberly Perez, Douglas Rubinson, Benjamin Schlechter, Cibelle Lima, Vasilena Gocheva, Geoffrey Shapiro, Alan D'Andrea, Andrew Aguirre, Jonathan Nowak, Brian Wolpin, James Cleary. Targeting replication stress in pancreatic cancer: results of a phase 1b trial of azenosertib and gemcitabine in second line pancreatic cancer after progression on FOLFIRINOX [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A127.