Abstract B005: A phase 1 expansion cohort study evaluating the safety and efficacy of the CHK1 inhibitor LY2880070 with low-dose gemcitabine in metastatic pancreatic adenocarcinoma
Authors: Huffman Brandon M. , Feng Hanrong , Parmar Kalindi , Wang Junning , Kapner Kevin , Kochupurakkal Bose , Martignetti David , Abrams Thomas , Biller Leah , Giannakis Marios , Ng Kimmie , Patel Anuj , Perez Kimberly , Singh Harshabad , Rubinson Douglas , Schlechter Benjamin , Andrews Elizabeth , Hannigan Alison , Dunwell Stanley , Getchell Zoe , Raghavan Srivatsan , Wolpin Brian , D'Andrea Alan , Aguirre Andrew , Shapiro Geoffrey , Cleary James 
Published: January 2024

Abstract
Background: Combining gemcitabine with CHK1 inhibition has shown promise in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we report the findings from a phase I expansion cohort study (NCT02632448) investigating low-dose gemcitabine combined with the CHK1 inhibitor LY2880070 in patients with previously treated advanced PDAC. Methods: Patients with metastatic PDAC were treated with gemcitabine intravenously at 100 mg/m2 on days 1, 8, and 15, and LY2880070 50 mg orally twice daily on days 2–6, 9–13, and 16–20 of each 21-day cycle. Pre-treatment tumor biopsies were obtained from each patient for correlative studies and generation of organoid cultures for drug sensitivity testing and biomarker analyses. Results: Eleven patients with PDAC were enrolled in the expansion cohort between August 27, 2020 and July 30, 2021. Four patients (36%) experienced drug-related grade 3 adverse events. No objective radiological responses were observed, and all patients discontinued the trial by 3.2 months. In contrast to the lack of efficacy observed in patients, organoid cultures derived from biopsies procured from two patients demonstrated strong sensitivity to the gemcitabine/LY2880070 combination and showed treatment-induced upregulation of replication stress and DNA damage biomarkers, including pKAP1, pRPA32, and gamma-H2AX, as well as induction of replication fork instability. Conclusions: No evidence of clinical activity was observed for combined low dose gemcitabine and LY2880070 in this treatment refractory PDAC cohort. However, the gemcitabine/LY2880070 combination showed in vitro efficacy, suggesting that drug sensitivity for this combination in organoid cultures may not predict clinical benefit in patients.
Citation Format: Brandon M. Huffman, Hanrong Feng, Kalindi Parmar, Junning Wang, Kevin Kapner, Bose Kochupurakkal, David Martignetti, Thomas Abrams, Leah Biller, Marios Giannakis, Kimmie Ng, Anuj Patel, Kimberly Perez, Harshabad Singh, Douglas Rubinson, Benjamin Schlechter, Elizabeth Andrews, Alison Hannigan, Stanley Dunwell, Zoe Getchell, Srivatsan Raghavan, Brian Wolpin, Alan D'Andrea, Andrew Aguirre, Geoffrey Shapiro, James Cleary. A phase 1 expansion cohort study evaluating the safety and efficacy of the CHK1 inhibitor LY2880070 with low-dose gemcitabine in metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B005.