A Phase 1 Trial of Low-dose Gemcitabine Combined with ATR Inhibitor Elimusertib for Advanced Solid Tumors

Abstract Purpose: Preclinical data suggest that the anti-cancer efficacy of ATR inhibitors can be synergistically enhanced by low-dose gemcitabine. To test the clinical feasibility of this regimen, we conducted a phase 1 trial of low-dose gemcitabine combined with the ATR inhibitor elimusertib (BAY1895344). Patients and Methods: This phase 1 study evaluated the combination of gemcitabine and elimusertib in patients with previously treated, incurable solid tumors. The primary objective was to assess the safety and tolerability of this regimen and to determine the maximum tolerated dose (MTD). Secondary objectives included assessment of objective response rate (ORR) per RECIST v.1.1 and characterization of the pharmacokinetic (PK) profile. Results: Fourteen patients were enrolled; most patients had pancreatic cancer (n=6) or ovarian cancer (n=6). The median age was 63.5 years of age, and the median number of prior therapies was 2. The regimen caused significant toxicity, and four patients (28%) discontinued the trial due to treatment-related adverse events. The trial was stopped prior to establishing an MTD due to the pharmaceutical company's decision to halt development of the agent. A confirmed partial response was observed in one patient with platinum-refractory ovarian cancer harboring a gain in CCNE1. Another patient with pancreatic adenocarcinoma harboring biallelic ATM loss remained on trial for 9.5 months with stable disease, with an 85% decrease in CA19-9. Conclusions: The combination of low-dose gemcitabine combined with elimusertib was not tolerable. Although evidence of anti-tumor activity was observed, significant improvements in tolerability are required for future ATR inhibitor combinations to be clinically feasible.

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Publication Details

Journal
Cancer Research Communications
Published
2026-11-03
DOI
https://doi.org/10.1158/2767-9764.crc-26-0505
Primary Topic
PARP inhibition in cancer therapy
Type
article
Field-Weighted Citation Impact
0.00
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article

A Phase 1 Trial of Low-dose Gemcitabine Combined with ATR Inhibitor Elimusertib for Advanced Solid Tumors

Kimberly J. Perez, Elizabeth K. Lee, Thejus Jayakrishnan, James M. Cleary et al.
Cancer Research Communications
PARP inhibition in cancer therapy
article

A Phase 1 Trial of Low-dose Gemcitabine Combined with ATR Inhibitor Elimusertib for Advanced Solid Tumors

Kimberly J. Perez, Elizabeth K. Lee, Thejus Jayakrishnan, James M. Cleary, Jan Hendrik Beumer, Srivatsan Raghavan, Alexi A. Wright, Brandon M. Huffman, Douglas Adam Rubinson, Alan D. D’Andrea, Alice P. Chen, Geoffrey Ira Shapiro, Brian Matthew Wolpin, Ursula A. Matulonis, Jonathan Andrew Nowak, Nabihah Tayob, Renata Rocha de Almeida, Ningxuan Zhou, Leah H. Biller, Lorenzo Trippa, Panagiotis A. Konstantinopoulos, Andrew J. Aguirre, Rebecca L. Porter, Massimiliano Russo, Julianne L. Holleran, Steven D. Gore, Kaitlyn Ramsey, Mckenzie Kelly, Carolyn Krassner
article en

Abstract

Abstract Purpose: Preclinical data suggest that the anti-cancer efficacy of ATR inhibitors can be synergistically enhanced by low-dose gemcitabine. To test the clinical feasibility of this regimen, we conducted a phase 1 trial of low-dose gemcitabine combined with the ATR inhibitor elimusertib (BAY1895344). Patients and Methods: This phase 1 study evaluated the combination of gemcitabine and elimusertib in patients with previously treated, incurable solid tumors. The primary objective was to assess the safety and tolerability of this regimen and to determine the maximum tolerated dose (MTD). Secondary objectives included assessment of objective response rate (ORR) per RECIST v.1.1 and characterization of the pharmacokinetic (PK) profile. Results: Fourteen patients were enrolled; most patients had pancreatic cancer (n=6) or ovarian cancer (n=6). The median age was 63.5 years of age, and the median number of prior therapies was 2. The regimen caused significant toxicity, and four patients (28%) discontinued the trial due to treatment-related adverse events. The trial was stopped prior to establishing an MTD due to the pharmaceutical company's decision to halt development of the agent. A confirmed partial response was observed in one patient with platinum-refractory ovarian cancer harboring a gain in CCNE1. Another patient with pancreatic adenocarcinoma harboring biallelic ATM loss remained on trial for 9.5 months with stable disease, with an 85% decrease in CA19-9. Conclusions: The combination of low-dose gemcitabine combined with elimusertib was not tolerable. Although evidence of anti-tumor activity was observed, significant improvements in tolerability are required for future ATR inhibitor combinations to be clinically feasible.

Cancer Research Communications
Brigham and Women's Hospital (US), Dana-Farber Cancer Institute (US), UPMC Hillman Cancer Center (US), National Cancer Institute (MY), Dana-Farber/Harvard Cancer Center (US), National Cancer Institute (US), Dana-Farber Brigham Cancer Center (US), Sidney Kimmel Comprehensive Cancer Center (US), The Ohio State University (US)
Openalex Percentile: Top 17%
PARP inhibition in cancer therapy
DOIOpen Access PDFOpenAlex
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