A Phase 1 Trial of Low-dose Gemcitabine Combined with ATR Inhibitor Elimusertib for Advanced Solid Tumors
Thejus Jayakrishnan, Rebecca Porter, Alice Chen, Ningxuan Zhou, Julianne L. Holleran, Massimiliano Russo, Douglas A. Rubinson, Brandon M. Huffman, Nabihah Tayob, Lorenzo Trippa, Kaitlyn Ramsey, Mckenzie Kelly, Leah H. Biller, Panagiotis A. Konstantinopoulos, Carolyn Krassner, Elizabeth K. Lee, Ursula A. Matulonis, Kimberly J. Perez, Renata R. Almeida, Srivatsan Raghavan, Alexi A. Wright, Brian M. Wolpin, Jonathan A. Nowak, Alan D. D'Andrea, Andrew J. Aguirre, Steven Gore, Geoffrey I. Shapiro, Jan H. Beumer, James M. ClearyAbstract
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.