TY - JOUR
T1 - Phase I trial of ATR inhibitor elimusertib with FOLFIRI in advanced or metastatic gastrointestinal malignancies (ETCTN 10406)
AU - Krishnamurthy, Anuradha
AU - Wang, Hong
AU - Rhee, John C.
AU - Davar, Diwakar
AU - Moy, Ryan H.
AU - Ratner, Lee
AU - Christner, Susan M.
AU - Holleran, Julianne L.
AU - Deppas, Joshua
AU - Sclafani, Carina
AU - Schmitz, John C.
AU - Gore, Steve
AU - Chu, Edward
AU - Bakkenist, Christopher J.
AU - Beumer, Jan H.
AU - Villaruz, Liza C.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.
PY - 2025/12
Y1 - 2025/12
N2 - Background: ATR is an apical DDR kinase activated at damaged replication forks. Elimusertib is an oral ATR inhibitor and potentiates irinotecan in human colorectal cancer models. Methods: To establish dose and tolerability of elimusertib with FOLFIRI, a Bayesian Optimal Interval trial design was pursued. Starting elimusertib dose was 20 mg BID days 1, 2, 15 and 16 every 28-day cycle, combined with irinotecan (150 mg/m2) and 5-FU (2000 mg/m2). Results: The trial was stopped after 10 accruals, with four DLT across 4 dose levels including grade 3 febrile neutropenia, mucositis, nausea, vomiting and grade 4 neutropenia. The most common grade 3/4 adverse events were neutropenia, leukopenia, lymphopenia and mucositis. Based on significant toxicities the trial was stopped. PK data for 5-FU and irinotecan were unremarkable and did not account for DLTs. Among the six response evaluable patients, four had stable disease as their best response. Median PFS was 7 months. A first case of ATRi chemotherapy combination related AML (t-AML) was observed. Conclusions: The combination of elimusertib with FOLFIRI was associated with intolerable toxicity. Combination of ATR kinases with chemotherapies that target DNA replication may be associated with significant myelotoxicity. Ongoing ATRi trials should monitor for t-AML. ClinicalTrials.gov
AB - Background: ATR is an apical DDR kinase activated at damaged replication forks. Elimusertib is an oral ATR inhibitor and potentiates irinotecan in human colorectal cancer models. Methods: To establish dose and tolerability of elimusertib with FOLFIRI, a Bayesian Optimal Interval trial design was pursued. Starting elimusertib dose was 20 mg BID days 1, 2, 15 and 16 every 28-day cycle, combined with irinotecan (150 mg/m2) and 5-FU (2000 mg/m2). Results: The trial was stopped after 10 accruals, with four DLT across 4 dose levels including grade 3 febrile neutropenia, mucositis, nausea, vomiting and grade 4 neutropenia. The most common grade 3/4 adverse events were neutropenia, leukopenia, lymphopenia and mucositis. Based on significant toxicities the trial was stopped. PK data for 5-FU and irinotecan were unremarkable and did not account for DLTs. Among the six response evaluable patients, four had stable disease as their best response. Median PFS was 7 months. A first case of ATRi chemotherapy combination related AML (t-AML) was observed. Conclusions: The combination of elimusertib with FOLFIRI was associated with intolerable toxicity. Combination of ATR kinases with chemotherapies that target DNA replication may be associated with significant myelotoxicity. Ongoing ATRi trials should monitor for t-AML. ClinicalTrials.gov
KW - ATR inhibition
KW - BAY 1895344
KW - Elimusertib
KW - FOLFIRI
KW - Pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=85216597904&partnerID=8YFLogxK
U2 - 10.1007/s00280-024-04745-6
DO - 10.1007/s00280-024-04745-6
M3 - Article
C2 - 39841295
AN - SCOPUS:85216597904
SN - 0344-5704
VL - 95
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 1
M1 - 27
ER -