Phase I trial of ATR inhibitor elimusertib with FOLFIRI in advanced or metastatic gastrointestinal malignancies (ETCTN 10406)

被引:0
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作者
Krishnamurthy, Anuradha [1 ,2 ]
Wang, Hong [3 ]
Rhee, John C. [4 ]
Davar, Diwakar [2 ]
Moy, Ryan H. [5 ]
Ratner, Lee [6 ]
Christner, Susan M. [1 ]
Holleran, Julianne L. [1 ]
Deppas, Joshua [1 ,7 ]
Sclafani, Carina [8 ]
Schmitz, John C. [1 ]
Gore, Steve [9 ]
Chu, Edward [10 ]
Bakkenist, Christopher J. [8 ]
Beumer, Jan H. [1 ,3 ,4 ,11 ]
Villaruz, Liza C. [1 ,2 ]
机构
[1] UPMC, Hillman Canc Ctr, Canc Therapeut Program, Pittsburgh, PA USA
[2] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA USA
[3] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA
[4] UPMC, Hillman Canc Ctr, Pittsburgh, PA 15232 USA
[5] Columbia Univ, Irving Med Ctr, Dept Med, Div Hematol & Oncol, New York, NY USA
[6] Washington Univ, Sch Med, Div Oncol, St Louis, MO USA
[7] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA USA
[8] Univ Pittsburgh, UPMC, Sch Med,Hillman Canc Ctr, Dept Radiat Oncol, Pittsburgh, PA USA
[9] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD USA
[10] Albert Einstein Coll Med, Bronx, NY USA
[11] Univ Pittsburgh, Canc Inst, Canc Inst, Room G27E,5117 Ctr Ave, Pittsburgh, PA 15213 USA
关键词
Elimusertib; BAY; 1895344; FOLFIRI; Pharmacokinetics; ATR inhibition; DNA-DAMAGE RESPONSE; ADVANCED SOLID TUMORS; COLORECTAL-CANCER; KINASE INHIBITOR; IRINOTECAN; COMBINATION; FLUOROURACIL; MULTICENTER; CISPLATIN; THERAPY;
D O I
10.1007/s00280-024-04745-6
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BackgroundATR is an apical DDR kinase activated at damaged replication forks. Elimusertib is an oral ATR inhibitor and potentiates irinotecan in human colorectal cancer models.MethodsTo 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).ResultsThe 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.ConclusionsThe 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 IDNCT04535401
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页数:12
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