A phase I dose escalation, dose expansion and pharmacokinetic trial of gemcitabine and alisertib in advanced solid tumors and pancreatic cancer.

Autor: Chen JA; Division of Hematology and Oncology, Davis Comprehensive Cancer Center, University of California, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA., Huynh JC; Division of Hematology and Oncology, Davis Comprehensive Cancer Center, University of California, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA., Wu CY; Bioanalysis and Pharmacokinetics Core Facility, University of California, Sacramento, CA, 95817, USA., Yu AM; Department of Biochemistry and Molecular Medicine, University of California, Sacramento, CA, 95817, USA., Matsukuma K; Department of Pathology and Laboratory Medicine, University of California, Sacramento, CA, 95817, USA., Semrad TJ; Gene Upshaw Memorial Tahoe Forest Cancer Center, Truckee, CA, 96161, USA., Gandara DR; Division of Hematology and Oncology, Davis Comprehensive Cancer Center, University of California, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA., Li T; Division of Hematology and Oncology, Davis Comprehensive Cancer Center, University of California, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA., Riess JW; Division of Hematology and Oncology, Davis Comprehensive Cancer Center, University of California, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA., Tam K; Division of Hematology and Oncology, Davis Comprehensive Cancer Center, University of California, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA., Mack PC; Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Martinez A; Office of Clinical Research, Davis Comprehensive Cancer Center, University of California, Sacramento, CA, 95817, USA., Mahaffey N; Office of Clinical Research, Davis Comprehensive Cancer Center, University of California, Sacramento, CA, 95817, USA., Kelly KL; Division of Hematology and Oncology, Davis Comprehensive Cancer Center, University of California, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA., Kim EJ; Division of Hematology and Oncology, Davis Comprehensive Cancer Center, University of California, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA. jhkim@ucdavis.edu.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2022 Sep; Vol. 90 (3), pp. 217-228. Date of Electronic Publication: 2022 Jul 30.
DOI: 10.1007/s00280-022-04457-9
Abstrakt: Purpose: Aurora Kinase A (AKA) inhibition with gemcitabine represents a potentially synergistic cancer treatment strategy via mitotic catastrophe. The feasibility, safety, and preliminary efficacy of alisertib (MLN8237), an oral AKA inhibitor, with gemcitabine was evaluated in this open-label phase I trial with dose escalation and expansion.
Methods: Key inclusion criteria included advanced solid tumor with any number of prior chemotherapy regimens in the dose escalation phase, and advanced pancreatic adenocarcinoma with up to two prior chemotherapy regimens. Four dose levels (DLs 1-4) of alisertib (20, 30, 40, or 50 mg) were evaluated in 3 + 3 design with gemcitabine 1000 mg/m 2 on days 1, 8, and 15 in 28-day cycles.
Results: In total, 21 subjects were treated in dose escalation and 5 subjects were treated in dose expansion at DL4. Dose-limiting toxicities were observed in 1 of 6 subjects each in DL3 and DL4. All subjects experienced treatment-related adverse events. Grade ≥ 3 treatment-related adverse events were observed in 73% of subjects, with neutropenia observed in 54%. Out of 22 subjects evaluable for response, 2 subjects (9%) had partial response and 14 subjects (64%) had stable disease. Median PFS was 4.1 months (95% CI 2.1-4.5). No significant changes in pharmacokinetic parameters for gemcitabine or its metabolite dFdU were observed with alisertib co-administration.
Conclusions: This trial established the recommended phase 2 dose of alisertib 50 mg to be combined with gemcitabine. Gemcitabine and alisertib are a feasible strategy with potential for disease control in multiple heavily pre-treated tumors, though gastrointestinal and hematologic toxicity was apparent.
(© 2022. The Author(s).)
Databáze: MEDLINE
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