Dose-escalation trial of the ALK, MET & ROS1 inhibitor, crizotinib, in patients with advanced cancer

Clark, J. W., Camidge, D. R., Kwak, E. L., Maki, R. G., Shapiro, G. I., Chen, I., Tan, W., Randolph, S., Christensen, J. G., Ozeck, M., Tang, Y., Wilner, K. D., Salgia, R. (January 2020) Dose-escalation trial of the ALK, MET & ROS1 inhibitor, crizotinib, in patients with advanced cancer. Future Oncol, 16 (1). pp. 4289-4301. ISSN 1479-6694

Abstract

Aim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily-300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced >/=1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195.

Item Type: Paper
Additional Information: Future oncology (London, England)
Uncontrolled Keywords: Alk MET pharmacodynamics crizotinib dose escalation non-small cell lung cancer pharmacokinetics
Subjects: bioinformatics
diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
Investigative techniques and equipment
diseases & disorders > neoplasms
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
organism description > animal
Investigative techniques and equipment > biomarker
therapies > cancer drugs - see diseases-cancer-drugs and therapies
diseases & disorders > cancer > drugs and therapies > chemotherapy
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
diseases & disorders > cancer > prognosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
organism description > animal > mammal > rodent
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Adrian Gomez
Date: January 2020
Date Deposited: 18 Dec 2019 18:11
Last Modified: 29 Jan 2024 20:51
Related URLs:
URI: https://repository.cshl.edu/id/eprint/38786

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