Jeffrey W Clark1, D Ross Camidge2, Eunice L Kwak1, Robert G Maki3, Geoffrey I Shapiro4, Isan Chen5, Weiwei Tan5, Sophia Randolph5, James G Christensen5, Mark Ozeck5, Yiyun Tang5, Keith D Wilner5, Ravi Salgia6. 1. Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. 2. Division of Medical Oncology, University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA. 3. Don Monti Division of Medical Oncology & Hematology, Northwell Cancer Institute & Cold Spring Harbor Laboratory, Lake Success, NY 11724, USA. 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. 5. Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA. 6. Department of Medical Oncology & Therapeutics Research, The City of Hope, Duarte, CA 91010, USA.
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.
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.