W Fiedler1, G Giaccone2, P Lasch3, I van der Horst2, N Brega4, R Courtney5, A Abbattista6, D R Shalinsky7, C Bokemeyer3, E Boven2. 1. Department of Oncology, Hematology, BMT With Section Pneumology, Hubertus Wald Tumorzentrum, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: fiedler@uke.uni-hamburg.de. 2. Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. 3. Department of Oncology, Hematology, BMT With Section Pneumology, Hubertus Wald Tumorzentrum, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 4. Clinical Oncology, Pfizer Italia S.r.l., Milan, Italy. 5. Clinical Pharmacology, Pfizer Oncology, San Diego, CA, USA. 6. Exploratory Development Asset Team, Pfizer Italia S.r.l., Milan, Italy. 7. Translational Oncology, Pfizer Oncology, San Diego, CA, USA.
Abstract
BACKGROUND: this phase I, open-label, dose-escalation study investigated SU14813, an oral multitargeted tyrosine kinase inhibitor, in adults with solid tumors. PATIENTS AND METHODS: seventy-seven patients received once-daily SU14813, either for 4 weeks followed by 1 week off treatment (schedule 4/1) or continuously [continuous daily dosing (CDD)]. The primary end point was to determine the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. RESULTS: MTDs were 200 mg/day on schedule 4/1 and 100 mg/day with CDD. Adverse events included fatigue (64%), diarrhea (61%), nausea (44%), anorexia (43%), and vomiting (42%). SU14813 steady state was attained by day 8. Exposure increased in a generally dose-proportional manner and SU14813 was eliminated with a mean terminal half-life of 9-34 h. Target plasma concentrations (>100 ng/ml SU14813) were achieved and sustained over 12 h at ≥ 100 mg/day. Progression-free survival among the 1 complete responder and 12 partial responders was 1.4-53.2 months. Fifteen patients remained on treatment at 1 year and 3 patients at 2 years. CONCLUSION: SU14813 has manageable safety and tolerability and allows once-daily continuous oral dosing. SU14813 shows dose-proportional pharmacokinetics, with target plasma concentrations achieved at doses ≥ 100 mg/day. Clinically meaningful activity with durable responses was observed, meriting further study.
BACKGROUND: this phase I, open-label, dose-escalation study investigated SU14813, an oral multitargeted tyrosine kinase inhibitor, in adults with solid tumors. PATIENTS AND METHODS: seventy-seven patients received once-daily SU14813, either for 4 weeks followed by 1 week off treatment (schedule 4/1) or continuously [continuous daily dosing (CDD)]. The primary end point was to determine the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. RESULTS: MTDs were 200 mg/day on schedule 4/1 and 100 mg/day with CDD. Adverse events included fatigue (64%), diarrhea (61%), nausea (44%), anorexia (43%), and vomiting (42%). SU14813 steady state was attained by day 8. Exposure increased in a generally dose-proportional manner and SU14813 was eliminated with a mean terminal half-life of 9-34 h. Target plasma concentrations (>100 ng/ml SU14813) were achieved and sustained over 12 h at ≥ 100 mg/day. Progression-free survival among the 1 complete responder and 12 partial responders was 1.4-53.2 months. Fifteen patients remained on treatment at 1 year and 3 patients at 2 years. CONCLUSION:SU14813 has manageable safety and tolerability and allows once-daily continuous oral dosing. SU14813 shows dose-proportional pharmacokinetics, with target plasma concentrations achieved at doses ≥ 100 mg/day. Clinically meaningful activity with durable responses was observed, meriting further study.
Authors: Justine Yang Bruce; Patricia M LoRusso; Priscila H Goncalves; Elisabeth I Heath; Elizabeth Sadowski; David R Shalinsky; Yanwei Zhang; Anne M Traynor; Aurora Breazna; Alejandro D Ricart; Michael Tortorici; Glenn Liu Journal: Cancer Chemother Pharmacol Date: 2016-01-20 Impact factor: 3.333