Phase I trial of SU14813 in patients with advanced solid malignancies.
BACKGROUND
this phase I, open-label, dose-escalation study investigated SU14813, an oral multitargeted tyrosine kinase inhibitor, in adults with solid tumors.


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.


CONCLUSIONS
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.
Fiedler
W
W
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.
Giaccone
G
G
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Lasch
P
P
Department of Oncology, Hematology, BMT With Section Pneumology, Hubertus Wald Tumorzentrum, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
van der Horst
I
I
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Brega
N
N
Clinical Oncology, Pfizer Italia S.r.l., Milan, Italy.
Courtney
R
R
Clinical Pharmacology, Pfizer Oncology, San Diego, CA, USA.
Abbattista
A
A
Exploratory Development Asset Team, Pfizer Italia S.r.l., Milan, Italy.
Shalinsky
D R
DR
Translational Oncology, Pfizer Oncology, San Diego, CA, USA.
Bokemeyer
C
C
Department of Oncology, Hematology, BMT With Section Pneumology, Hubertus Wald Tumorzentrum, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Boven
E
E
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D055815:Young Adult
C513935:5-((5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl)-N-(2-hydroxy-3-morpholin-4-ylpropyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; D007211:Indoles; D009025:Morpholines