A phase I dose-escalation study of SR271425, an intravenously dosed thioxanthone analog, administered weekly in patients with refractory solid tumors.
OBJECTIVE
The thioxanthone analog, SR271425, is a novel cytotoxic DNA-interacting agent with broad antitumor activity in preclinical models. The objectives of this phase I study were to determine the dose-limiting toxicities, maximum tolerated dose, recommended phase II dose, pharmacokinetic profile, and trend for efficacy in patients with advanced cancer.


METHODS
SR271425 was administered intravenously over 1-hour, weekly for 2 weeks, followed by 1 week rest. Because of Cmax-related corrected QT (QTc) prolongation in preclinical testing of SR271425, all patients underwent an extensive pretreatment cardiac assessment.


RESULTS
Eighteen patients received SR271425 at 5 dose levels ranging from 64 to 675 mg/m/wk. No dose-limiting toxicities were identified. In all tested dose-levels, Grade 3 adverse events were observed in 10/18 patients (55.6%) and Grade 4 in 4/18 patients (22.2%). QTc prolongation was reported at the 3 highest dose levels but did not exceed Grade 2. Six deaths occurred during the study, 5 of them because of disease progression and 1 because of disease related bowel perforation. SR271425 exposure increased in a near dose-proportional manner. The mean terminal plasma half-life of SR271425 was 6 hours and there was no drug accumulation after repeated dosing. Stable disease was the best outcome observed (5 patients).


CONCLUSIONS
SR271425 was administered safely at doses up to 675 mg/m/wk on a 2-week on, 1-week off schedule. No dose-limiting toxicities were observed. Grade 2 QTc prolongation was observed at the highest dose levels. Maximum tolerated dose was not reached because of early termination of the SR271425 program by the sponsor.
Lockhart
A Craig
AC
Vanderbilt University Medical Center, Nashville, Tennessee, USA. Craig.Lockhart@Vanderbilt.edu
Calvo
Emiliano
E
Tolcher
Anthony W
AW
Rowinsky
Eric K
EK
Shackleton
Gareth
G
Morrison
J Gilmour
JG
Rafi
Rezvan
R
VerMeulen
Wendy
W
Rothenberg
Mace L
ML
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D016879:Salvage Therapy; D013892:Thioxanthenes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution
D013892:Thioxanthenes; C402303:SR 271425