Abstract
Objectives: 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/m2/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/ m2/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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 9-14 |
| Number of pages | 6 |
| Journal | American Journal of Clinical Oncology: Cancer Clinical Trials |
| Volume | 32 |
| Issue number | 1 |
| DOIs | |
| State | Published - Feb 1 2009 |
| Externally published | Yes |
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Keywords
- Clinical trial
- Phase I
- Prolongation
- Qt
- SR271425
- Thioxanthone
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
A phase I dose-escalation study of SR271425, an intravenously dosed thioxanthone analog, administered weekly in patients with refractory solid tumors. / Lockhart, Albert; Calvo, Emiliano; Tolcher, Anthony W.; Rowinsky, Eric K.; Shackleton, Gareth; Morrison, J. Gilmour; Rafi, Rezvan; VerMeulen, Wendy; Rothenberg, Mace L.
In: American Journal of Clinical Oncology: Cancer Clinical Trials, Vol. 32, No. 1, 01.02.2009, p. 9-14.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A phase I dose-escalation study of SR271425, an intravenously dosed thioxanthone analog, administered weekly in patients with refractory solid tumors
AU - Lockhart, Albert
AU - Calvo, Emiliano
AU - Tolcher, Anthony W.
AU - Rowinsky, Eric K.
AU - Shackleton, Gareth
AU - Morrison, J. Gilmour
AU - Rafi, Rezvan
AU - VerMeulen, Wendy
AU - Rothenberg, Mace L.
PY - 2009/2/1
Y1 - 2009/2/1
N2 - Objectives: 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/m2/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/ m2/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.
AB - Objectives: 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/m2/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/ m2/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.
KW - Clinical trial
KW - Phase I
KW - Prolongation
KW - Qt
KW - SR271425
KW - Thioxanthone
UR - http://www.scopus.com/inward/record.url?scp=60549092154&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=60549092154&partnerID=8YFLogxK
U2 - 10.1097/COC.0b013e318178331b
DO - 10.1097/COC.0b013e318178331b
M3 - Article
C2 - 19194116
AN - SCOPUS:60549092154
VL - 32
SP - 9
EP - 14
JO - American Journal of Clinical Oncology
JF - American Journal of Clinical Oncology
SN - 0277-3732
IS - 1
ER -