sr-271425 and Neoplasms

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.. 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.. 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).. 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.

Topics: Adult; Aged; Area Under Curve; Cohort Studies; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Neoplasms; Prognosis; Salvage Therapy; Thioxanthenes; Tissue Distribution

This study was performed to determine the dose limiting toxicity (DLT), the recommended phase II dose and the pharmacokinetic profile for SR271425, given over 1 h every 3 weeks. The initial starting dose of SR271425 was 17 mg/m(2). Patient selection was based on common phase I criteria as well as additional cardiac criteria. Thirty-eight patients were accrued to 16 dose levels from 17 to 1,320 mg/m(2). Patient characteristics included 24 males and 14 females ages 35-78 with an Eastern Cooperative Oncology Group performance status of 0 (ten patients), 1 (27) and 2 (1). Tumor types were typical for a phase I study. The maximum administered dose was 1,320 mg/m(2) with two DLTs, both QTc grade 3 prolongation. No drug related hematological toxicity was noted. Grade 1 toxicities included rash, flushing, pruritus, weight loss, diarrhea, hypertension and fatigue. Grade 2 toxicities included yellow discoloration of the skin, nausea and vomiting. QTc prolongation and hyperbilirubinemia were the only grade 3 toxicities noted. No confirmed tumor response was observed; however, two patients had prolonged stable disease. Both C(end) and area under the plasma concentration-time curve increased in a dose related manner. Plasma drug concentrations declined in a biphasic manner with a mean terminal elimination half-life (t (1/2)) of 7.1 h (+/-1.3). There was no change in clearance or volume of distribution over the dose range studied. Due to cardiac toxicity occurring with both the parent compound, SR233377, as well as this analog, this series of agents was abandoned from further clinical development.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Long QT Syndrome; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Thioxanthenes; Tissue Distribution

SR271425 is a novel DNA-binding cytotoxic agent with a broad spectrum of antitumor activity in preclinical models,across a variety of the schedule of administration. In toxicological studies, it has been reported to prolong QTc proportionally to C (max). In order to circumvent this C (max)-related QTc prolongation, 5 phase I studies were initiated to investigate 1-h, 24-h, weekly, and split iv infusions. This phase I study assessed a split-dose regimen (a 1-h infusion on each of Days 1 to 3, repeated every 3 weeks) to establish the dose limiting toxicities (DLT), to recommended a phase II dose, and to characterize PK/PD.. Patient with advanced solid tumors, adequate bone marrow, hepatic, renal function and on specific cardiac criteria were eligible and "3 + 3" design was used for dose escalation. That dose escalation was guided by PK data, toxicities observed and information from other ongoing phase I studies with SR271425. SR271425 plasma levels (PK samples) were measured using a validated LC-MS/MS method. Careful monitoring of ECGs was done, and ECGs were read centrally.. Three centers enrolled 19 heavily pretreated patients to six dose levels, from 75 to 450 mg/m(2)/day (i.e., 225-1,350 mg/m(2)/cycle): 12 males and 7 females. Median age 56. Median ECOG, PS = 1. Main tumor types were brain, breast, gynecological, and urological. Patients received a median of 2 cycles (range: 1-6). NCI-CTC Grade 1-2 toxicities included nausea, vomiting, asthenia, rash, and yellow skin discoloration. No DLTs were reported, and there were no dose-limiting prolongations of QTc. Both C (end) and AUC increased in a dose-related manner, with no evidence of accumulation between Day 1 and Day 3, consistent with the mean (+/-SD) terminal elimination half-life of 5.11 +/- 1.21 h. Stable disease was observed in five cases.. Split doses allow high cumulative exposure to SR271425 without significant toxicity, especially without QTc prolongation. MTD was not reached due to the early termination of the SR271425 program by the sponsor.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Chromatography, Liquid; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Electrocardiography; Female; Half-Life; Humans; Injections, Intravenous; Male; Mass Spectrometry; Middle Aged; Neoplasms; Thioxanthenes

SR271425 is a thioxanthone cytotoxic drug that induces dose-related cardiac electrophysiologic changes in preclinical models. A phase I trial was conducted to determine the maximally tolerated dose and safety profile, notably cardiac events.. SR271425 was administered weekly as a 2-hour single intravenous infusion with a fixed 30 mg/m2 increment at each dose level (DL). A sustained cardiac evaluation was performed. ECG parameters were evaluated at bedside by an investigator or a cardiologist, as well as by central reading for dose limiting toxicity (DLT) determination.. Sixteen patients were treated. Five DLs were explored, from 75 mg/m2/wk to 195 mg/m2/wk. Fourteen patients (87.5%) experienced noncardiac adverse events related to treatment; only 2 patients presented grade 3 toxicity (nausea/vomiting and GGT increase) and no grade 4 toxicities were reported. Asymptomatic grade 1 or 2 QTcF prolongations were observed in 5 patients during central readings, and in 4 cases at bedside. One QTc-DLT, registered at bedside (grade 2), was unconfirmed at central reading, while another QTc-DLT, not noted at bedside, was highlighted by central reading. No arrhythmias or QRS prolongations were observed.. The maximum tolerated dose of SR271425 was not reached in this trial due to early termination of the trial, not related to cardiac toxicity, following the termination of the development program by the sponsor. Sustained ECG monitoring is quite feasible in oncology phase I trials, but discrepancies between bedside and central evaluation could lead to conflicting decisions for management of patient care.

Topics: Adult; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Male; Monitoring, Physiologic; Neoplasms; Patient Selection; Thioxanthenes

Anticancer drugs have to cross many layers of cells and the extracellular matrix to reach the tumor cells and elicit their pharmacological action. The three dimensional structure (micro-environment) of tumors poses a penetration barrier to antitumor drugs resulting in poor response. Two in vitro model barriers representing the extracellular matrix and multilayered structure of tumors were used in this study to evaluate the permeability of four structurally related antitumor compounds, thioxanthones. Matrigel was used to represent the tumor extracellular matrix and multilayered Caco-2 cells were used to represent the multilayered confluence of solid tumor. The in vitro permeability characteristics of the thioxanthones across the model barriers were correlated to their in vivo distribution. The apparent permeability coefficients of thioxanthone analogs are in the range of 2.9 x 10(-6) to 11.8 x 10(-6) cm/s across matrigel and 12.6 x 10(-6) to 24.5 x 10(-6) cm/s across Caco-2 multilayers. This high in vitro permeability of thioxanthones across the model barriers suggested their good tissue distribution in vivo. Therefore, the use of in vitro model barriers was found to predict in vivo tissue distribution for thioxanthones.

Topics: Antineoplastic Agents; Caco-2 Cells; Collagen; Drug Combinations; Drug Evaluation, Preclinical; Extracellular Matrix; Humans; Laminin; Neoplasms; Permeability; Proteoglycans; Thioxanthenes; Tissue Distribution; Xanthones