Phase I dose-escalation study of the thioxanthone SR271425 administered intravenously once every 3 weeks in patients with advanced malignancies

Abstract

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.

Experimental and theoretical investigation of molecular structure and conformation of the 4-isopropylthioxanthone

“…Previous studies have investigated the in vivo efficacy of SR 233377 derivatives against the murine solid tumor Panc03 [8]. Recently, a promising thioxanthone analog of third-generation, SR 271425, has presented antitumor activity against a wide range of tumor types, and it already is in phase I studies [9].…”

Theoretical and Practical Application of Traditional and Accelerated Titration Phase I Clinical Trial Designs: The Wayne State University Experience

“…Although there were other Phase I trials conducted at our institution during the 13-year period, the nine Phase I trials in this manuscript were selected for discussion because they were primarily investigator-initiated trials and/or trials that were within our design control. One Phase I trial evaluating SR271425 was conducted as a multi-institutional trial with WSU/KCI as the lead clinical site (Goncalves et al, 2008). The number of patients, number of dose levels, total time to completion of the study, and adverse events were obtained from published manuscripts, meeting abstracts, and when necessary, from the original study database.…”

Screening a Small Library of Xanthones for Antitumor Activity and Identification of a Hit Compound which Induces Apoptosis

“…Nevertheless, although presenting similarity with other intercalating agents, their mutagenicity (mainly due to their methylene moiety directly bound to C-4) discouraged their use in cancer chemotherapy [2,4]. Other examples of thioxanthones with antitumor activity are SR233377 and SR271425 [5,6]. SR233377, a hycanthone derivative, is a second-generation aminated thioxanthone which presented selectivity for mouse solid tumors when compared to normal cells (using a disc diffusion in vitro assay) and was also confirmed to be active in vivo in tumors implanted in murine models [5].…”

“…Nevertheless, it was found to be hepatotoxic. This problem was latter overcome by the development of SR271425, a third-generation thioxanthone, which presented a broad-spectrum activity against solid tumors both in vitro and in vivo (in murine as well as in human xenograft tumor models) [6].…”

“…Although several thioxanthone derivatives have entered clinical trials as antitumor agents in the last decade, their toxicity has largely limited their clinical utility [2,5,6,7]. In order to circumvent this toxicity problem, which was associated with their pattern of substitution, and in order to improve their efficiency, a small library of new thioxanthone derivatives with potential as antitumor agents and simultaneously with P-glycoprotein (P-gp) inhibitory activity, was designed and recently obtained by some of us [4].…”