Phase I and pharmacokinetic study of brostallicin (PNU-166196), a new DNA minor-groove binder, administered intravenously every 3 weeks to adult patients with metastatic cancer (original) (raw)
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Annals of Oncology, 2003
The aim of this study was to assess the feasibility of administering bizelesin, a cyclopropylpyrroloindole with extraordinarily high potency as a bifunctional DNA-damaging agent and selectivity for specific AT-rich DNA sequences, as a single i.v. bolus injection every 4 weeks in patients with advanced solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) of bizelesin, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity.
Brostallicin, a Novel Anticancer Agent Whose Activity Is Enhanced upon Binding to Glutathione1
2000
Brostallicin (PNU-166196) is a synthetic -bromoacrylic, second- generation DNA minor groove binder structurally related to distamycin A, presently in Phase II trials in Europe and the United States. The compound shows broad antitumor activity in preclinical models and dramatically reduced in vitro myelotoxicity in human hematopoietic pro- genitor cells compared with that of other minor groove binders. Brostal- licin showed
Brostallicin, a novel anticancer agent whose activity is enhanced upon binding to glutathione
Cancer Research, 2002
Brostallicin (PNU-166196) is a synthetic ␣-bromoacrylic, secondgeneration DNA minor groove binder structurally related to distamycin A, presently in Phase II trials in Europe and the United States. The compound shows broad antitumor activity in preclinical models and dramatically reduced in vitro myelotoxicity in human hematopoietic progenitor cells compared with that of other minor groove binders. Brostallicin showed a 3-fold higher activity in melphalan-resistant L1210 murine leukemia cells than in the parental line (IC 50 ؍ 0.46 and 1.45 ng/ml, respectively) under conditions in which the cytotoxicity of conventional antitumor agents was either unaffected or reduced. This melphalan-
Clinical Cancer Research, 2009
This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. Experimental Design: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 Ag/m 2) given as a 10-minute i.v. infusion every 21days. The dose was subsequently reduced in incremental steps to 45 Ag/m 2 due to unexpected toxicity. Results:The maximum tolerated dose of SJG-136 was 45 Ag/m 2 .The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive g-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. Conclusions: SJG-136 was associated with dose-limitingVLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.
Clinical Cancer Research, 2009
Purpose: This study was designed to determine the safety, tolerability, and pharmacokinetics, and to seek preliminary evidence of anticancer activity of trabectedin, a novel marine-derived DNA minor grove binder, when administered as a 1-hour or 3-hour i.v. infusion for 3 consecutive weeks every 4 weeks in patients with advanced solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) levels of trabectedin on these schedules, as well as to recommend doses for disease-directed studies. Experimental Design: A total of 32 and 31 patients were treated in sequential cohorts with trabectedin on the 1-hour schedule (doses ranging from 0.46 to 0.80 mg/m2) and on the 3-hour schedule (doses ranging from 0.30 to 0.65 mg/m2). Results: Neutropenia, transient elevations in hepatic transaminases and creatine phosphokinase, and fatigue precluded dose escalation above 0.70 mg/m2 (1-hour schedule) and 0.65 mg/m2 (3-hour schedule), which were determined to be the MTD lev...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2002
The purpose of this study was to (a) assess the feasibility of administering ecteinascidin-743 (ET-743), a novel DNA minor-groove disrupting agent of marine origin, administered as a daily i.v. infusion for 5 days every 3 weeks; (b) recommend a dose for Phase II studies; (c) characterize its pharmacokinetic behavior; and (d) seek preliminary evidence of anticancer activity. Patients with advanced solid malignancies were treated with escalating doses of ET-743 as a daily 1-h i.v. infusion for 5 days every 3 weeks. Plasma and urine were sampled on both days 1 and 5 of the first course. Pharmacokinetic parameters were related to the principal toxicities. Forty-two patients were treated with 118 courses of ET-743 at doses ranging from 6 to 380 microg/m(2)/day. Elevations in hepatic transaminases were common at ET-743 dose levels > or =216 microg/m(2)/day, resolved rapidly, and were never dose limiting nor cumulative. Instead, hematological toxicity was the principal toxicity that pre...