Phase I and Pharmacokinetic Study of LU79553, a DNA Intercalating Bisnaphthalimide, in Patients With Solid Malignancies

Villalona‐Calero, Miguel A.; Eder, Joseph P.; Toppmeyer, Deborah; Allen, Lee F.; Fram, Robert J.; Velagapudi, Raja; Myers, Michael; Amato, Anthony A.; Kagen-Hallet, Kathleen; Razvillas, Betty; Küfe, Donald; Hoff, Daniel D. Von; Rowinsky, Eric K.

doi:10.1200/jco.2001.19.3.857

Cited by 44 publications

(39 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, the toxicity profiles of trabectedin and gemcitabine overlap, in particular with regard to myelosuppression and increases in transaminases. Trabectedin has also been tested in a daily ×5 schedule every 3 weeks [38], where the MTD was 0.325 mg/m 2 due to cytopenias. Interestingly, in that study hepatotoxicity was common in doses >0.216 mg/m 2 , but this was not dose-limiting.…”

Section: Discussionmentioning

confidence: 99%

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Messersmith

Jimeno

Ettinger

et al. 2008

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

Purpose-To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors.Methods-Patients with ECOG performance status 0-1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m 2 ) followed by trabectedin (starting dose, 0.3 mg/m 2 ). Strict liver function test treatment criteria were employed to avoid hepatic toxicity seen in previous trabectedin studies. Plasma samples were collected during cycles 1 and 2 for pharmacokinetic analyses.Results-Fifteen patients received ≥1 dose, with a median of two treatment cycles (range 1-10). The most common drug-related toxicity was hepatic. Dose reductions were required for $watermark-text $watermark-text $watermark-text trabectedin in four (27%) patients and gemcitabine in six (40%) patients. Cycle delays/dose holds were required in 11 (73%) patients and doses above trabectedin 0.4 mg/m 2 and gemcitabine 1,000 mg/m 2 , which is the recommended phase II dose, were not feasible. Seven patients maintained stable disease after two cycles. Gemcitabine and trabectedin pharmacokinetics were not altered substantially with concomitant administration.Conclusions-Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.

show abstract

Section: Discussionmentioning

confidence: 99%

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Messersmith

Jimeno

Ettinger

et al. 2008

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

show abstract

“…Present research also reports that linking naphthalimide with a polyamine backbone improves their cytotoxicity (3,9,10) as well as selectivity against tumor cells and normal cells (11). Elinafide, a bisnaphthalimide polyamine derivative with dramatic anti-tumor activity, has been selected and progressed to clinical treatment against solid tumors (7,12). Indeed, many anti-tumor drugs are poorly tumor selective resulting in high incidences of adverse effects.…”

Section: Introductionmentioning

confidence: 89%

Reactive oxygen species (ROS) accumulation induced by mononaphthalimide-spermidine leads to intrinsic and AIF-mediated apoptosis in HeLa cells

Zhao

2011

Oncol Rep

View full text Add to dashboard Cite

Abstract. Developing polyamine conjugates having the potential of transporting naphthalimide selectively into tumor cells is attractive. However, the evaluation of their cytotoxic mechanism has not been comprehensive. This study focused on the effects of mononaphthalimide spermidine (MNISpd) conjugate on apoptosis induction and the relationship between MNISpd-induced apoptosis and reactive oxygen species (ROS) in HeLa cells. Our findings indicated that 9 μM MNISpd induced apoptosis in HeLa cells during a 48-h period. MNISpd induced apoptosis in HeLa cells following cytochrome c release, elevation of caspase 3/9 activity, apoptosisinducing factor (AIF) translocation and up-/down-regulation of Bax/Bcl-2 protein expression, respectively, and these effects were completely antagonized by pre-incubation with 10 mM NAC for 2 h. MNISpd induced significant ROS accumulation following up-regulation of polyamine oxidase (PAO) activity and complex variations in glutathione levels. It is concluded that MNISpd-induced apoptosis is related to intrinsic caspase-dependent and AIF-mediated caspaseindependent apoptosis pathways in HeLa cells. MNISpdinduced apoptosis correlates to MNISpd-induced ROS production resulting from GSH (reduced form of glutathione) pool depletion, and PAO is likely to be the source of ROS.

show abstract

“…In recently completed phase I studies performed in the U.S. and Europe, patients with leiomyosarcoma, liposarcoma, osteosarcoma, melanoma, mesothelioma, and ovarian and breast cancer responded to treatment with ET-743 [18][19][20][21]. In the initial phase I study and compassionate use program of ET-743, four patients with chemorefractory STSs had partial responses, and three patients with GISTs had stable disease among a cohort of 29 patients treated with 1.5 mg/m 2 of ET-743 given as a 24-hour continuous i.v.…”

Section: Introductionmentioning

confidence: 99%

A Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients with Gastrointestinal Stromal Tumors

et al. 2002

View full text Add to dashboard Cite

Purpose. To assess the efficacy, tolerability, and pharmacokinetics of ecteinascidin 743 (ET-743) in patients with advanced gastrointestinal stromal tumors (GISTs).Patients and Methods. The study was confined to adult patients with radiographically measurable GISTs. ET-743 was administered as a 24-hour continuous i.v. infusion at a dose of 1.5 mg/m 2 repeated every 3 weeks. Pharmacokinetic blood sampling was performed during the first cycle of therapy. Tumors were restaged after every second cycle of therapy.Results. A total of 20 patients was enrolled in the study, 19 of whom were treated with 47 cycles of ET-743 (median 2, range 1-10). Severe toxicities were limited to reversible grade 3 transaminitis in 10 patients and grade 3 fatigue in one patient. There were no objective responses, and disease stabilization occurred in two patients lasting for periods of 4 and 10 months. The 1-year survival rate was 71.1%. Mean ± standard deviation values of the maximum plasma concentration and total plasma clearance were 1.1 ± 0.4 ng/ml and 44 ± 16 l/h/m 2 , respectively, for 19 of the 20 patients.Conclusion. This study is the first report of a prospective phase II trial to evaluate a cytotoxic agent in patients with GISTs. This study underscores the primary resistance of GISTS to chemotherapy and stands in stark contrast to the encouraging results recently achieved with STI571. The lack of response may be associated with a therapeutically ineffective exposure to the drug based upon the lower incidence of severe toxicities and greater clearance than described in phase I and II trials of ET-743. The Oncologist 2002;7:531-538 The Oncologist 2002;7:531-538 www.TheOncologist.com Correspondence: David P. Ryan, M.D., MGH Cancer Center, 100 Blossom Street, Cox 640, Boston, Massachusetts 02114, USA. Telephone: 617-724-4000; Fax: 617-724-3166; e-mail: dpryan@partners.org Received August 6, 2002; accepted for publication October 17, 2002. ©AlphaMed Press 1083-7159/2002 The Oncologist ® LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Describe the mechanism of action, administration, and pharmacokinetics of ecteinascidin 743.2. Recognize the classification and pathophysiology of gastrointestinal stromal tumors.3. Appreciate that conventional cytotoxic chemotherapy has no efficacy in patients with gastrointestinal stromal tumors and that STI571 has dramatic efficacy.Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com CME CME

show abstract

Phase I and Pharmacokinetic Study of LU79553, a DNA Intercalating Bisnaphthalimide, in Patients With Solid Malignancies

Cited by 44 publications

References 25 publications

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Reactive oxygen species (ROS) accumulation induced by mononaphthalimide-spermidine leads to intrinsic and AIF-mediated apoptosis in HeLa cells

A Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients with Gastrointestinal Stromal Tumors

Contact Info

Product

Resources

About