Phase I and Pharmacokinetic Study of the Dolastatin-15 Analogue Tasidotin (ILX651) Administered Intravenously on Days 1, 3, and 5 Every 3 Weeks in Patients with Advanced Solid Tumors

Cunningham, Casey; Appleman, Leonard J.; Visovatti, Moira; Ryan, David P.; Regan, Eileen; Vukelja, Svetislava J.; Bonate, Peter L.; Ruvuna, Francis; Fram, Robert J.; Jekunen, Antti; Weitman, Steven; Hammond, Lisa A.; Eder, Joseph P.

doi:10.1158/1078-0432.ccr-05-0058

Cited by 46 publications

(20 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Samples were shipped to MicroConstants, Inc. (San Diego, CA), on dry ice and stored at À20jC until analysis. Samples were analyzed using the methods reported in Lewiston (12) and Cunningham (13). Also analyzed was the carboxylate metabolite of tasidotin, which had a linear range of 1 to 500 ng/mL.…”

Section: Methodsmentioning

confidence: 99%

“…Two 20-mL aliquots were frozen at À20jC, and then shipped to MicroConstants for analysis. Urine tasidotin concentrations were analyzed at MicroConstants using a validated liquid chromatography-tandem mass spectrometry assay having a linear range of 0.1 to 50 Ag/mL (12,13). The accuracy of the method at the limit of quantification (0.1 Ag/mL) was À0.2% from the theoretical value.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Phase I and Pharmacokinetic Study of Tasidotin Hydrochloride (ILX651), a Third-Generation Dolastatin-15 Analogue, Administered Weekly for 3 Weeks Every 28 Days in Patients with Advanced Solid Tumors

Mita

Hammond

Bonate³

et al. 2006

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks. Experimental Design: Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m 2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin. Results: A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m 2 . At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non^small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11months. Conclusions: The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m 2 . The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Phase I and Pharmacokinetic Study of Tasidotin Hydrochloride (ILX651), a Third-Generation Dolastatin-15 Analogue, Administered Weekly for 3 Weeks Every 28 Days in Patients with Advanced Solid Tumors

Mita

Hammond

Bonate³

et al. 2006

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Currently, ILX-651 (Synthadotin), a third-generation analogue with a terminal tert-butyl moiety in place of dolapyrolidone, has successfully completed a phase I clinical trial and a phase II trial has been recommended. 30 Apratoxin A is a cyclodepsipeptide isolated from a Lyngbya sp. collected from Guam.…”

Section: Anticancer Activitymentioning

confidence: 99%

Cyanobacteria: an emerging source for drug discovery

et al. 2011

View full text Add to dashboard Cite

The c group of Gram-negative gliding bacteria, has a long history of cosmopolitan occurrence. It has great biodiversity despite the absence of sexual reproduction. This wide biodiversity may be reflected in the wide spectrum of its secondary metabolites. These cyanobacterial secondary metabolites are biosynthesized by a variety of routes, notably by non-ribosomal peptide synthetase or polyketide synthetase systems, and show a wide range of biological activities including anticancer, antibacterial, antiviral and protease inhibition activities. This high degree of chemical diversity in cyanobacterial secondary metabolites may thus constitute a prolific source of new entities leading to the development of new pharmaceuticals.

show abstract

“…Because of the longer half-life, the metabolite ratio was estimated to be 0.59, indicating that tasidotin-C-carboxylate contributed ~59% to the total exposure. [4][5][6] In A549 cells incubated with tasidotin, tasidotin was rapidly taken up into cells where it was metabolized to the more active metabolite tasidotin-C-carboxylate by cleavage of the t-butyl-amine group via the enzyme prolyl oligopeptidase (POP). 7 Tasidotin-C-carboxylate was then metabolized to desprolyl-tasidotin-C-carboxylate, also called the M2-metabolite, releasing free proline by an unknown enzyme.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics in mice implanted with xenografted tumors after intravenous administration of tasidotin (ILX651) or its carboxylate metabolite

Bonate

Beyerlein

Crawford

et al. 2007

AAPS J

Self Cite

View full text Add to dashboard Cite

The pharmacokinetics of tasidotin (ILX651), a depsipeptide currently in phase II for the treatment of advanced solid tumors, and tasidotin-C-carboxylate, the main metabolite, were characterized in male nude mice implanted with LOX tumors, which are sensitive to tasidotin, or H460 tumors, which are resistant to tasidotin. The pharmacokinetics of tasidotin and its metabolites were characterized after singledose administration of tasidotin (20 and 120 mg/kg), tasidotin-C-carboxylate (150 mg/kg), or tasidotin (53 mg/kg) in the presence and absence of Z-prolyl prolinal (5 mg/kg administered 1 hour prior to tasidotin administration), a competitive antagonist of prolyl oligopeptidase, the enzyme responsible for the metabolism of tasidotin to tasidotin-Ccarboxylate. A secondary study was done comparing tumor growth in tasidotin-treated mice with implanted LOX tumors in the presence and absence of Z-prolyl-prolinal. After tasidotin administration, the pharmacokinetics of tasidotin and tasidotin-C-carboxylate were similar in plasma and tumors in LOX-and H460-implanted mice, indicating the resistance was not due to pharmacokinetic factors. Tumor carboxylate concentrations were much higher than in plasma after tasidotin administration. The metabolite appeared to contribute ~17% to 33% to the total exposure in LOX tumors and 20% to 49% in H460 tumors but <5% in plasma. Less than 5% of the administered tasidotin dose was converted to tasidotin-C-carboxylate, with no apparent differences between LOX-and H460-treated animals. The presence of Z-prolyl-prolinal decreased the amount of tasidotin converted to tasidotin-C-carboxylate from 5.5% to 0.90%, a reduction of almost 80%. After tasidotin-Ccarboxylate administration, the half-life was on the order of minutes compared with hours when observed after tasidotin administration. Tasidotin-C-carboxylate elimination was not dependent on tasidotin pharmacokinetics, suggesting that the rate of efÀ ux from cells into plasma was the ratelimiting step in its elimination. Tasidotin-C-carboxylate was also further metabolized to desprolyl-tasidotin-C-carboxylate, although the metabolite ratios were <10%. Pretreatment with Z-prolyl-prolinal completely abolished the antitumor activity of tasidotin, indicating that the metabolite is the main moiety responsible for activity and that, despite tasidotin itself having activity in vitro, tasidotin is acting mainly as a prodrug.

show abstract

Phase I and Pharmacokinetic Study of the Dolastatin-15 Analogue Tasidotin (ILX651) Administered Intravenously on Days 1, 3, and 5 Every 3 Weeks in Patients with Advanced Solid Tumors

Cited by 46 publications

References 31 publications

Phase I and Pharmacokinetic Study of Tasidotin Hydrochloride (ILX651), a Third-Generation Dolastatin-15 Analogue, Administered Weekly for 3 Weeks Every 28 Days in Patients with Advanced Solid Tumors

Phase I and Pharmacokinetic Study of Tasidotin Hydrochloride (ILX651), a Third-Generation Dolastatin-15 Analogue, Administered Weekly for 3 Weeks Every 28 Days in Patients with Advanced Solid Tumors

Cyanobacteria: an emerging source for drug discovery

Pharmacokinetics in mice implanted with xenografted tumors after intravenous administration of tasidotin (ILX651) or its carboxylate metabolite

Contact Info

Product

Resources

About