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Phase II trial of sagopilone, a novel epothilone analog in metastatic melanoma.

DeConti RC, Algazi AP, Andrews S, Urbas P, Born O, Stoeckigt D, Floren L, Hwang J, Weber J, Sondak VK, Daud AI - Br. J. Cancer (2010)

Bottom Line: Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%).Unlike other epothilones, it shows activity against melanoma even in pretreated patients.Further clinical testing is warranted.

View Article: PubMed Central - PubMed

Affiliation: Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, USA.

ABSTRACT

Background: Sagopilone is a novel fully synthetic epothilone with promising preclinical activity and a favourable toxicity profile in phase I testing.

Methods: A phase II pharmacokinetic and efficacy trial was conducted in patients with metastatic melanoma. Patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate haematological, and organ function, with up to 2 previous chemotherapy and any previous immunotherapy regimens. Sagopilone, 16 mg m⁻², was administered intravenously over 3 h every 21 days until progression or unacceptable toxicity.

Results: Thirty-five patients were treated. Sagopilone showed multi-exponential kinetics with a mean terminal half-life of 64 h and a volume of distribution of 4361 l m⁻² indicating extensive tissue/tubulin binding. Only grade 2 or lower toxicity was observed: these included sensory neuropathy (66%), leukopenia (46%), fatigue (34%), and neutropenia (31%). The objective response rate was 11.4% (one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response). Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%).

Conclusion: Sagopilone was well tolerated with mild haematological toxicity and sensory neuropathy. Unlike other epothilones, it shows activity against melanoma even in pretreated patients. Further clinical testing is warranted.

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Related in: MedlinePlus

Mean plasma concentration–time curve of sagopilone after single intravenous infusion of 16 mg m−2 sagopilone over 3 h (N=9–10).
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fig1: Mean plasma concentration–time curve of sagopilone after single intravenous infusion of 16 mg m−2 sagopilone over 3 h (N=9–10).

Mentions: Nine of the subjects were evaluable since one patient was excluded from the PK analysis owing to three missing PK samples necessary to define the Cmax and AUC. Maximum average sagopilone concentrations of 33.3 ng ml−1 were reached 2.92 h after the start of the infusion (Figure 1). Plasma concentrations dropped about 10-fold within 30 min after the end of infusion. Thereafter, the concentration–time profile turned into a slow terminal disposition phase. Drug disposition appeared to be multi-exponential, with sagopilone plasma concentrations decreasing to about 10% of peak concentration by 0.5 h after the end of the 3-h intravenous infusion. After the rapid distribution phase, a long terminal disposition phase followed (mean terminal half-life 64.1 h). The large apparent volume of distribution indicates extensive tissue/tubulin binding. Therefore, the long terminal half-life was thought to reflect the release of sagopilone from deep tissue compartments rather than the actual rate of its metabolism or excretion. The rate of total body clearance was 120 l h−1 (2000 ml min−1) and the apparent volume of distribution during the terminal phase was 4361 l m−2. The net average area under the plasma concentration–time curve was 252 ng.h ml−1. The kinetic parameter estimates observed in this study were similar to those determined in previous studies at the same dose and dosing schedule.


Phase II trial of sagopilone, a novel epothilone analog in metastatic melanoma.

DeConti RC, Algazi AP, Andrews S, Urbas P, Born O, Stoeckigt D, Floren L, Hwang J, Weber J, Sondak VK, Daud AI - Br. J. Cancer (2010)

Mean plasma concentration–time curve of sagopilone after single intravenous infusion of 16 mg m−2 sagopilone over 3 h (N=9–10).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2990578&req=5

fig1: Mean plasma concentration–time curve of sagopilone after single intravenous infusion of 16 mg m−2 sagopilone over 3 h (N=9–10).
Mentions: Nine of the subjects were evaluable since one patient was excluded from the PK analysis owing to three missing PK samples necessary to define the Cmax and AUC. Maximum average sagopilone concentrations of 33.3 ng ml−1 were reached 2.92 h after the start of the infusion (Figure 1). Plasma concentrations dropped about 10-fold within 30 min after the end of infusion. Thereafter, the concentration–time profile turned into a slow terminal disposition phase. Drug disposition appeared to be multi-exponential, with sagopilone plasma concentrations decreasing to about 10% of peak concentration by 0.5 h after the end of the 3-h intravenous infusion. After the rapid distribution phase, a long terminal disposition phase followed (mean terminal half-life 64.1 h). The large apparent volume of distribution indicates extensive tissue/tubulin binding. Therefore, the long terminal half-life was thought to reflect the release of sagopilone from deep tissue compartments rather than the actual rate of its metabolism or excretion. The rate of total body clearance was 120 l h−1 (2000 ml min−1) and the apparent volume of distribution during the terminal phase was 4361 l m−2. The net average area under the plasma concentration–time curve was 252 ng.h ml−1. The kinetic parameter estimates observed in this study were similar to those determined in previous studies at the same dose and dosing schedule.

Bottom Line: Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%).Unlike other epothilones, it shows activity against melanoma even in pretreated patients.Further clinical testing is warranted.

View Article: PubMed Central - PubMed

Affiliation: Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, USA.

ABSTRACT

Background: Sagopilone is a novel fully synthetic epothilone with promising preclinical activity and a favourable toxicity profile in phase I testing.

Methods: A phase II pharmacokinetic and efficacy trial was conducted in patients with metastatic melanoma. Patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate haematological, and organ function, with up to 2 previous chemotherapy and any previous immunotherapy regimens. Sagopilone, 16 mg m⁻², was administered intravenously over 3 h every 21 days until progression or unacceptable toxicity.

Results: Thirty-five patients were treated. Sagopilone showed multi-exponential kinetics with a mean terminal half-life of 64 h and a volume of distribution of 4361 l m⁻² indicating extensive tissue/tubulin binding. Only grade 2 or lower toxicity was observed: these included sensory neuropathy (66%), leukopenia (46%), fatigue (34%), and neutropenia (31%). The objective response rate was 11.4% (one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response). Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%).

Conclusion: Sagopilone was well tolerated with mild haematological toxicity and sensory neuropathy. Unlike other epothilones, it shows activity against melanoma even in pretreated patients. Further clinical testing is warranted.

Show MeSH
Related in: MedlinePlus