Clinical and pharmacokinetic phase I dose-finding study of kahalalide F (KF) administered as a prolonged infusion in patients with solid tumors
2005; Lippincott Williams & Wilkins; Volume: 23; Issue: 16_suppl Linguagem: Inglês
10.1200/jco.2005.23.16_suppl.2059
ISSN1527-7755
AutoresRamón Salazar, E. Casado, Ana López Martín, Beatriz Pardo, J. M. Roca, Rafael Riosmena‐Rodríguez, Montse García, Josep Tabernero, Begoña de las Heras, L. Paz-Ares,
Tópico(s)Computational Drug Discovery Methods
Resumo2059 Background: KF is a cytotoxic cyclic peptide derived from the mollusc Elysia rufescens. Two prior phase 1 studies assessed 1 hour (h) infusions in 5-day 3-weekly and 1-day weekly schedules. The recommended doses (RD) were 560 and 650 μg/m2, respectively. The dose limiting toxicity (DLT) was reversible transaminase elevation (RTE) which was acute, asymptomatic and believed to be related to Cmax. A prolonged infusion may attenuate this effect and allow a higher non toxic systemic exposure. Therefore the current trial evaluates the safety and pharmacokinetics (PK) of prolonged (3h) weekly infusions to define its RD. Methods: The starting dose was 530 μg/m2. Cohorts of 3–6 patients were treated at increasing doses (530, 650, 800, 1000, 1200 and 1400 μg/m2), PK sampling being performed after the first and second infusion. Results: Thirty-six pts have been registered. Median age is 57 years (range 30–80) and median performance status is 0 (range 0–1). DLT was observed at the two higher dose levels (2/4 and 2/6 pts at 1400 and 1200 μ g/m2 respectively). DLT was grade 4 RTE. No other relevant toxicity has been observed, except paresthesias and pruritus on hands during and early post- infusion. The putative RD of 1000 μ g/m2 is being expanded to 13 pts. One complete response (CR) in non measurable lesions after 26 infusions was obtained in a locally advanced melanoma at 530 μg/m2. KF shows a rapid elimination half life (median 40 minutes) with restricted volume of distribution (median 8.3 L/m2). KF PK appears dose linear on graphical analysis in this schedule. Comparison of PK results at toxic levels in this study with those of prior studies shows that AUC values are similar, whereas Cmax values are lower, suggesting that DLTs are AUC rather than Cmax related. Conclusions: Weekly 3h infusions of KF are feasible and well tolerated. DLT was grade 4 acute, asymptomatic RTE. The RD of 1000 μg/m2 is being expanded to further characterize its toxicity and PK profile. No significant financial relationships to disclose.
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