Phase I Clinical and Pharmacokinetic Study of Plitidepsin as a 1-Hour Weekly Intravenous Infusion in Patients with Advanced Solid Tumors

Abstract

Purpose: Plitidepsin, given as a 1-hour weekly i.v. infusion for 3 consecutive weeks during a 4-week treatment cycle, was investigated in patients with solid tumors to determine the maximum tolerated dose and the recommended dose (RD) using this administration schedule. Experimental Design: Consecutive cohorts of patients with metastatic solid tumors or non^Hodgkin's lymphomas were to be treated at escalating doses of plitidepsin in a conventional phase I study including pharmacokinetic analyses of plitidepsin in plasma, whole blood, and blood cell pellets. Results: Forty-nine patients with solid tumors were enrolled, and 48 were treated with plitidepsin (doses from 0.133 to 3.6 mg/m 2 /week). Dose-limiting toxicities (defining 3.6 mg/m 2 /week as the maximum tolerated dose) included myalgia, increased creatine phosphokinase levels, and sustained grade 3/4 increases of hepatic enzyme levels. The RD was established at 3.2 mg/m 2 /week. The most common toxicities were fatigue, vomiting/nausea, anorexia, injection site reaction, and pain, mostly of mild or moderate severity. Muscular toxicity manifested by mild-moderate myalgia, weakness, and/or creatine phosphokinase elevations occurred in f25% of patients and seemed to be dose related. Transient transaminase elevations were frequent but achieved grade 3 or 4 in only f10% of patients. Plitidepsin lacked significant hematologic toxicity. No complete or partial tumor responses were observed; however, five patients had disease stabilization (including one patient with medullary thyroid carcinoma with an unconfirmed partial response and one patient with renal carcinoma with major tumor shrinkage in lung metastases). Pharmacokinetic results for the RD indicated a long plasma half-life give value (16.8 F 7.7 hour) and a high volume of distribution value (525.2 F 219.3 L). Conclusions: The recommended dose for plitidepsin given as a weekly 1-hour schedule was 3.2 mg/m 2 /week. Muscular and liver toxicity were dose limiting at 3.6 mg/m 2 /week. Additional evaluation of this dose dense schedule is warranted.

Medullary Thyroid Cancer: Molecular Biology and Novel Molecular Therapies

“…Plitidepsin induces an early oxidative stress response, which results in a rapid and sustained activation of the EGF-R, the non-receptor protein tyrosine kinase Src, the serine threonine kinases c-Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase. These early events rapidly trigger the induction of the mitochondrial apoptotic pathway via cytochrome c release, activation of the caspase cascade, and activation of protein kinase C, which seems to exert an important effector role in mediating cellular death induced by the drug [146]. In a phase I clinical trial, the single MTC patient showed disease stabilization [146].…”

“…These early events rapidly trigger the induction of the mitochondrial apoptotic pathway via cytochrome c release, activation of the caspase cascade, and activation of protein kinase C, which seems to exert an important effector role in mediating cellular death induced by the drug [146]. In a phase I clinical trial, the single MTC patient showed disease stabilization [146]. Further studies with large patient groups are needed to evaluate the drug’s effect on MTC.…”

Multicenter phase II study of plitidepsin in patients with relapsed/refractory non-Hodgkin's lymphoma

“…The overall safety profile was in accordance with that reported in a previous phase I clinical trial with this single-agent schedule in patients with solid tumors. 12 Of note, many of the side effects commonly induced by cytotoxic agents, such as alopecia, mucositis/stomatitis or clinically relevant myelosuppression, were not characteristic of plitidepsin.…”

“…12 The time course of plitidepsin whole blood concentrations in NHL patients was appropriately described by an open,…”

“…In addition, 3.2 mg/m 2 was defined as the recommended dose for phase II studies with this schedule. 12 The objective of this phase II clinical trial was to evaluate the efficacy, safety and pharmacokinetics (PK) of plitidepsin given at this dose and schedule to adult patients with relapsed or refractory aggressive NHL.…”