Pooled analysis of three pharmacokinetic studies comparing biosimilar MB02 and reference bevacizumab.

AIM: The aim of this study was to add robustness and provide further evidence on the bioequivalence, safety and immunogenicity between MB02 and reference bevacizumab. No similar study has been performed before with a biosimilar monoclonal antibody. METHODS: Population analysis by pooling data from three independent pharmacokinetic (PK) studies was performed. The studies had a single-dose, double-blind, three-arm, parallel-group design and two studies, MB02-A-02-17 and MB02-A-05-18, compared MB02 to EU- and US-bevacizumab in Caucasian subjects, while study MB02-A-04-18 compared MB02 and EU-bevacizumab in Japanese participants. Primary endpoints included maximum observed serum concentration (Cmax ), area under the serum concentration-time curve (AUC) from time zero and extrapolated to infinity (AUC0-∞ ) and AUC from time zero to the time of last quantifiable concentration (AUC0-t ). Secondary endpoints included other PK parameters, safety and immunogenicity. A sensitivity analysis using actual protein concentration as a correction factor was applied to primary PK parameters. RESULTS: Point estimates and 90% confidence intervals for the geometric mean ratios of primary PK parameters for MB02, EU- and US-bevacizumab were all contained within the predefined bioequivalence margins (80%-125%) for all pairwise comparisons. The same results for all pairwise comparisons were observed when protein-corrected primary PK parameters were analyzed. Safety and immunogenicity were similar between MB02 and the EU- and US-reference bevacizumab in healthy subjects. CONCLUSIONS: This pooled analysis of three comparable PK studies further supports the bioequivalence of biosimilar MB02 to EU- and US-reference bevacizumab. No clinically meaningful differences in safety or immunogenicity were observed.

Pharmacokinetics and excretion of 14C-Plitidepsin in patients with advanced cancer.

Plitidepsin (Aplidin®) is a marine-derived anticancer compound currently investigated in phase III clinical trials. This article describes the distribution, metabolism and excretion of this novel agent and it mainly aims to identify the major routes of elimination. Six subjects were enrolled in a mass balance study during which radiolabelled plitidepsin was administered as a 3-h intravenous infusion. Blood samples were taken and urine and faeces were collected. Total radioactivity (TRA) analysis using Liquid Scintillation Counting (LSC) was done to determine the amount of radioactivity excreted from the body and plitidepsin concentrations in whole blood, plasma and urine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. In total, a mean of 77.4% of the administered radioactivity was excreted over a time period of 20 days, of which 71.3% was recovered in faeces and 6.1% was found in urine. The majority excreted in urine was accounted for by unchanged plitidepsin, with only 1.5% of the total administered dose explained by metabolites in urine. Faeces, on the other hand contained low levels of parent compound, which means that most of the TRA excreted in faeces was accounted for by metabolites. TRA levels were 3.7 times higher in whole blood compared to plasma. Plitidepsin was widely distributed and plasma clearance was low. This study shows that red blood cells are a major distribution compartment and that the biliary route is the main route of total radioactivity excretion.

Phase I study of weekly kahalalide F as prolonged infusion in patients with advanced solid tumors.

PURPOSE: Kahalalide F (KF) is a dehydroaminobutyric acid-containing peptide from marine origin with activity against several human malignant cell lines. This dose-escalating phase I clinical trial evaluated the maximum tolerated dose (MTD), and the recommended dose for further phase II studies (RD) of weekly KF given as a prolonged (3- to 24-h) intravenous (i.v.) infusion. METHODS: Eligible patients with advanced solid tumors and adequate performance status, hematologic, renal, and hepatic function were recruited into this study. RESULTS: A total of 106 patients were treated with KF at four different weekly schedules: 3-h (n = 40), 24-h (n = 59), and two transitional schedules [6-h (n = 4) and 12-h (n = 3)]. For the 3-h weekly schedule, the MTD was 1,200 µg/m² and the RD was 1,000 µg/m². For the 24-h weekly schedule, the MTD was reached (6,650 µg/m²), but the RD could not be confirmed. Asymptomatic and reversible grade 3/4 transaminase increase was the most common dose-limiting toxicity in both schedules. Fatigue, paresthesia, pruritus, nausea, vomiting, and rash were the most common KF-related adverse events. No major deviations from linearity were detected in the pharmacokinetic (PK) profiles of both schedules, which showed a narrow distribution and short body residence. Prolonged disease stabilization (≥3 months) occurred in eight patients: two with the 3-h schedule and six with the 24-h schedule. CONCLUSIONS: Administration of KF as prolonged weekly infusion appears feasible, with 3-h and 24-h infusion times having an acceptable safety profile.

Spisulosine (ES-285) given as a weekly three-hour intravenous infusion: results of a phase I dose-escalating study in patients with advanced solid malignancies.

PURPOSE: Spisulosine is a marine compound that showed antitumor activity in preclinical studies. We report results of a phase I trial performed in patients with advanced solid tumors with the marine compound, with the aim to determine the maximum tolerated dose (MTD) of a weekly 3-h intravenous (iv.) infusion, and to evaluate the safety, efficacy, and pharmacokinetics (PK) of the compound. PATIENTS AND METHODS: Two centers contributed 25 patients to the trial, and 7 dose levels were explored. RESULTS: In dose levels ranging from 4 to 128 mg/m²/day, no dose-limiting toxicities (DLT) were observed. One patient had DLT at 200 mg/m², a reversible grade 3 ALT increase. The MTD was not reached due to early termination of the Spisulosine trial program but is considered to be likely in the range of 200 mg/m² for this schedule. Drug-related adverse reactions included mild to moderate nausea, pyrexia, injection site reactions, and vomiting. One case of grade 4 peripheral motor and sensory neuropathy associated with general weakness and pain was observed during treatment cycle 4 and possibly contributed to the death of the patient. Grade 3 laboratory abnormalities included anemia and lymphopenia and increases in liver enzymes (alkaline phosphatase, transaminases, and bilirubin). Objective responses were not observed, and only four patients had short-lasting stable disease (<3 months). The PK data indicated a wide distribution, a long residence time, and dose proportionality of the agent. CONCLUSIONS: Hepato- and neuro-toxicity are schedule independent dose-limiting adverse events for this marine compound, as illustrated by this and other early clinical trials.