kahalalide-f and Lung-Neoplasms

Because of the poor results observed after platinum-based first-line chemotherapy, research on new strategies for second-line treatment of advanced non-small-cell lung cancer (NSCLC) is warranted. Current research focuses on the development of new agents and the assessment of a combination of therapies, especially those with different mechanisms of action. PM02734 (elisidepsin, Irvalec) is a compound related to Kahalalide F (KF), a moderately soluble marine product that belongs to a family of dehydro aminobutyric acid-containing peptides isolated from the herbivorous marine mollusk Elysia rufescens. Preclinical and clinical studies showed that KF induces strong cytotoxic activity against different solid tumors, including NSCLC, particularly in patients with squamous histology; in fact, almost 40% of patients treated in the second line were still alive at 1 year after beginning treatment with KF. Analysis of data collected during clinical development has revealed that KF has a predictable and manageable toxicity profile. The toxicities most commonly associated with KF are generally transient and mild or moderate. The absence of hematologic toxicity and cumulative toxic effects suggests that KF may be suitable for combination trials with other anticancer agents. The development of KF could stopped because of the unavailability of a natural source of the compound. PM02734 is a closely related derivative of KF with similar activity and characteristics. Herein, we summarize the studies of PM02734 and future clinical perspectives.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Depsipeptides; Humans; Injections, Intravenous; Lung Neoplasms; Mollusk Venoms; Randomized Controlled Trials as Topic

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.. Eligible patients with advanced solid tumors and adequate performance status, hematologic, renal, and hepatic function were recruited into this study.. 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.. Administration of KF as prolonged weekly infusion appears feasible, with 3-h and 24-h infusion times having an acceptable safety profile.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Cohort Studies; Colorectal Neoplasms; Depsipeptides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Investigational; Female; Humans; Incidence; Infusions, Intravenous; Lung Neoplasms; Male; Middle Aged; Neoplasms; Severity of Illness Index; Spain