pm-01183 and Nausea

Lurbinectedin (PM01183) binds covalently to DNA and has broad activity against tumor cell lines. This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose for PM01183 as a 1-hour intravenous infusion every three weeks (q3wk).. Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design.. PM01183 was safely escalated over 200-fold, from 0.02 to 5.0 mg/m(2). Dose doubling was utilized, requiring 15 patients and nine dose levels to identify DLT. The recommended dose was 4.0 mg/m(2), with one of 15 patients having DLT (grade 4 thrombocytopenia). Clearance was independent of body surface area; thus, a flat dose of 7.0 mg was used during expansion. Myelosuppression, mostly grade 4 neutropenia, occurred in 40% of patients but was transient and manageable, and none was febrile. All other toxicity was mild and fatigue, nausea and vomiting were the most common at the recommended dose. Pharmacokinetic parameters showed high interindividual variation, though linearity was observed. At or above the recommended dose, the myelosuppressive effect was significantly associated with the area under the concentration-time curve from time zero to infinity (white blood cells, P = 0.0007; absolute neutrophil count, P = 0.016). A partial response was observed in one patient with pancreatic adenocarcinoma at the recommended dose.. A flat dose of 7.0 mg is the recommended dose for PM01183 as a 1-hour infusion q3wk. This dose is tolerated and active. Severe neutropenia occurred at this dose, although it was transient and with no clinical consequences in this study.

Topics: Adult; Aged; Anemia; Area Under Curve; Carbolines; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Infusions, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Nausea; Neoplasms; Treatment Outcome; Vomiting; Young Adult

Few strategies exist for treatment of patients with small-cell lung cancer (SCLC) extended-stage after failure of first-line platinum-based chemotherapy. Lurbinectedin is a novel RNA-polymerase-II inhibitor investigated as a second-line therapy for SCLC. However, its efficacy and safety profile in real clinical practice remain to be determined.. To determine the efficacy and safety of lurbinectedin in real-life among patients with SCLC previously treated with first-line platinum-based chemotherapy.. We retrospectively evaluated patients who received at least one dose of lurbinectedin (3.2 mg/m. Thirteen patients were included. The median age was 60 years (range: 42-77), seven (54%) were females, nine (69%) having a performance status of 0-1. Lurbinectedin was given as second-line treatment before platinum rechallenge in four (31%) patients. After a mean follow-up of 4.1 months, the objective response rate (ORR) was 17%. The median time to treatment discontinuation (TTD) was 2.3 months (interquartile range [IQR], 1.2-3.6). The median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.9 (IQR, 0.1.8) and 4.1 (IQR, 2.0-3.5) months. No significant difference regarding TTD, PFS or OS was found in the two groups according to treatment history or according to chemotherapy-free intervall (CMI) 〈1 or 〉1 month. The most common adverse events (AEs) were asthenia, nausea, and anemia in nine (70%) patients. Grade 3 AEs were reported, fatigue, vomiting, nausea, anorexia, and neutropenia.. Lurbinectedin in real clinical practice could have had a lower efficacy than in phase II trial, but a better hematological and bioclinical tolerance than previously reported. Early relapse after platinum-based chemotherapy seems to have a lower response to lurbinectedin.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbolines; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Male; Middle Aged; Nausea; Neoplasm Recurrence, Local; Neutropenia; Retrospective Studies; Small Cell Lung Carcinoma