title: Phase I study of weekly plitidepsin as 1-hour infusion combined with carboplatin in patients with advanced solid tumors or lymphomas.
abstract: This dose-escalating phase I clinical trial was designed to determine the recommended dose (RD) and to assess the safety and feasibility of weekly plitidepsin (1-hour i.v. infusion, Days 1, 8 and 15) combined with carboplatin (1-hour i.v. infusion, Day 1, after plitidepsin) in 4-week (q4wk) cycles given to patients with advanced solid tumors or lymphomas. Twenty patients were enrolled and evaluable for both safety and efficacy. The starting dose was plitidepsin 1.8 mg/m(2) and carboplatin area under the curve (AUC) = 5 min*mg/ml; dose escalation proceeded based on worst toxicity in the previous cohort. The maximum tolerated dose (MTD) was plitidepsin 3.0 mg/m(2) and carboplatin AUC = 5 min*mg/ml, with grade 3 transaminase increases as the most common dose-limiting toxicities (DLTs). The RD for phase II studies was plitidepsin 2.4 mg/m(2) and carboplatin AUC = 5 min*mg/ml, with fatigue, myalgia and nausea as the most common drug-related adverse events (AEs). No unexpected toxicity was seen. Twelve patients (60%), ten of whom were heavily pretreated (≥2 previous chemotherapy lines) showed stable disease (SD), with a median time to progression (TTP) of 4.4 months. In conclusion, plitidepsin 2.4 mg/m(2) and carboplatin AUC = 5 min*mg/ml is a safe dose for future phase II studies evaluating the use of this combination in cancer patients potentially sensitive to platinum-based therapy.
authors.affiliation: Instituto Catalán de Oncología, Ctra. Gran Vía, s/n, L'Hospitalet de Llobregat, 08907, Barcelona, Spain. ramonsalazar@iconcologia.net
authors.forename: Ramón
authors.initials: R
authors.lastname: Salazar
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.forename: Ana
authors.initials: A
authors.lastname: Oaknin
authors.forename: Angela
authors.initials: A
authors.lastname: Robinson
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pardo
authors.forename: Arturo
authors.initials: A
authors.lastname: Soto-Matos
authors.forename: Alejandro
authors.initials: A
authors.lastname: Yovine
authors.forename: Sergio
authors.initials: S
authors.lastname: Szyldergemajn
authors.forename: Alan Hilary
authors.initials: AH
authors.lastname: Calvert
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage; D047630:Depsipeptides / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010456:Peptides, Cyclic; D016896:Treatment Outcome
chemical_list: D047630:Depsipeptides; D010456:Peptides, Cyclic; D016190:Carboplatin; C098980:plitidepsin