title: Phase I dose-escalation study of plitidepsin in combination with sorafenib or gemcitabine in patients with refractory solid tumors or lymphomas.
abstract: This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients. The study included two treatment arms: a sorafenib/plitidepsin (S/P) and a gemcitabine/plitidepsin (G/P) arm. In the S/P arm, patients were treated orally with sorafenib continuous dosing at two dose levels (DL1: 200 mg twice daily and DL2: 400 mg twice daily) combined with plitidepsin (1.8 mg/m, day 1, day 8, day 15, and, q4wk, intravenously). In the G/P arm, patients with solid tumors or lymphoma were treated at four different DLs with a combination of gemcitabine (DL1: 750 mg/m, DL2-DL4: 1000 mg/m) and plitidepsin (DL1-DL2: 1.8 mg/m; DL3: 2.4 mg/m; DL4: 3 mg/m). Both agents were administered intravenously on day 1, day 8, day 15, and, q4wk. Forty-four patients were evaluable for safety and toxicity. The safety of the combination of plitidepsin with sorafenib or gemcitabine was manageable. Most adverse events (AEs) were mild; no grade 4 treatment-related AEs were reported in any of the groups (except for one grade 4 thrombocytopenia in the gemcitabine arm). The most frequently reported study drug-related (or of unknown relationship) AEs were palmar-plantar erythrodysesthesia, erythema, nausea, vomiting, and fatigue in the S/P arm and nausea, fatigue, and vomiting in the G/P arm. In the S/P arm, one dose-limiting toxicity occurred in two out of six patients treated at the maximum dose tested (DL2): palmar-plantar erythrodysesthesia and grade 2 aspartate aminotransferase/alanine aminotransferase increase that resulted in omission of days 8 and 15 plitidepsin infusions. In the G/P arm, one dose-limiting toxicity occurred in two out of six patients at DL4: grade 2 alanine aminotransferase increase resulted in omission of days 8 and 15 plitidepsin infusions and grade 4 thrombocytopenia. The recommended dose for the combination of plitidepsin with sorafenib was not defined because of a sponsor decision (no expansion cohort to confirm) and for plitidepsin with gemcitabine, it was 2.4 mg/m plitidepsin with 1000 mg/m gemcitabine. In the S/P group, objective disease responses were not observed; however, disease stabilization (≥3months) was observed in four patients. In the gemcitabine group, two lymphoma patients showed an objective response (partial response and complete response) and nine patients showed disease stabilization (≥3months). Combining plitidepsin with gemcitabine and sorafenib is feasible for advanced cancer patients; some objective responses were observed in heavily pretreated lymphoma patients.
authors.affiliation: aGustave Roussy Cancer Centre, Paris-Saclay University, Drug Development Department (DITEP), Villejuif bHospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Benite Cedex cHematology and Cellular Therapy Department, CIC INSERM 1415, University Hospital Centre, Tours, France dCancer Institute of New Jersey, New Brunswick, New Jersey, USA ePharmaMar, S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Aspeslagh
authors.forename: Mark
authors.initials: M
authors.lastname: Stein
authors.forename: Rastilav
authors.initials: R
authors.lastname: Bahleda
authors.forename: Antoine
authors.initials: A
authors.lastname: Hollebecque
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gyan
authors.forename: Salvador
authors.initials: S
authors.lastname: Fudio
authors.forename: Sonia
authors.initials: S
authors.lastname: Extremera
authors.forename: Vicente
authors.initials: V
authors.lastname: Alfaro
authors.forename: Arturo
authors.initials: A
authors.lastname: Soto-Matos
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D047630:Depsipeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D010456:Peptides, Cyclic; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D011446:Prospective Studies; D000077157:Sorafenib; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D047630:Depsipeptides; D010456:Peptides, Cyclic; D010671:Phenylurea Compounds; D003841:Deoxycytidine; D009536:Niacinamide; D000077157:Sorafenib; C098980:plitidepsin; D000093542:Gemcitabine