Phase I dose-escalation study of plitidepsin in combination with sorafenib or gemcitabine in patients with refractory solid tumors or lymphomas
| Autor: | Antoine Hollebecque, Sonia Extremera, Gilles Salles, Vicente Alfaro, Sandrine Aspeslagh, Mark N. Stein, Emmanuel Gyan, Salvador Fudio, Rastilav Bahleda, Arturo Soto-Matos, Jean-Charles Soria |
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| Přispěvatelé: | Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medical Oncology |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Male Cancer Research Lymphoma Administration Oral Deoxycytidine Gastroenterology Depsipeptides/administration & dosage 0302 clinical medicine Depsipeptides Neoplasms Antineoplastic Combined Chemotherapy Protocols Medicine Pharmacology (medical) Prospective Studies Fatigue Nausea Antineoplastic Combined Chemotherapy Protocols/administration & dosage Middle Aged 3. Good health 030220 oncology & carcinogenesis Toxicity Vomiting young adult Female France medicine.symptom medicine.drug Niacinamide Sorafenib Adult medicine.medical_specialty Patients [SDV.CAN]Life Sciences [q-bio]/Cancer Peptides Cyclic 03 medical and health sciences Niacinamide/administration & dosage Refractory Internal medicine Humans Adverse effect Deoxycytidine/administration & dosage Aged Lymphoma/drug therapy Pharmacology therapy Dose-Response Relationship Drug business.industry Phenylurea Compounds toxicity medicine.disease Gemcitabine Thrombocytopenia Neoplasms/drug therapy SORAFENIB 030104 developmental biology Phenylurea Compounds/administration & dosage Erythema business aged 80 and over |
| Zdroj: | Anti-Cancer Drugs Anti-Cancer Drugs, Lippincott, Williams & Wilkins, 2016, ⟨10.1097/CAD.0000000000000457⟩ |
| ISSN: | 0959-4973 1473-5741 |
| DOI: | 10.1097/CAD.0000000000000457⟩ |
| Popis: | International audience; 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 (\textgreater/=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 (\textgreater/=3months). Combining plitidepsin with gemcitabine and sorafenib is feasible for advanced cancer patients; some objective responses were observed in heavily pretreated lymphoma patients |
| Databáze: | OpenAIRE |
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