Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation
Purpose: To evaluate the safety and tolerability of LiPlaCis, a liposomal formulated platinum compound, in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous (i.v.) LiPlaCis. and to assess plasma and urine pharmacokinetics and plasma biomarkers. Patients and methods: Patients with solid tumours without standard therapeutic options were enrolled to receive LiPlaCis administered as a 1 h infusion without additional hydration every 3 weeks until RECIST progression or unacceptable toxicity. Cohorts of 3-6 patients were treated at each dose level until MTD was reached. Results: Eighteen patients were enrolled and 64 cycles were delivered. At the first dose level 3 patients experienced an infusion reaction. Despite prophylactic pre-medication and prolongation of the infusion to 2 h in further patients, three other patients had mild acute infusion reactions. Toxicity at the fifth dose level of 120 mg consisted of grade 2 renal toxicity reversible after hydration in 2 patients and grade 4 thrombocytopaenia in one of these patients. Peak plasma concentrations and AUC were dose proportional. The interpatient variability in the clearance of total LiPlaCis-derived platinum was 41%. Platinum was excreted via the urine mainly during the first 24 h after administration. Investigated plasma biomarkers sPLA2 and SC5b-9 were related to, but not predictive for, acute infusion reactions. Conclusion: The observed safety profile suggests no benefit over standard cisplatin formulations and LiPlaCis will require reformulation to enable further development.
|Keywords||Cisplatin, LiPlaCis, Liposomal, Phase I, Solid tumour, anemia, area under the curve, article, biological marker, breast tumor, cisplatin, clemastine, clinical trial, dexamethasone, diarrhea, dose response, drug blood level, drug clearance, drug dose escalation, drug excretion, drug safety, drug tolerability, drug urine level, esophagus tumor, fatigue, female, human, hypopharynx cancer, infusion reaction, injection site reaction, leukopenia, liposomal cisplatin, major clinical study, male, maximum tolerated dose, melanoma, mucosa inflammation, multiple cycle treatment, nausea, nephrotoxicity, neutropenia, oropharynx cancer, parotid gland carcinoma, phase 1 clinical trial, priority journal, prostate tumor, secretory phospholipase A2, solid tumor, thrombocytopenia, unclassified drug, urinary tract tumor, vomiting|
|Persistent URL||dx.doi.org/10.1016/j.ejca.2010.07.015, hdl.handle.net/1765/21734|
|Journal||European Journal of Cancer|
de Jonge, M.J.A, Slingerland, M, Wiemer, E.A.C, Burger, H, Mathijssen, A.H.J, Kroep, J.R, & Hollander, M.A.G. (2010). Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation. European Journal of Cancer, 46(16), 3016–3021. doi:10.1016/j.ejca.2010.07.015