Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation

de Jonge, Maja J.A.; Slingerland, Marije; Loos, Walter J.; Wiemer, Erik A.C.; Burger, Herman; Mathijssen, Ron H.J.; Kroep, Judith R.; den Hollander, Margret A.G.; van der Biessen, Diane; Lam, Mei-Ho; Verweij, Jaap; Gelderblom, Hans

doi:10.1016/j.ejca.2010.07.015

« Previous Next »European Journal of Cancer
Volume 46, Issue 16 , Pages 3016-3021, November 2010

Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation☆

Maja J.A. de Jonge
- Erasmus University Medical Center Daniel Den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands
- Authors contributed equally.
- Corresponding author: Tel.: +31 10 439 1760; fax: +31 10 439 1003.
Marije Slingerland
- Leiden University Medical Center, Department of Clinical Oncology, Leiden, The Netherlands
- Authors contributed equally.
Walter J. Loos
- Erasmus University Medical Center Daniel Den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands
Erik A.C. Wiemer
- Erasmus University Medical Center Daniel Den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands
Herman Burger
- Erasmus University Medical Center Daniel Den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands
Ron H.J. Mathijssen
- Erasmus University Medical Center Daniel Den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands
Judith R. Kroep
- Leiden University Medical Center, Department of Clinical Oncology, Leiden, The Netherlands
Margret A.G. den Hollander
- Leiden University Medical Center, Department of Clinical Oncology, Leiden, The Netherlands
Diane van der Biessen
- Erasmus University Medical Center Daniel Den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands
Mei-Ho Lam
- Erasmus University Medical Center Daniel Den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands
Jaap Verweij
- Erasmus University Medical Center Daniel Den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands
Hans Gelderblom
- Leiden University Medical Center, Department of Clinical Oncology, Leiden, The Netherlands

Received 31 May 2010; accepted 14 July 2010. published online 30 August 2010.

Abstract

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 1h infusion without additional hydration every 3weeks 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 2h in further patients, three other patients had mild acute infusion reactions. Toxicity at the fifth dose level of 120mg 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 24h 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: LiPlaCis, Liposomal, Cisplatin, Phase I, Solid tumour