|Spisulosine (ES-285) given as a weekly three-hour intravenous infusion: results of a phase I dose-escalating study in patients with advanced solid malignancies|Schoffski, P.; Dumez, H.; Ruijter, R.; Miguel-Lillo, B.; Soto-Matos, A.; Alfaro, V.; Giaccone, G. (2011). Spisulosine (ES-285) given as a weekly three-hour intravenous infusion: results of a phase I dose-escalating study in patients with advanced solid malignancies. Cancer Chemother. Pharmacol. 68(6): 1397-1403. dx.doi.org/10.1007/s00280-011-1612-1
In: Cancer Chemotherapy and Pharmacology. Springer: Berlin. ISSN 0344-5704, more
ES-285; Spisulosine; Phase I; Marine compounds; Pharmacokinetics;Hepatotoxicity; Neurotoxicity
|Authors|| || Top |
- Schoffski, P.
- Dumez, H.
- Ruijter, R.
- Miguel-Lillo, B.
- Soto-Matos, A.
- Alfaro, V.
- Giaccone, G.
Spisulosine is a marine compound that showed antitumor activity in preclinical studies. We report results of a phase I trial performed in patients with advanced solid tumors with the marine compound, with the aim to determine the maximum tolerated dose (MTD) of a weekly 3-h intravenous (iv.) infusion, and to evaluate the safety, efficacy, and pharmacokinetics (PK) of the compound. Two centers contributed 25 patients to the trial, and 7 dose levels were explored. In dose levels ranging from 4 to 128 mg/mA(2)/day, no dose-limiting toxicities (DLT) were observed. One patient had DLT at 200 mg/mA(2), a reversible grade 3 ALT increase. The MTD was not reached due to early termination of the Spisulosine trial program but is considered to be likely in the range of 200 mg/mA(2) for this schedule. Drug-related adverse reactions included mild to moderate nausea, pyrexia, injection site reactions, and vomiting. One case of grade 4 peripheral motor and sensory neuropathy associated with general weakness and pain was observed during treatment cycle 4 and possibly contributed to the death of the patient. Grade 3 laboratory abnormalities included anemia and lymphopenia and increases in liver enzymes (alkaline phosphatase, transaminases, and bilirubin). Objective responses were not observed, and only four patients had short-lasting stable disease (< 3 months). The PK data indicated a wide distribution, a long residence time, and dose proportionality of the agent. Hepato- and neuro-toxicity are schedule independent dose-limiting adverse events for this marine compound, as illustrated by this and other early clinical trials.