Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors
Background:Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours.Methods:Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7–1.4 mg m−2 and CP 60–75 mg m−2. Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m−2, CP 60 mg m−2) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days.Results:On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m−2, 60 mg m−2); G 3 anorexia/fatigue/hypokalemia (1.2 mg m−2, 60 mg m−2); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m−2, 60 mg m−2). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m−2, 60 mg m−2); G 4 mucositis (1.4 mg m−2, 60 mg m−2); and G 3 hypokalemia (1.2 mg m−2, 75 mg m−2). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m−2 (days 1, 8) and CP 75 mg m−2 (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers).Conclusions:On the 21-day cycle, eribulin mesylate 1.2 mg m−2, administered on days 1 and 8, in combination with CP 75 mg m−2, administered on day 1 is well tolerated and showed preliminary anticancer activity.