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.