Phase i study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors

M. Koczywas, P. H. Frankel, T. W. Synold, H. J. Lenz, J. E. Mortimer, A. B. El-Khoueiry, David R Gandara, M. C. Cristea, V. M. Chung, D. Lim, K. L. Reckamp, Derick H Lau, L. A. Doyle, C. Ruel, M. I. Carroll, E. M. Newman

Research output: Contribution to journalArticle

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Abstract

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<sup>-2</sup> and CP 60-75 mg m<sup>-2</sup>. 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<sup>-2</sup>, CP 60 mg m<sup>-2</sup>) 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<sup>-2</sup>, 60 mg m<sup>-2</sup>); G 3 anorexia/fatigue/hypokalemia (1.2 mg m<sup>-2</sup>, 60 mg m<sup>-2</sup>); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m<sup>-2</sup>, 60 mg m<sup>-2</sup>). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m<sup>-2</sup>, 60 mg m<sup>-2</sup>); G 4 mucositis (1.4 mg m<sup>-2</sup>, 60 mg m<sup>-2</sup>); and G 3 hypokalemia (1.2 mg m<sup>-2</sup>, 75 mg m<sup>-2</sup>). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m<sup>-2</sup> (days 1, 8) and CP 75 mg m<sup>-2</sup> (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<sup>-2</sup>, administered on days 1 and 8, in combination with CP 75 mg m<sup>-2</sup>, administered on day 1 is well tolerated and showed preliminary anticancer activity.

Original languageEnglish (US)
Pages (from-to)2268-2274
Number of pages7
JournalBritish Journal of Cancer
Volume111
Issue number12
DOIs
StatePublished - Dec 9 2014

Fingerprint

eribulin
Cisplatin
Hypokalemia
Neoplasms
Appointments and Schedules
Maximum Tolerated Dose
Fatigue
Febrile Neutropenia
Stomatitis
Mucositis
halichondrin B
Hyponatremia
Anorexia
Esophageal Neoplasms
Neutropenia
Ketones
Pancreatic Neoplasms
Urinary Bladder Neoplasms

Keywords

  • advanced solid tumours
  • cisplatin
  • eribulin mesylate (E7389)

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Koczywas, M., Frankel, P. H., Synold, T. W., Lenz, H. J., Mortimer, J. E., El-Khoueiry, A. B., ... Newman, E. M. (2014). Phase i study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors. British Journal of Cancer, 111(12), 2268-2274. https://doi.org/10.1038/bjc.2014.554

Phase i study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors. / Koczywas, M.; Frankel, P. H.; Synold, T. W.; Lenz, H. J.; Mortimer, J. E.; El-Khoueiry, A. B.; Gandara, David R; Cristea, M. C.; Chung, V. M.; Lim, D.; Reckamp, K. L.; Lau, Derick H; Doyle, L. A.; Ruel, C.; Carroll, M. I.; Newman, E. M.

In: British Journal of Cancer, Vol. 111, No. 12, 09.12.2014, p. 2268-2274.

Research output: Contribution to journalArticle

Koczywas, M, Frankel, PH, Synold, TW, Lenz, HJ, Mortimer, JE, El-Khoueiry, AB, Gandara, DR, Cristea, MC, Chung, VM, Lim, D, Reckamp, KL, Lau, DH, Doyle, LA, Ruel, C, Carroll, MI & Newman, EM 2014, 'Phase i study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors', British Journal of Cancer, vol. 111, no. 12, pp. 2268-2274. https://doi.org/10.1038/bjc.2014.554
Koczywas, M. ; Frankel, P. H. ; Synold, T. W. ; Lenz, H. J. ; Mortimer, J. E. ; El-Khoueiry, A. B. ; Gandara, David R ; Cristea, M. C. ; Chung, V. M. ; Lim, D. ; Reckamp, K. L. ; Lau, Derick H ; Doyle, L. A. ; Ruel, C. ; Carroll, M. I. ; Newman, E. M. / Phase i study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors. In: British Journal of Cancer. 2014 ; Vol. 111, No. 12. pp. 2268-2274.
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abstract = "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.",
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TY - JOUR

T1 - Phase i study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors

AU - Koczywas, M.

AU - Frankel, P. H.

AU - Synold, T. W.

AU - Lenz, H. J.

AU - Mortimer, J. E.

AU - El-Khoueiry, A. B.

AU - Gandara, David R

AU - Cristea, M. C.

AU - Chung, V. M.

AU - Lim, D.

AU - Reckamp, K. L.

AU - Lau, Derick H

AU - Doyle, L. A.

AU - Ruel, C.

AU - Carroll, M. I.

AU - Newman, E. M.

PY - 2014/12/9

Y1 - 2014/12/9

N2 - 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.

AB - 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.

KW - advanced solid tumours

KW - cisplatin

KW - eribulin mesylate (E7389)

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