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 language | English (US) |
|---|---|
| Pages (from-to) | 2268-2274 |
| Number of pages | 7 |
| Journal | British Journal of Cancer |
| Volume | 111 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 9 2014 |
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Keywords
- advanced solid tumours
- cisplatin
- eribulin mesylate (E7389)
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
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 journal › Article
}
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)
UR - http://www.scopus.com/inward/record.url?scp=84927580970&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84927580970&partnerID=8YFLogxK
U2 - 10.1038/bjc.2014.554
DO - 10.1038/bjc.2014.554
M3 - Article
C2 - 25349975
AN - SCOPUS:84927580970
VL - 111
SP - 2268
EP - 2274
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 12
ER -