TY - JOUR
T1 - Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma
T2 - Results of a phase 1 study
AU - Tibes, Raoul
AU - Borad, Mitesh J.
AU - Dutcus, Corina E.
AU - Reyderman, Larisa
AU - Feit, Kevie
AU - Eisen, Andrew
AU - Verbel, David A.
AU - Von Hoff, Daniel D.
N1 - Funding Information:
We acknowledge Dawn Bassett, MSN, Ed RN, OCN; Lynne Hull, RN, BSN, OCN; Fanny Sparrow, BBA, CCRP; and Cathy Mast, APRN-BC, AOCNP, for their clinical trial assistance. Medical writing assistance was provided by Jenny Szkolar at Virgo Health Education and supported by Eisai Inc. Editorial assistance was provided by Oxford PharmaGenesis and supported by Eisai, Inc.
Funding Information:
Funding: This study was funded by Eisai Inc.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Background: This phase 1 first-in-human study aimed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and safety of E6201, and to establish recommended dosing in patients with advanced solid tumours, expanded to advanced melanoma. Methods: Part A (dose escalation): sequential cohorts received E6201 intravenously (IV) over 30 min (once-weekly [qw; days (D)1 + 8 + 15 of a 28-day cycle]), starting at 20 mg/m2, increasing to 720 mg/m2 or the MTD. Part B (expansion): patients with BRAF-mutated or wild-type (WT) melanoma received E6201 320 mg/m2 IV over 60 minutes qw (D1 + 8 + 15 of a 28-day cycle) or 160 mg/m2 IV twice-weekly (D1 + 4 + 8 + 11 + 15 + 18 of a 28-day cycle; BRAF-mutated only). Results: MTD in Part A (n = 25) was 320 mg/m2 qw, confirmed in Part B (n = 30). Adverse events included QT prolongation (n = 4) and eye disorders (n = 3). E6201 exposure was dose-related, with PK characterised by extensive distribution and fast elimination. One patient achieved PR during Part A (BRAF-mutated papillary thyroid cancer; 480 mg/m2 qw) and three during Part B (2 BRAF-mutated melanoma; 1 BRAF-WT melanoma; all receiving 320 mg/m2 qw). Conclusions: An intermittent regimen of E6201 320 mg/m2 IV qw for the first 3 weeks of a 28-day cycle was feasible and reasonably well-tolerated in patients with advanced solid tumours, including melanoma with brain metastases, with evidence of clinical efficacy.
AB - Background: This phase 1 first-in-human study aimed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and safety of E6201, and to establish recommended dosing in patients with advanced solid tumours, expanded to advanced melanoma. Methods: Part A (dose escalation): sequential cohorts received E6201 intravenously (IV) over 30 min (once-weekly [qw; days (D)1 + 8 + 15 of a 28-day cycle]), starting at 20 mg/m2, increasing to 720 mg/m2 or the MTD. Part B (expansion): patients with BRAF-mutated or wild-type (WT) melanoma received E6201 320 mg/m2 IV over 60 minutes qw (D1 + 8 + 15 of a 28-day cycle) or 160 mg/m2 IV twice-weekly (D1 + 4 + 8 + 11 + 15 + 18 of a 28-day cycle; BRAF-mutated only). Results: MTD in Part A (n = 25) was 320 mg/m2 qw, confirmed in Part B (n = 30). Adverse events included QT prolongation (n = 4) and eye disorders (n = 3). E6201 exposure was dose-related, with PK characterised by extensive distribution and fast elimination. One patient achieved PR during Part A (BRAF-mutated papillary thyroid cancer; 480 mg/m2 qw) and three during Part B (2 BRAF-mutated melanoma; 1 BRAF-WT melanoma; all receiving 320 mg/m2 qw). Conclusions: An intermittent regimen of E6201 320 mg/m2 IV qw for the first 3 weeks of a 28-day cycle was feasible and reasonably well-tolerated in patients with advanced solid tumours, including melanoma with brain metastases, with evidence of clinical efficacy.
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U2 - 10.1038/s41416-018-0099-5
DO - 10.1038/s41416-018-0099-5
M3 - Article
C2 - 29867224
AN - SCOPUS:85047975272
SN - 0007-0920
VL - 118
SP - 1580
EP - 1585
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 12
ER -