Dataset Information

Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study.

ABSTRACT: 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.

SUBMITTER: Tibes R

PROVIDER: S-EPMC6008465 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study.

Tibes Raoul R Borad Mitesh J MJ Dutcus Corina E CE Reyderman Larisa L Feit Kevie K Eisen Andrew A Verbel David A DA Von Hoff Daniel D DD

British journal of cancer 20180605 12

<h4>Background</h4>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.<h4>Methods</h4>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/m<sup>2</sup>, increasing to 720 mg/m<sup>2</sup> or the ...[more]

PMID: 29867224

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Project description:Background and objectiveOveractivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib.MethodsPharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80-800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2 days on, 5 days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariates assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A) inducers, CYP3A inhibitors and acid-reducing agents.ResultsA total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance (CL/F) presented a moderate time-dependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial CL/F was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours, CL/F decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration-time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80-480 mg after multiple doses but more than proportional beyond 480 mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib CL/F, with a 12% reduction in CL/F at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference).ConclusionsCapivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors.

Dataset Information

Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study.

Publications

Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study.

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