A phase I, open-label, single-arm study for QT assessment of eribulin mesylate in patients with advanced solid tumors

Lesimple, Thierry; Edeline, Julien; Carrothers, Timothy J.; Cvitkovic, F.; Darpö, Börje; Delord, Jean‐Pierre; Léna, H.; Penel, Nicolas; Edwards, G.; Law, K.; Wanders, J.; Kristensen, Allan; Reyderman, Larisa

doi:10.1007/s10637-012-9893-8

Cited by 20 publications

(18 citation statements)

References 26 publications

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“…As a conservative approach, focused attention was given to cardiac electrophysiology during this study due to a minor increase in the QTc noted in adult subjects receiving eribulin . In 22 subjects who received at least one dose of eribulin and who had at least one set of pre‐ and post‐dose EKGs, the baseline mean QTc was 419 msec (standard deviation 20 msec).…”

Section: Resultsmentioning

confidence: 99%

A phase 1 study of eribulin mesylate (E7389), a novel microtubule‐targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314)

Schafer

Rau

Berg

et al. 2018

Pediatric Blood & Cancer

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Section: Resultsmentioning

confidence: 99%

A phase 1 study of eribulin mesylate (E7389), a novel microtubule‐targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314)

Schafer

Rau

Berg

et al. 2018

Pediatric Blood & Cancer

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“…To characterize the PK of eribulin, data from seven phase 1 studies, one phase 2, and one phase 3 study, were combined. Eribulin PK was described well by a three‐compartment model with linear elimination from the central compartment.…”

Section: Discussionmentioning

confidence: 99%

“…An analysis of the pharmacokinetic (PK) profile of eribulin was conducted using combined data from seven phase 1 studies in patients with different tumor types, [10][11][12][13][14][15][16] and a phase 2 17 and phase 3 18 study, both in women with locally advanced or MBC ( Supplemental Table S1). In this combined dataset, the majority of patients had been previously treated with anthracyclines and taxanes.…”

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confidence: 99%

Population pharmacometric analyses of eribulin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes

Majid

Gupta

Reyderman

et al. 2014

The Journal of Clinical Pharmacology

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Pharmacometric investigation of eribulin was undertaken in patients with metastatic breast cancer (MBC) and other advanced solid tumors. A population pharmacokinetic (PK) model used data combined from seven phase 1 studies (advanced solid tumors; n = 129), and one phase 2 (MBC; n = 211), and one phase 3 study (MBC; n = 173). Phase 3 data were also used in a PK/pharmacodynamic (PD) model of efficacy and tumor response (sum of longest diameters of target lesions). All analyses used NONMEM 7.2. Eribulin PK, described by a dose-independent, three-compartment model with allometric relationship for body weight, was similar for all tumor types. Inter-individual variability (IIV) was 52% for both exposure and clearance. Liver function markers (albumin, alkaline phosphatase, bilirubin) significantly influenced eribulin PK (7.3% of IIV in clearance). Tumor shrinkage correlated with eribulin exposure; a 36% decrease in tumor size from baseline was modeled at week 36. No patient/disease factors significantly predicted eribulin's effect on tumor size. At week 6, a decrease in tumor size was associated with longer survival than an increase (P = .0055), suggesting survival may relate indirectly to eribulin exposure. These pharmacometric analyses provide a detailed overview of eribulin exposure-efficacy relationships to inform physicians treating patients with MBC.

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“…In this often immune-compromised and severely ill patient population, it is difficult to justify the use of placebo and an antibiotic (the positive control, moxifloxacin), and many ECG studies with oncology agents in cancer patients are therefore uncontrolled (Lesimple et al 2013) and frequently powered to exclude a somewhat larger effect (around 20 ms) than TQT studies in healthy subjects (Bello et al 2007;Graham et al 2013;Rock et al 2009;Sarapa and Britto 2008). Apart from these limitations, other elements from the TQT study design, such as strictly controlled experimental conditions, serial ECGs at baseline, and post-dosing, are implemented to the extent feasible into ECG studies in oncology patients (Rock et al 2009).…”

Section: Ecg Assessment With Oncology Drugsmentioning

confidence: 99%

Clinical ECG Assessment

Darpö

2015

Principles of Safety Pharmacology

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With the adoption of the ICH E14 guidance, the thorough QT/QTc (TQT) study has become the focus of clinical assessment of an NCE's effects on ECG parameters. The TQT study is used as a guide to the liability of a drug to cause proarrhythmias on the basis of delayed cardiac repolarization. Around 300 TQT studies have been performed since 2005 and through interactions between sponsors and regulators, especially FDA's Interdisciplinary Review Team (IRT) for QT studies. These studies can today be performed more effectively and with great confidence in the generated data. This chapter will discuss technical features and the design and analysis of TQT studies, how assay sensitivity is demonstrated, and examples from recently conducted studies. ECG assessment for drugs that cannot be safely given to healthy volunteers is also addressed, and examples from studies in cancer patients and in healthy volunteers with tyrosine kinase inhibitors are discussed. The TQT study is resource intensive and designed to solely evaluate whether an NCE prolongs the QTc interval. If data with similar confidence can be generated from other studies that are routinely performed as part of the clinical development, this would represent a more optimal use of human resources. Methods and approaches to increase the confidence in ECG data derived from "early QT assessment" in single-ascending/multiple-ascending dose studies are therefore discussed, and a path toward replacing the TQT study using these approaches will be outlined.

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A phase I, open-label, single-arm study for QT assessment of eribulin mesylate in patients with advanced solid tumors

Abstract: Eribulin demonstrated an acceptable safety profile and a minor prolongation of QTc not expected to be of clinical concern in oncology patients.

Cited by 20 publications

References 26 publications

A phase 1 study of eribulin mesylate (E7389), a novel microtubule‐targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314)

A phase 1 study of eribulin mesylate (E7389), a novel microtubule‐targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314)

Population pharmacometric analyses of eribulin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes

Clinical ECG Assessment

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