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Clinical Study

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

British Journal of Cancervolume 118pages15801585 (2018) | Download Citation

Subjects

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.

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Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License)

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Acknowledgements

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.

Author information

Affiliations

  1. Laura & Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA

    • Raoul Tibes
  2. Mayo Clinic, Scottsdale Campus, Scottsdale, AZ, USA

    • Mitesh J. Borad
  3. Eisai Inc., Woodcliff Lake, NJ, USA

    • Corina E. Dutcus
    • , Larisa Reyderman
    • , Kevie Feit
    •  & David A. Verbel
  4. Translational Medicine Consulting, Rockville, MD, USA

    • Andrew Eisen
  5. Translational Genomics Research Institute, Phoenix, AZ, USA

    • Daniel D. Von Hoff
  6. HonorHealth, Scottsdale, AZ, USA

    • Daniel D. Von Hoff

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Contributions

All authors were involved in the study design, data analysis and interpretation, writing and development of the manuscript, and approved the final draft.

Competing interests

RT: Institutional grant for clinical trial support. MJB: Clinical trial support received. CED: Employee of Eisai. LR: Employee of Eisai. KF: Employee of Eisai. AE: Former employee of Eisai. DAV: Employee of Eisai. DDVH: Institutional grant for clinical trials and consultant for Strategia Therapeutics.

Availability of data and material

The datasets generated during and/or analysed during the current study are on file with Eisai and not publicly available.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki. It was approved by an Institutional Review Board/Independent Ethics Committee at each study centre and in accordance with an assurance filed with and approved by the U.S. Department of Health and Human Services.

Informed consent

All patients provided signed informed consent prior to trial entry.

Funding

This study was funded by Eisai Inc.

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International licence (CC BY 4.0).

Corresponding author

Correspondence to Raoul Tibes.

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DOI

https://doi.org/10.1038/s41416-018-0099-5

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