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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

1648 - Phase I pharmacological study of continuous chronomodulated capecitabine treatment

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Presenters

Jeroen Roosendaal

Citation

Annals of Oncology (2018) 29 (suppl_8): viii649-viii669. 10.1093/annonc/mdy303

Authors

J. Roosendaal1, B.A.W. Jacobs2, D. Pluim2, H. Rosing1, B. Nuijen1, J.H. Beijnen1, A.D.R. Huitema1, J.H.M. Schellens2, S. Marchetti2

Author affiliations

  • 1 Department Of Pharmacy & Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, 1066CX - Amsterdam/NL
  • 2 Division Of Clinical Pharmacology, Department Of Medical Oncology, The Netherlands Cancer Institute, Amsterdam/NL
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Resources

Abstract 1648

Background

Capecitabine is an oral prodrug of the anti-cancer drug 5-fluorouracil (5-FU). The 5-FU degrading enzyme, dihydropyrimidine dehydrogenase, and the target enzyme thymidylate synthase, are subject to circadian rhythmicity. The primary aims of this study were to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), recommended dose (RD) and safety of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy).

Methods

Patients aged ≥ 18 years, with WHO performance status of ≤ 2, and advanced solid tumors potentially benefitting from capecitabine therapy were enrolled. DPYD*2A or 2846A>T mutation carriers were excluded. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered twice daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 09:00h and 24:00h, respectively. The ratio of the morning to the evening dose was 3:5 (morning:evening). Toxicity was assessed according to the Common Terminology Criteria for Adverse Events version 4.03. DLT was evaluated during the first three weeks of treatment.

Results

A total of 21 patients was enrolled. The daily capecitabine dose was escalated from 1000 mg/m2 up to 2550 mg/m2 over five dose-levels. Three DLTs were observed in two patients at the highest dose-level (grade III hand-foot syndrome (2x) and grade III diarrhea (1x)). The MTD was established at 2000 mg/m2 per day (750 mg/m2 at 9:00 h and 1250 mg/m2 at 24:00 h). Continuous chronomodulated capecitabine therapy was generally well tolerated at the MTD level with main adverse events being grade 1-2 hand-foot syndrome and fatigue.

Conclusions

The cumulative dose of capecitabine at the MTD/RD (i.e., 750 mg/m2 at 9:00h and 1250 mg/m2 at 24:00h, continuous chronomodulated regimen) is 20% higher than the cumulative dose of the approved regimen (1250 mg/m2 bi-daily on day 1-14 of every 21-day cycle). Chronomodulation therefore represents a promising strategy as it could lead to improved tolerability and efficacy of capecitabine. Further investigation is warranted.

Clinical trial identification

EudraCT: 2014-000889-22.

Legal entity responsible for the study

The Netherlands Cancer Institute.

Funding

The Netherlands Cancer Institute.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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