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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

2350 - Influence of the proton pump inhibitor esomeprazole on the bioavailability of regorafenib

Date

21 Oct 2018

Session

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

Presenters

Femke de Man

Citation

Annals of Oncology (2018) 29 (suppl_8): viii150-viii204. 10.1093/annonc/mdy281

Authors

F.M. de Man1, K.G.A.M. Hussaarts1, M. de With1, E. Oomen-De Hoop1, H.K. van Halteren2, N.C.H.P. van der Burg-De Graauw3, F.A.L.M. Eskens1, T. van Gelder4, R.W.F. van Leeuwen4, R.H.J. Mathijssen1

Author affiliations

  • 1 Medical Oncology, Erasmus MC Cancer Institute, 3015 CE - Rotterdam/NL
  • 2 Internal Medicine, Admiraal de Ruijter Hospital, 4380 DD - Vlissingen/NL
  • 3 Internal Medicine, Bravis Hospital, 4700 AZ - Roosendaal/NL
  • 4 Hospital Pharmacy, Erasmus University Medical Center, 3015CE - Rotterdam/NL
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Resources

Abstract 2350

Background

The multikinase inhibitor regorafenib (REG) is currently registered for the treatment of colorectal cancer (CRC), gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma. REG exhibits a pH-dependent solubility, and therefore acid reducing drugs such as proton pump inhibitors (PPIs, e.g. esomeprazole) might reduce REG absorption by increasing the stomach pH as was shown for many other kinase inhibitors (van Leeuwen, Lancet Oncol, 2014). We performed a randomized, 3-phase, cross-over trial to compare the exposure of REG alone to REG with esomeprazole (concomitantly or 3 hours prior to REG intake) in CRC and GIST patients.

Methods

Patients were randomized into 2 sequence groups consisting of 3 phases: REG intake alone, REG with concomitant esomeprazole (for 5 days), and REG 3 hours preceded by esomeprazole (for 5 days). Pharmacokinetic (PK) blood sampling was performed at the 21th, 49th and 77th day of the trial. All patients were treated with REG 120 mg at steady-state. Primary endpoint was the relative difference (RD) in geometric means for REG AUC0-24h. A linear mixed model was used to analyze log-transformed area under the curve (AUC). For multiple testing a Bonferroni correction was applied.

Results

A total of 14 patients were evaluable for the primary endpoint. Exposure (AUC0-24h) to REG alone was: 55.9 µg*h/mL (CV: 40.3%). For REG with concomitant esomeprazole or with esomeprazole 3 hours prior AUC0-24h was: 53.7 µg*h/mL (CV: 33.5%) and 53.6 µg*h/mL (CV: 42.6%) respectively. No significant differences were identified when REG alone was compared to REG with concomitant esomeprazole (RD: -3.9%, 95% CI: -20.5-16.1%, p = 1.0) or REG with esomeprazole 3 hours prior (RD: -4.1%, 95% CI: -22.8-19.2%, p = 1.0). Furthermore, no significant differences were observed in other PK parameters of REG and its active metabolites M-2 and M-5 (i.e. Cmax, Tmax). Most common adverse events ≥ grade 2 were hypertension (71%), fatigue (43%) and hand foot skin reaction (36%).

Conclusions

The use of esomeprazole concomitantly or 3 hours prior to REG intake did not alter REG pharmacokinetics. Our results indicate that PPIs like esomeprazole can be combined with REG without the appearance of a significant drug interaction.

Clinical trial identification

NCT02800330, 01-05-2016.

Legal entity responsible for the study

Erasmus University Medical Center.

Funding

Bayer.

Editorial Acknowledgement

Disclosure

R.H.J. Mathijssen: Research support: Astellas, Bayer, Boehringer Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche Sanofi; Consultation fees: Novartis, Servier, Travel support: Astellas, Pfizer. All other authors have declared no conflicts of interest.

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