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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 3/2019

Open Access 01-03-2019 | Original Article

A phase II trial of the effect of perindopril on hand–foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC

Authors: Barbara L. Melosky, Howard John Lim, Janine Marie Davies, Sharlene Gill, Christian K. Kollmannsberger, Maria Yi Ho, Solomon A. Vandt, Daniel John Renouf

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2019

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Abstract

Purpose

Regorafenib is an oral multi-kinase inhibitor that offers an OS benefit to patients with mCRC refractory to standard therapy (Grothey et al., in Lancet 381:303–312, 2013), but comes with potential significant toxicities including grade 3 hand–foot skin reaction (HFSR). The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. We hypothesized that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, indicated for the treatment of hypertension (Ceconi et al., in Cardiovasc Res 73:237–246, 2007), and which plays a role in preventing endothelial dysfunction, may help to prevent or reduce the severity of regorafenib-induced HFSR.

Patients and methods

In this single-center phase II open-label trial, patients with refractory mCRC were treated with both regorafenib (160 mg/day) and perindopril (4 mg/day) for 21 days per 28-day cycle. The primary end point was to assess the proportion of patients with any grade HFSR toxicity. Secondary end points included time to development of worst (grade 3) HFSR, reduction of all grades of hypertension and all grade toxicities, as well as progression-free survival. All toxicities were evaluated using CTCAE v4.03.

Results

A planned interim analysis was performed after ten evaluable patients had completed their first cycle of study treatment. As 50% (5/10) experienced grade 3 HFSR, enrolment was stopped as the addition of perindopril did not lead to a reduced level of HFSR compared with regorafenib alone. Other grade 3 toxicities included hypertension (16.7%) and increased AST (16.7%).

Conclusion

The addition of an ACE inhibitor perindopril to regorafenib did not reduce HFSR incidence or severity in patients with refractory mCRC.
Literature
1.
2.
Scheithauer W, Rosen H, Kornek GV et al (1993) Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 306:752–755CrossRefPubMedPubMedCentral
3.
Venook AP, Niedzwiecki D, Lenz HJ et al (2017) Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA 317:2392–2401CrossRefPubMedPubMedCentral
4.
Grothey A, Van Cutsem E, Sobrero A et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:303–312CrossRef
5.
Li J, Qin S, Xu R et al (2015) Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 16:619–629CrossRef
6.
7.
Erber R, Thurnher A, Katsen AD et al (2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18:338–340CrossRefPubMed
8.
Robert C, Soria JC, Spatz A et al (2005) Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 6:491–500CrossRefPubMed
9.
10.
Taddei S (2012) New evidence for endothelial protection. Medicographica 34:17–24
11.
Anderson TJ, Elstein E, Haber H et al (2000) Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol 35:60–66CrossRefPubMed
12.
Ceconi C, Fox KM, Remme WJ et al (2007) ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: Pertinent. Cardiovasc Res 73:237–246CrossRefPubMed
13.
Ceconi C, Francolini G, Olivares A et al (2007) Angiotensin-converting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic ACE. Eur J Pharmacol 577:1–6CrossRefPubMed
14.
Zhuo JL, Mendelsohn FA, Ohishi M (2002) Perindopril alters vascular angiotensin-converting enzyme, AT(1) receptor, and nitric oxide synthase expression in patients with coronary heart disease. Hypertension 39:634–638CrossRefPubMed
15.
Bekaii-Saab TS, Ou F-S, Anderson DM et al (2018) Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC): An ACCRU Network study. J Clin Oncol 36:611–611CrossRef
Metadata
Title
A phase II trial of the effect of perindopril on hand–foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC
Authors
Barbara L. Melosky
Howard John Lim
Janine Marie Davies
Sharlene Gill
Christian K. Kollmannsberger
Maria Yi Ho
Solomon A. Vandt
Daniel John Renouf
Publication date
01-03-2019
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 3/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-018-3738-x

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