A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor

Abbas, Richat; Hug, Bruce A.; Leister, Cathie; Sonnichsen, Daryl

doi:10.1007/s00280-012-1857-3

Cited by 19 publications

(8 citation statements)

References 29 publications

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“…T84 monolayer cell lines lack other mucosal cell interactions, and of particular importance in this study, the impact that inflammation has on tight junctions. Clinical studies have also indicated that neratinib, a pan‐HER ErbB TKI has a fecal osmotic gap that is consistent with the values for secretory diarrhea . Previous work investigating lapatinib, an ErbB1 and ErbB2 TKI, suggested that diarrhea was associated with chloride secretion, indicated by decreased serum chloride levels, which the authors proposed may be due to loss of chloride via the intestinal lumen .…”

Section: Discussionsupporting

confidence: 53%

Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer

Sebille

Gibson

Wardill

et al. 2017

Intl Journal of Cancer

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Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea, which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an antisecretory agent may be an effective intervention. T84 monolayers were treated with 1 µM dacomitinib and 10 µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats (n = 48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib-induced diarrhea (p = 0.0003), and did not attenuate weight loss (p < 0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti-secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib-induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO-1 and occludin, and internalization of claudin-1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib-induced ileal damage. Crofelemer worsened dacomitinib-induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting.

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Section: Discussionsupporting

confidence: 53%

Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer

Sebille

Gibson

Wardill

et al. 2017

Intl Journal of Cancer

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“…Furthermore, data from at least one trial suggested that neratinib in combination with trastuzumab provided benefit to patients with HER2/neu positive breast cancer, who had previously failed therapy with single agent trastuzumab, TDM-1, lapatinib, and cytotoxic chemotherapy [28]. Trials have also revealed that neratinib is efficacious and well tolerated with the most common side effect being grade 1-2 diarrhea [32]. Fatigue, abdominal pain and anorexia have also been reported [21].…”

Section: Discussionmentioning

confidence: 95%

Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo

Schwab

English

Roque

et al. 2014

Gynecologic Oncology

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“…In addition, it was the cause of dose reduction in 19 of 22 patients and was the adverse event that most frequently led to treatment discontinuation (14%) 26. This dose-escalation study suggested a potential relationship between neratinib dose/exposure and diarrhea,78 but a follow-up study by Abbas et al revealed that there was no difference in the onset or severity of diarrhea in healthy subjects who were given neratinib either 240 mg once daily or 120 mg twice daily 84. However, several studies have reported that diarrhea could be controlled with concurrent use of antidiarrheal agents 79,81.…”

Section: Introductionmentioning

confidence: 92%

Profile of neratinib and its potential in the treatment of breast cancer

Feldinger

Kong²

2015

BCTT

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The HER (ErbB) receptor tyrosine kinase receptors are implicated in many cancers and several anti-HER treatments are now approved. In recent years, a new group of compounds that bind irreversibly to the adenosine triphosphate binding pocket of HER receptors have been developed. One of these compounds, neratinib, has passed preclinical phases and is currently undergoing various clinical trials. This manuscript reviews the preclinical as well as clinical data on neratinib. As a pan-HER inhibitor, this irreversible tyrosine kinase inhibitor binds and inhibits the tyrosine kinase activity of epidermal growth factor receptors, EGFR (or HER1), HER2 and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib has been shown to be effective against HER2-overexpressing or mutant tumors in vitro and in vivo. Neratinib is currently being investigated in various clinical trials in breast cancers and other solid tumors, including those with HER2 mutation. Earlier studies have already shown promising clinical activity for neratinib. However, more translational research is required to investigate biomarkers that could help to predict response and resistance for selection of appropriate patients for treatment with neratinib, either as monotherapy or in combination with other drug(s).

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A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor

Abstract: Incidences and onsets of at least grade 1 and at least grade 2 diarrhea were not improved on BID dosing compared with QD dosing.

Cited by 19 publications

References 29 publications

Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer

Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer

Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo

Profile of neratinib and its potential in the treatment of breast cancer

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