Abstract 580: Effects of oral crofelemer on neratinib-induced diarrhea in beagle dogs

Abstract

Crofelemer is a novel allosteric modulator of cystic fibrosis transmembrane conductance regulator (CFTR) that is approved as an antidiarrheal in HIV patients receiving antiretroviral therapy. Neratinib is an oral, irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment of early stage HER2+ breast cancer. The objective of this study was to evaluate the effects of crofelemer in reducing the incidence and severity of diarrhea following daily oral neratinib dosing for 28 days in healthy female dogs, without concomitant use of loperamide. Female beagle dogs (mean 7.2 kg (6.4-8.5)) were randomized into three groups of 8 dogs each and all groups received neratinib oral doses (40 mg for the first 5 days, then 80 mg) for 28 days. Group 1 dogs received one placebo capsule orally four times daily, control (CTR) group; group 2 dogs received one crofelemer 125 mg tablet four times a day (QID group); and group 3 dogs received one crofelemer 125 mg tablet twice daily (BID group). Dogs were evaluated twice daily for bowel movements, which were scored according to a 7-point scale analogous to the human Bristol Stool Form Scale. Dogs with moderate dehydration were given subcutaneous fluids and/or a single-day neratinib dose reduction or holiday. Weekly assessments of clinical chemistry and hematology parameters were conducted. Pharmacological effects were assessed by: 1) determining the proportion of “responder” dogs, defined as dogs with <7 watery stools per week for at least 2 weeks of the 4 week period; 2) reduction in the number of watery stools over the 28-day period; and 3) assessment of change in stool consistency. Summary statistics were computed at each week and pair-wise p-values were computed via t-test to determine differences from control group. Analysis of covariance (ANCOVA) was conducted using baseline fecal scores as a covariate. Following 28 days of oral dosing of neratinib receiving concomitant crofelemer tablets or placebo capsules, 3 of 8 placebo (CTR) dogs were “responders”; 6/8 crofelemer BID group dogs (p=0.03) and 7/8 QID group dogs (p=0.02) were “responders”. The average number of watery stools per week, a measure of the incidence of diarrhea, across the 4-week treatment period were 9, 6, and 6 for the control, BID, and QID groups (p=0.01) respectively. The average number of weeks with no loose/watery stools were determined to be 1.3, 2.1, and 2.3 for the control, BID, and QID groups respectively, with 1-sided p-values of 0.043 and 0.0295, respectively. Least squares weekly mean fecal scores, a measure of diarrhea severity reflecting stool consistency, averaged across the 4-week period were 5.1, 3.9, and 4.1 for control, BID, and QID groups (p=0.005 and p=0.017, respectively). In this experimental preclinical model, concomitant treatment of crofelemer without any use of loperamide reduces the incidence and severity of neratinib-associated diarrhea in female dogs by about 30% over a 28-day treatment period. Citation Format: Michael K. Guy, Andre Teixeira, Alshad S. Lalani, Irmina Diala, Leanne McCulloch, James Bolognese, Pravin Chaturvedi. Effects of oral crofelemer on neratinib-induced diarrhea in beagle dogs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 580.

Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs

“…These findings indicate that daily administration of neratinib induced a severe clinical presentation of diarrhea, intestinal hemorrhage, and dehydration; however, these clinical symptoms did not produce mucosal changes. Preliminary results from this neratinib-crofelemer study have been previously reported (10).…”

“…Neratinib is an oral irreversible HER1, HER2, and HER4 tyrosine kinase inhibitor that requires loperamide prophylaxis due to the high incidence of severe diarrhea associated with the drug ( 10 ). However, prophylaxis and management guidelines using antimotility drugs, such as loperamide, an opiate agonist, are empirical interventions to reduce the severity of diarrhea.…”

Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs

“…These findings indicate that daily administration of neratinib induced a severe clinical presentation of diarrhea, intestinal hemorrhage, and dehydration; however, these clinical symptoms did not produce mucosal changes. Preliminary results from this neratinib-crofelemer study have been previously reported [22]. A responder dog (as defined a priori) was any dog with an average of � 7 loose/watery stools per week, which equals � 1 loose/watery stool per day, for at least 2 weeks of the 4-week study period (1A.).…”