Chronic diarrhea presents a significant challenge for managing nutritional and electrolyte deficiencies, especially in children, given the higher stakes of impacting growth and developmental consequence. Congenital secretory diarrhea (CSD) compounds this further, particularly in the case of the activating variants of the guanylate-cyclase 2C (GUCY2C) gene. GUCY2C encodes for the guanylate-cyclase 2C (GC-C) receptor that activates the downstream cystic fibrosis transmembrane receptor (CFTR) that primarily drives the severity of diarrhea with an unclear extent of influence on other intestinal channels. Thus far, management for CSD primarily consists of mitigating nutritional, electrolyte, and volume deficiencies with no known pathophysiology-driven treatments. For activating variants of GUCY2C, experimental compounds have shown efficacy in vitro for direct inhibition of GC-C but are not currently available for clinical use. However, Crofelemer, a CFTR inhibitory modulator with negligible systemic absorption, can theoretically help to treat this type of CSD. Herein, we describe and characterize the clinical course of a premature male infant with a de novo missense variant of GUCY2C not previously reported and highly consistent with CSD. With multi-disciplinary family-directed decision-making, a treatment for CSD was evaluated for the first time to our knowledge with Crofelemer.

AbstractManagement guidelines for cancer therapy-related diarrhea (CTD) should be revised because newer targeted therapies have increased CTD burden, with high incidence and/or severity of diarrhea for some agents that inhibit epidermal growth factor receptor and receptor tyrosine kinases. Neratinib, a pan-HER tyrosine kinase inhibitor, approved for breast cancer treatment, causes severe diarrhea in >95% of patients. Crofelemer, a novel intestinal chloride ion channel modulator, is an approved antidiarrheal for patients with HIV receiving antiretroviral therapy. The objective of this study was to evaluate the effectiveness of crofelemer prophylaxis in reducing the incidence and severity of neratinib-induced diarrhea without loperamide in dogs. Female dogs received neratinib orally daily concomitantly with either matching placebo tablets (CTR) or crofelemer 125 mg delayed-release tablet two or four times/day (BID or QID) for 28 consecutive days. At the end of treatment, 37.5%, 75%, and 87.5% of the CTR, BID, and QID dogs were ‘responders’ defined as ≤7 loose/watery stools/week for at least 2 of 4 weeks (p<0.05). The average number of watery stools per week was 9, 6, and 6 in the CTR, BID, and QID groups, respectively (p<0.05). The average number of weeks with no loose/watery stools was 1.3, 2.1, and 2.3 for the CTR, BID, and QID groups, respectively (p<0.05). The weekly mean fecal scores and stool consistency were 5.1, 3.9, and 4.1 for the CTR, BID, and QID groups (p<0.05). In this 28-day preclinical study, crofelemer prophylaxis without loperamide reduced the incidence and severity of neratinib-associated diarrhea in female dogs by 30%.Ethical ComplianceAll procedures performed in studies involving canine participants were in accordance with the ethical standards of the institutional and/or national research committee and applicable Institutional Animal Care and Use Committee (IACUC).

12111 Background: We studied the impact that cancer related diarrhea (CRD) has on cancer therapy and treatment patterns, including persistence, discontinuation, adherence, and switching of chemotherapy and targeted therapies in patients with and without CRD. Methods: We performed a longitudinal observational study among adult ( > 18 yrs) patients with CRD identified by diagnosis codes or pharmacy claims compared to matched (1:1) non-CRD patients using claims data derived from the IQVIA PharMetrics Plus database. Index date was defined as the date of the first cancer claim, and we re-indexed patients based on CRD claims. Each patient had a 6-month pre-index period and a minimum 3-month follow-up post-index period. To adjust for selection bias and baseline differences, we directly matched the CRD patients to non-CRD patients. Treatment patterns were evaluated and stratified for the first cancer therapy with or without CRD (chemotherapy vs targeted therapy vs both targeted and chemotherapy). Discontinuation was defined as a 30-day gap for chemotherapy and a 14-day gap for targeted therapies from index therapy; switching was a new chemotherapy or targeted therapy prescription within 30 days following discontinuation of index therapy. We computed adherence as the proportion of days covered over the 12-month post-index period and persistence as mean number of days on index therapy. A Cox proportional hazards model was used to estimate the difference in risk of discontinuation of index therapy between CRD and non-CRD cohorts. Results: We evaluated a total of 104,135 matched pairs of CRD and non-CRD adult patients with solid or hematologic cancer; each group further grouped by those receiving either chemotherapy (n = 47,220), targeted therapy (n = 2,427), or both treatments (n = 5,313). Patients with CRD discontinued the index therapy more frequently than non-CRD patients for chemotherapy (81.5% vs 62.3%), targeted therapy (69.2% vs 64.3%) or both (96.0% vs 85.5%) (p < 0.0001). Also, the overall percentage of discontinuation (82.4% vs. 64.6%) was significantly higher among patients with CRD. The mean time to discontinuation (59.6±54.1 vs. 68.3±76.6 days) was significantly lower (p < 0.0001) in patients with CRD. The mean time to switch (72.0±48.6 vs. 96.9±84.0 days), mean persistence (95.1±98.1 vs. 154.3±142.7 days), and mean adherence (25.5%±37.2 vs. 47.9±41%) were significantly lower (all p < 0.0001) among patients with CRD compared to non-CRD. The percentage of patients requiring a dose titration for their index cancer therapy was significantly higher (21.8%) for the CRD cohort versus 8.5% for non-CRD patients (p < 0.0001). Conclusions: Patients with CRD were 40% (adjusted) more likely to discontinue the index therapy than patients without CRD. The persistence of index cancer therapy and time to switch were also lower for patients with CRD. Strategies to control CRD and continue cancer therapy are urgently needed.

e18625 Background: In clinical oncology practice, diarrhea is a very common and severe side effect of cancer treatments including from radiotherapy, chemotherapy, and targeted therapies. Cancer-related diarrhea (CRD) leads to increased healthcare resource consumption due to unscheduled outpatient visits, and , increased hospital stays requiring intensive supportive care measures. We evaluated CRD patients receiving chemotherapy, targeted therapy, or both, requiring emergency department (ED), physician office visits, hospitalizations, and length of stay (LOS) compared to a matched cohort of non-CRD patients. Methods: We performed a longitudinal study among adult patients ( > 18 yrs) with CRD identified by diagnosis codes or pharmacy claims compared to matched non-CRD patients using claims data derived from the IQVIA PharMetrics Plus database. Index date was the first cancer claim date and patients were re-indexed based on their CRD claim. Each patient had a 6-month pre-index period, a minimum 3-month post-index period and had ≥12 months of continuous enrollment following the CRD index date. To adjust for selection bias and baseline differences, we matched CRD patients to non-CRD patients (1:1) by age, gender, geography and payer type. Patients were stratified by cancer therapy type (chemotherapy, targeted therapy or both treatments). We reported proportion of patients with hospitalizations, average length of stay (LOS), and ED visits. A generalized estimating equation model with log link and binomial distribution adjusted for type of cancer, therapy, and Charlson Comorbidity Index (CCI) was built to estimate the difference in occurrence of hospitalization between CRD and non-CRD cohorts. Results: We evaluated a total of 104,135 matched pairs of CRD and non-CRD adult patients with solid or hematologic cancer with 12-month continuous enrollment. The proportion of patients with ED visits (36.2% vs 18.9%, p < 0.0001) and hospitalizations (29.6% vs 12.8%, p < 0.0001) were significantly higher among CRD versus non-CRD cohort. When compared to non-CRD patients, CRD patients were more likely to be hospitalized (adjusted OR 2.28. 95% CI of 2.23-2.33). Mean CRD-specific office/hospital visits were significantly higher in the CRD cohort compared to the non-CRD cohort over the 12-month post-index period and patients had more CRD-specific visits to ED (7.5% vs 1.8%); physician’s offices (14.7% vs 3.8%); laboratory testing (11.6% vs 3.2%) and outpatient ancillary services (10.9% vs 2.6%) (all p < 0.0001). Mean hospital LOS among patients with CRD was higher than non-CRD patients (6.6±8.9 vs 5.8±10.5 days, p < 0.0001). Conclusions: Patients with CRD used significantly more resources, including outpatient services, ED visits, and hospitalizations. Effective prevention of CRD remains an unmet strategy to reduce the overall cost of cancer care.

e18623 Background: Diarrhea is a common toxicity of cancer treatments, including radiotherapy, chemotherapy, and/or targeted therapies. Cancer-related diarrhea (CRD) leads to increased healthcare utilization and cost. This study evaluated the all-cause and CRD-specific healthcare utilization and cost of patients with CRD compared to a matched non-CRD cohort. Methods: We conducted a longitudinal observational study among adult patients ( > 18 years) with CRD using diagnosis codes or pharmacy claims compared to matched non-CRD patients using claims data from the IQVIA PharMetrics Plus database (October 2015 to March 2020). The index date was the date of the first cancer claim, and we re-indexed patients based on their CRD claim. Each patient had a 6-month pre-index period and a minimum 3-month post-index period. Patients were also required to have ≥12 months of continuous enrollment following the CRD index date. We directly matched patients 1:1 from the CRD cohort to the non-CRD cohort to adjust for selection bias and baseline differences. Our aim was to compare all-cause healthcare costs over a fixed 12-month post-index period, converting all costs to 2020 USD using the Consumer Price Index's medical component. We analyzed healthcare utilization for CRD-treated, CRD-inadequately treated, and CRD-untreated sub-cohorts (per Buono et al., J Econ 2017). Secondary endpoints included healthcare cost (proportion of patients, per-patient mean and median) and healthcare utilization (prescription fills and visits to the emergency department [ED], physician office, lab/pathology and outpatient ancillary services). We built one generalized estimating equation model with log link and gamma distribution adjusted for type of cancer, therapy and Charlson Comorbidity Index (CCI) to estimate the difference in total healthcare cost between CRD and non-CRD cohorts. Results: We evaluated a total of 104,135 matched pairs of CRD and non-CRD adult patients with solid or hematologic cancer receiving either targeted or chemotherapy, with 12-month continuous enrollment. Patients with CRD incurred significantly higher mean ($104,880 vs $39,664, p < 0.0001) and median ($59,969 vs $8,914, p < 0.0001) all-cause healthcare cost compared to patients without CRD over the 12-month post-index period. Inadequately treated CRD patients had the mean highest cost ($129,531) vs adequately CRD-treated ($107,050) or untreated CRD patients ($56,350) (all p < 0.0001). Mean pharmacy cost for CRD and non-CRD patients were ($35,190 vs $15,883); visits to the ED ($1,107 vs $431), physician office ($3,457 vs $2,058), lab/pathology ($4,074 vs $1,404), and outpatient ancillary services ($15,805 vs $4,940) (all p-values < 0.0001). Conclusions: Our findings show that patients with CRD had nearly 2.9 times higher all-cause total cost than patients without CRD after adjusting for covariates. Prevention of CRD may result in a significant reduction in cancer-treatment cost.

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.

The utility of testing for urinary tract infection (UTI) in febrile infants with bronchiolitis is indeterminate. The objective of this study was to investigate if the incidence of UTIs in febrile infants 2 to 12 months of age with bronchiolitis is higher than the presumed incidence of asymptomatic bacteriuria and determine risk factors associated with UTIs in this population. This prospective multicenter cross-sectional study was conducted in the emergency departments of 6 children's hospitals between November 2011 and June 2015. We obtained a convenience sample of febrile infants with bronchiolitis 2 to 12 months of age who were tested for UTI. Patient characteristics analyzed included age, maximum temperature, duration of fever, ethnicity, sex, and circumcision status. A total of 442 patients (including 86 from a previously published pilot study) were enrolled. Mean age was 5.5 months, 65.2% were Latino, 50.9% were male, and 27.6% of male infants were circumcised. Urinary tract infections were found in 33 patients (7.69%, binomial; 95% confidence interval [CI], 5.19%-10.33%). Urinary tract infections were not related to age, height of temperature, duration of fever, or ethnicity. Uncircumcised males were significantly more likely to have UTIs than circumcised males (7.64% vs 0%, P = 0.03). Odds ratios (ORs) were lower for circumcised males but not uncircumcised males when compared with females (OR, 0.12; CI, 0.0-0.71; P = 0.01 vs OR, 0.77; CI, 0.33-1.74; P = 0.64). Febrile infants 2 to 12 months of age with bronchiolitis have a clinically significant incidence of UTI, suggesting that UTI evaluation should be considered in these patients.