Abstract CT128: Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients (pts) with HER2+ early-stage breast cancer (eBC): the CONTROL trial
Authors: Ibrahim Emad , Tripathy Debu , Wilkinson Mary , Hurvitz Sara , Iannotti Nicholas , Kellum Andrew , Manalo Yvonne , Wong Serena , Hansen Vincent , Alvarez Ricardo , Chan Arlene , Gore Ira , Kendall DiSean , Wade James , Olek Elizabeth , Hunt Daniel , Fang Pearl , Ebtahaj Azita , Barcenas Carlos H. 
Published: July 2017

Abstract
Introduction: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor (TKI). Preclinical studies have suggested that diarrhea, the main toxicity of neratinib, may be multifactorial, including inflammatory, secretory and bile acid malabsorption etiologies. In a rat model of pan-HER TKI-induced diarrhea, a reduction in diarrhea was achieved with an anti-inflammatory or a bile acid resin. CONTROL is an international, open-label, sequential-cohort, phase II study investigating the effects of loperamide prophylaxis ± the long-acting corticosteroid budesonide or the bile acid sequestrant colestipol on neratinib-associated diarrhea. Methods: Pts with HER2+ eBC who had completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day (1 year) + loperamide prophylaxis (d1-28 or 56). Budesonide or colestipol were added on d1–28 in sequential cohorts. Primary endpoint: incidence of grade ≥3 diarrhea (NCI-CTCAE, v4.0). ExteNET, which included an analogous population but no mandatory antidiarrheal prophylaxis, was used as a historical control. Clinicaltrials.gov: NCT02400476. Results: At the December 2016 data cut-off, 186 pts have been enrolled (loperamide cohort, n=135; budesonide cohort, n=47; colestipol cohort, n=4). Treatment is ongoing and enrollment into the colestipol cohort will continue to a planned maximum (n=40). Incidence of grade ≥3 diarrhea was 28.9% with loperamide prophylaxis, 14.9% with budesonide + loperamide prophylaxis vs 39.9% without mandatory loperamide prophylaxis (ExteNET). Prior treatment with pertuzumab may influence grade 3 diarrhea rates.
StudyCONTROLExteNET4Cohort or study armLoperamideBudesonideNeratinibAntidiarrheal prophylaxisLoperamide (original schedule)1Loperamide (modified schedule)2Loperamide (original + modified)Budesonide + loperamide2,3Loperamide prnN (at data cut-off)28107135471408Diarrhea, %Any grade82.173.875.666.095.4Grade 135.721.524.429.822.9Grade 221.422.422.221.332.5Grade 325.029.928.914.939.8Grade 400000.1Grade 3 diarrhea, %Prior pertuzumab036.535.211.1-No prior pertuzumab26.923.624.720.0-Median cumulative duration of diarrhea, daysAny grade9.011.011.06.059.0Grade ≥25.04.04.03.010.0Grade ≥352.03.03.03.05.0Median episodes of diarrhea per pt, nAny grade2.02.02.03.08.0Grade ≥22.01.52.01.03.0Grade ≥351.01.01.01.02.0Median duration of neratinib treatment, mo69.78.28.22.111.61. Oral loperamide 4 mg with first neratinib dose, then 2 mg q4h d1–3, then 2 mg q6–8h d4–56. 2. Oral loperamide 4 mg with first neratinib dose, then 4 mg tid d1–14, then 4 mg bid d15–56. 3. Oral budesonide 9 mg qd d1–28. 4. Chan et al. Lancet Oncol 2016. 5. No grade 4 events in the CONTROL study; one grade 4 event in the ExteNET study. 6. Treatment ongoing in all CONTROL cohorts.CONTROL data cut-off: December 2016.
Conclusions: Loperamide prophylaxis reduces the incidence, severity and duration of neratinib-associated diarrhea compared with ExteNET; adding budesonide appears to further improve outcomes. Updated findings from the budesonide and colestipol cohorts will be presented at the meeting.
Citation Format: Emad Ibrahim, Debu Tripathy, Mary Wilkinson, Sara Hurvitz, Nicholas Iannotti, Andrew Kellum, Yvonne Manalo, Serena Wong, Vincent Hansen, Ricardo Alvarez, Arlene Chan, Ira Gore, DiSean Kendall, James Wade, Elizabeth Olek, Daniel Hunt, Pearl Fang, Azita Ebtahaj, Carlos H. Barcenas. Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients (pts) with HER2+ early-stage breast cancer (eBC): the CONTROL trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT128. doi:10.1158/1538-7445.AM2017-CT128