HALT-D: a randomized open-label phase II study of crofelemer for the prevention of chemotherapy-induced diarrhea in patients with HER2-positive breast cancer receiving trastuzumab, pertuzumab, and a taxane

Paula R Pohlmann, Deena Graham, Tianmin Wu, Yvonne Ottaviano, Mahsa Mohebtash, Shweta Kurian, Donna McNamara, Filipa Lynce, Robert Warren, Asma Dilawari, Suman Rao, Candace Mainor, Nicole Swanson, Ming Tan, Claudine Isaacs, Sandra M Swain, Paula R Pohlmann, Deena Graham, Tianmin Wu, Yvonne Ottaviano, Mahsa Mohebtash, Shweta Kurian, Donna McNamara, Filipa Lynce, Robert Warren, Asma Dilawari, Suman Rao, Candace Mainor, Nicole Swanson, Ming Tan, Claudine Isaacs, Sandra M Swain

Abstract

Purpose: To assess whether crofelemer would prevent chemotherapy-induced diarrhea (CID) diarrhea in patients with HER2-positive, any-stage breast cancer receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with/without carboplatin (C; always combined with docetaxel rather than paclitaxel).

Methods: Patients scheduled to receive ≥ 3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally twice daily during chemotherapy cycles 1 and 2 or no scheduled prophylactic medication (control). All received standard breakthrough antidiarrheal medication (BTAD) as needed. The primary endpoint was incidence of any-grade CID for ≥ 2 consecutive days. Secondary endpoints were incidence of all-grade and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; use of BTAD; and quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score).

Results: Fifty-one patients were randomized to crofelemer (n = 26) or control (n = 25). There was no statistically significant difference between arms for the primary endpoint; however, incidence of grade ≥ 2 CID was reduced with crofelemer vs control (19.2% vs 24.0% in cycle 1; 8.0% vs 39.1%, in cycle 2). Patients receiving crofelemer were 1.8 times more likely to see their diarrhea resolved and had less frequent watery diarrhea.

Conclusion: Despite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CID in patients with HER2-positive breast cancer receiving P-based therapy. These data are supportive of further testing of crofelemer in CID.

Trial registration: Clinicaltrials.gov, NCT02910219, prospectively registered September 21, 2016.

Keywords: Chemotherapy-induced diarrhea; Crofelemer; HER2-positive breast cancer; Pertuzumab; Taxane; Trastuzumab.

Conflict of interest statement

Paula R. Pohlmann reports honoraria from the FRONTIERS Editorial Board; consulting/advisory board roles for Personalized Cancer Therapy (Perthera), Immunonet BioSciences, Sirtex, Xcenda/Sirtex, CARIS, Pfizer, Heron, Puma, BOLT Therapeutics, and AbbVie; lectures for Genentech/Roche, Dava Oncology, ASCO Courses, ION Oral Oncolytics, and OncLive; research funding to her institution from Pfizer, Genentech/Roche, Pieris, Fabre-Kramer, BOLT, Byondis, and SEAGEN; and patents (United States Patent no. 9,745,377; 8,501,417; 8,486,413; 9,023,362; patent application CTC-CRC). Deena Graham reports research funding to her institute from Genentech, MedStar Health, and Napo. Tianmin Wu reports research funding to her institution from Genentech through MedStar Health. Yvonne Ottaviano reports research funding to her institution from Genentech through MedStar Health and study drug supply from Napo. Mahsa Mohebtash reports research funding to her institution from Genentech through MedStar Health and study drug supply from Napo. Shweta Kurian reports research funding to her institution from Genentech through MedStar Health and study drug supply from Napo. Donna McNamara reports research funding to her institution from Genentech through MedStar Health and study drug supply from Napo. Filipa Lynce has consulted for AstraZeneca and Daiichi Sankyo and has received research funding to her institution from AstraZeneca, CytomX, and Zentalis. Robert Warren reports research funding to his institution from Genentech. Asma Dilawari has served on the Paxman Scalp Cooling Research Advisory Committee but did not receive monetary compensation and reports research funding to her institution to conduct the study from Genentech. Suman Rao reports funding to her institution from Genentech. Candace Mainor reports research funding to her institution from Genentech through MedStar Health and study drug supply from Napo. Nicole Swanson reports research funding to her institution from Genentech (funding source) and study drug supply by Napo Pharmaceuticals. Ming Tan reports research funding to his institution from Genentech through MedStar Health. Claudine Isaacs reports consultancies for Genentech, Seattle Genetics, and PUMA. Sandra M. Swain reports grants/contracts to her institution from Breast Cancer Research Foundation, Genentech/Roche, and Kailos Genetics; consulting fees from AstraZeneca, Daiichi Sankyo, Molecular Templates, Silverback Therapeutics, Eli Lilly, Merck, Natera, Exact Sciences, Athenex, Biotheranostics, and Genentech/Roche; non-promotional speaking fees from Genentech/Roche, Daiichi Sankyo, and Beijing Medical Foundation; travel support from Genentech/Roche, Caris, and Daiichi Sankyo; serving on a data safety and monitoring board for AstraZeneca; and leadership or a fiduciary role for ASCO Conquer Cancer Foundation and The National Surgical Adjuvant Breast and Bowel Project Foundation (all outside of the submitted work). All authors received third-party medical writing support from Genentech, Inc.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study schema. BID twice daily, C, carboplatin; H trastuzumab, P pertuzumab, T taxane. Reprinted from Clinical Breast Cancer, 17, Gao JJ, Tan M, Pohlmann PR, and Swain SM, HALT-D: A Phase II Evaluation of Crofelemer for the Prevention and Prophylaxis of Diarrhea in Patients With Breast Cancer on Pertuzumab-Based Regimens, 76–78, Copyright (2016), with permission from Elsevier
Fig. 2
Fig. 2
Frequency of diarrhea for ≥ 2 consecutive days (primary endpoint) (a); frequency of diarrhea according to taxane and treatment cycle (crofelemer arm only) in cycle 1 (b) and cycle 2 (c). aInvestigator-assessed

References

    1. Richardson G, Dobish R. Chemotherapy induced diarrhea. J Oncol Pharm Pract. 2007;13:181–198. doi: 10.1177/1078155207077335.
    1. Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: Pathophysiology, frequency and guideline-based management. Ther Adv Medi Oncol. 2010;2:51–63. doi: 10.1177/1758834009355164.
    1. Swain SM, Schneeweiss A, Gianni L, Gao JJ, Stein A, Waldron-Lynch M, Heeson S, Beattie MS, Yoo B, Cortes J, Baselga J. Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab. Ann Oncol. 2017;28:761–768. doi: 10.1093/annonc/mdw695.
    1. Dang C, Iyengar N, Datko F, D'Andrea G, Theodoulou M, Dickler M, Goldfarb S, Lake D, Fasano J, Fornier M, Gilewski T, Modi S, Gajria D, Moynahan ME, Hamilton N, Patil S, Jochelson M, Norton L, Baselga J, Hudis C. Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015;33:442–447. doi: 10.1200/jco.2014.57.1745.
    1. Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM, CLEOPATRA Study Group Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Eng J Med. 2012;366:109–119. doi: 10.1056/nejmoa1113216.
    1. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA) Ann Oncol. 2013;24:2278–2284. doi: 10.1093/annonc/mdt182.
    1. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J, Investigators ASC. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377:122–131. doi: 10.1056/nejmoa1703643.
    1. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25–32. doi: 10.1016/s1470-2045(11)70336-9.
    1. Tao G, Chityala PK. Epidermal growth factor receptor inhibitor-induced diarrhea: Clinical incidence, toxicological mechanism, and management. Toxicol Res (Camb) 2021;10:476–486. doi: 10.1093/toxres/tfab026.
    1. Hirsh V, Blais N, Burkes R, Verma S, Croitoru K. Management of diarrhea induced by epidermal growth factor receptor tyrosine kinase inhibitors. Current Oncol (Toronto, Ont) 2014;21:329–336. doi: 10.3747/co.21.2241.
    1. Pessi MA, Zilembo N, Haspinger ER, Molino L, Di Cosimo S, Garassino M, Ripamonti CI. Targeted therapy-induced diarrhea: A review of the literature. Crit Rev Oncol Hematol. 2014;90:165–179. doi: 10.1016/j.critrevonc.2013.11.008.
    1. Duan T, Cil O, Thiagarajah JR, Verkman AS. Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB tyrosine kinase inhibitor diarrhea. JCI Insight. 2019;4:e126444. doi: 10.1172/jci.insight.126444.
    1. Rugo HA-O, Di Palma JA, Tripathy D, Bryce R, Moran S, Olek E, Bosserman L. The characterization, management, and future considerations for ErbB-family TKI-associated diarrhea. Breast Cancer Res Treat. 2019;175:5–15. doi: 10.1007/s10549-018-05102-x.
    1. Kim Y, Quach A, Das S, Barrett KE. Potentiation of calcium-activated chloride secretion and barrier dysfunction may underlie EGF receptor tyrosine kinase inhibitor-induced diarrhea. Physiol Rep. 2020;8:e14490. doi: 10.14814/phy2.14490.
    1. Harada Y, Sekine H, Kubota K, Sadatomi D, Iizuka S, Fujitsuka N. Calcium-activated chloride channel is involved in the onset of diarrhea triggered by EGFR tyrosine kinase inhibitor treatment in rats. Biomed Pharmacother. 2021;141:111860. doi: 10.1016/j.biopha.2021.111860.
    1. Fischer H, Machen TE, Widdicombe JH, Carlson TJ, King SR, Chow JW, Illek B. A novel extract SB-300 from the stem bark latex of Croton lechleri inhibits CFTR-mediated chloride secretion in human colonic epithelial cells. J Ethnopharmacol. 2004;93:351–357. doi: 10.1016/j.jep.2004.04.005.
    1. Tradtrantip L, Namkung W, Verkman AS. Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol. 2010;77:69–78. doi: 10.1124/mol.109.061051.
    1. Macarthur RD, Hawkins TN, Brown SJ, Lamarca A, Clay PG, Barrett AC, Bortey E, Paterson C, Golden PL, Forbes WP. Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study. HIV Clin Trials. 2013;14:261–273. doi: 10.1310/hct1406-261.
    1. Frampton JE. Crofelemer: a review of its use in the management of non-infectious diarrhoea in adult patients with HIV/AIDS on antiretroviral therapy. Drugs. 2013;73:1121–1129. doi: 10.1007/s40265-013-0083-6.
    1. Cottreau J, Tucker A, Crutchley R, Garey KW. Crofelemer for the treatment of secretory diarrhea. Expert Rev Gastroenterol Hepatol. 2012;6:17–23. doi: 10.1586/egh.11.87.
    1. Patel TS, Crutchley RD, Tucker AM, Cottreau J, Garey KW. Crofelemer for the treatment of chronic diarrhea in patients living with HIV/AIDS. HIV AIDS (Auckl) 2013;15:153–162. doi: 10.2147/hiv.s30948.
    1. Napo Pharmaceuticals Inc. (2020) MYTESI® (crofelemer). Prescribing Information. . Accessed August 2022
    1. Blake MR, Raker JM, Whelan K. Validity and reliability of the bristol stool form scale in healthy adults and patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2016;44:693–703. doi: 10.1111/apt.13746.
    1. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute (2010) Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. Published: May 28, 2009 (v4.03: June 14, 2010). . Accessed Feb 2020
    1. Benson AB, 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA, McCallum R, Mitchell EP, O'Dorisio TM, Vokes EE, Wadler S. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22:2918–2926. doi: 10.1200/jco.2004.04.132.
    1. O'Donnell LJ, Virjee J, Heaton KW. Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate. BMJ (Clinical research ed) 1990;300:439–440. doi: 10.1136/bmj.300.6722.439.
    1. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997;32:920–924. doi: 10.3109/00365529709011203.
    1. Gao JJ, Tan M, Pohlmann PR, Swain SM. HALT-D: A phase II evaluation of crofelemer for the prevention and prophylaxis of diarrhea in patients with breast cancer on pertuzumab-based regimens. Clin Breast Cancer. 2017;17:76–78. doi: 10.1016/j.clbc.2016.08.005.
    1. Skarke C, Jarrar M, Schmidt H, Kauert G, Langer M, Geisslinger G, Lötsch J. Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics. 2003;13:651–660. doi: 10.1097/00008571-200311000-00001.
    1. Okura T, Morita Y, Ito Y, Kagawa Y, Yamada S. Effects of quinidine on antinociception and pharmacokinetics of morphine in rats. J Pharm Pharmacol. 2010;61:593–597. doi: 10.1211/jpp.61.05.0007.
    1. Barcenas CH, Hurvitz SA, Di Palma JA, Bose R, Chien AJ, Iannotti N, Marx G, Brufsky A, Litvak A, Ibrahim E, Alvarez RH, Ruiz-Borrego M, Chan N, Manalo Y, Kellum A, Trudeau M, Thirlwell M, Garcia Saenz J, Hunt D, Bryce R, McCulloch L, Rugo HS, Tripathy D, Chan A, CONTROL Study Investigators Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: The CONTROL trial. Ann Oncol. 2020;31:1223–1230. doi: 10.1016/j.annonc.2020.05.012.
    1. Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358:1663–1671. doi: 10.1056/nejmoa0707056.
    1. Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. Journal Clin Oncol. 2005;23:5542–5551. doi: 10.1200/jco.2005.02.027.
    1. Bossi P, Antonuzzo A, Cherny NI, Rosengarten O, Pernot S, Trippa F, Schuler U, Snegovoy A, Jordan K, Ripamonti CI, Guidelines Committee ESMO. Diarrhoea in adult cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2018;29:IV126–IV142. doi: 10.1093/annonc/mdy145.
    1. Michael M, Brittain M, Nagai J, Feld R, Hedley D, Oza A, Siu L, Moore MJ. Phase II study of activated charcoal to prevent irinotecan-induced diarrhea. J. Clin Oncol. 2004;22:4410–4417. doi: 10.1200/jco.2004.11.125.
    1. Karthaus M, Ballo H, Abenhardt W, Steinmetz T, Geer T, Schimke J, Braumann D, Behrens R, Behringer D, Kindler M, Messmann H, Boeck HP, Greinwald R, Kleeberg U. Prospective, double-blind, placebo-controlled, multicenter, randomized phase III study with orally administered budesonide for prevention of irinotecan (CPT-11)-induced diarrhea in patients with advanced colorectal cancer. Oncology. 2005;68:326–332. doi: 10.1159/000086971.

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