Abstract P5-18-09: Halt-d: A randomized open label phase 2 study of crofelemer for the prevention of chemotherapy induced diarrhea (cid) in patients with breast cancer receiving trastuzumab, pertuzumab, and a taxane
Authors: Pohlmann Paula R , Graham Deena , Wu Tianmin , Ottaviano Yvonne , Mohebtash Mahsa , Kurian Shweta , McNamara Donna , Lynce Filipa , Warren Robert , Dilawari Asma , Rao Suman , Mainor Candace , Swanson Nicole , Tan Ming , Isaacs Claudine , Swain Sandra M. 
Published: March 2022

Abstract
Background: CID occurs in up to 80% of patients with breast cancer who receive trastuzumab (H), pertuzumab (P), and a taxane, with grade 3 experienced by 8-12% of patients. Crofelemer is an extract of the Croton lechleri tree that inhibits luminal chloride efflux, implicated in the HP-related CID. We hypothesized crofelemer would prevent diarrhea in patients with HER2+ breast cancer receiving HP and docetaxel or paclitaxel, with/without carboplatin (THP or TCHP) in the neoadjuvant, adjuvant, or metastatic setting. Clinical trial information: NCT02910219. Methods: Adult patients with HER2+ any stage breast cancer, scheduled to receive at least 3 consecutive cycles of TCHP (docetaxel, carboplatin, trastuzumab and pertuzumab) or THP (trastuzumab and pertuzumab with paclitaxel or docetaxel), normal organ function, PS 0-2, who provided written informed consent were randomized 1:1 to receive crofelemer 125 mg PO 2x/day during cycles 1 and 2 of chemotherapy or no scheduled prophylactic medication. Randomization was stratified according to chemotherapy regimen. The primary endpoint was the incidence of CID of any grade for ≥2 consecutive days assessed by NCI CTCAE v4.0. Provider reported outcomes were collected during clinic visits and prospectively documented in clinical notes. Patient reported outcomes (PRO) were collected from patient diaries. Secondary endpoints were incidence of all grades and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; frequency of break through anti-diarrheal medications use; and FACIT-D total score. Fisher’s exact test was used for comparing binary and categorical variables and summary statistics and Wilcoxon test for ordinal grade variables. The trial was designed to detect a 40% absolute decrease in incidence of CID (from 60% to 20%), two-sided significance level of 0.10. Results: A total of 53 patients were enrolled between 02/21/2017- 08/25/2020 on crofelemer (n=27) or control (n=26) arms. One patient withdrew consent prior to starting protocol procedures and was substituted. Early treatment discontinuation occurred in 7 cases: complications of diarrhea (n=1, control group), chemotherapy regimen changed for other cause than diarrhea (n=4) and non-compliance with trial procedures (n=2). 29 patients had early stage disease treated with TCHP; 23 patients had metastatic disease treated with THP (16 with paclitaxel and 7 with docetaxel). The primary endpoint was not statistically different between the two groups. The incidence of Grade 2 or greater diarrhea was 20.9% vs 26.4% of patients receiving crofelemer or placebo respectively in cycle 1, and 9.5% vs 41.1% in cycle 2 (Table). Results were consistent between provider assessments and patient reported outcomes (PRO). Detailed description of pooled cycle 1-2 data using correlated ordinal model and the additional secondary endpoints will be presented. Conclusions: Although there was no significant difference between crofelemer and control for diarrhea for 2 or more consecutive days in both cycles, there was a clinically meaningful difference between the crofelemer and control groups in maximum within-cycle diarrhea ordinal CTCAE grade diarrhea. These data are supportive for further testing of crofelemer in the ongoing randomized Phase 3 trial OnTARGET (NCT04538625).
CycleCTCAE bCrofelemerControlPDiarrhea &gt;= 2 consecutive days a168.069.6NS d265.272.2Maximum diarrhea grade a1Grade 0 c33.321.1NS eGrade 145.852.6Grade 216.721.1Grade 34.25.3Grade 40.00.02Grade 0 c38.117.60.0261 eGrade 152.441.2Grade 29.523.5Grade 30.017.6Grade 40.00.0Maximum diarrhea grade PRO f1Grade 0 c4.08.7NS eGrade 172.039.1Grade 216.043.5Grade 38.08.7Grade 40.00.02Grade 0 c9.10.00.0361 eGrade 181.866.7Grade 24.522.2Grade 34.511.1Grade 40.00.0aProvider assessedbCTCAE: NCI Common Terminology Criteria for Adverse Events v4.0cGrade 0: no diarrheadFisher''s exact testeWilcoxon rank sum testfPRO: Patient reported outcomes
Citation Format: 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. Halt-d: A randomized open label phase 2 study of crofelemer for the prevention of chemotherapy induced diarrhea (cid) in patients with breast cancer receiving trastuzumab, pertuzumab, and a taxane [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-09.