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

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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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10549-022-06743-9.

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Most cited references 34

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Stool form scale as a useful guide to intestinal transit time.

S J Lewis, K W Heaton (2009)

Stool form scales are a simple method of assessing intestinal transit rate but are not widely used in clinical practice or research, possibly because of the lack of evidence that they are responsive to changes in transit time. We set out to assess the responsiveness of the Bristol stool form scale to change in transit time. Sixty-six volunteers had their whole-gut transit time (WGTT) measured with radiopaque marker pellets and their stools weighed, and they kept a diary of their stool form on a 7-point scale and of their defecatory frequency. WGTT was then altered with senna and loperamide, and the measurements were repeated. The base-line WGTT measurements correlated with defecatory frequency (r = 0.35, P = 0.005) and with stool output (r = -0.41, P = 0.001) but best with stool form (r = -0.54, P < 0.001). When the volunteers took senna (n = 44), the WGTT decreased, whereas defecatory frequency, stool form score, and stool output increased (all, P < 0.001). With loperamide (n = 43) all measurements changed in the opposite direction. Change in WGTT from base line correlated with change in defecatory frequency (r = 0.41, P < 0.001) and with change in stool output (n = -0.54, P < 0.001) but best with change in stool form (r = -0.65, P < 0.001). This study has shown that a stool form scale can be used to monitor change in intestinal function. Such scales have utility in both clinical practice and research.

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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.

Luca Gianni, Tadeusz Pienkowski, Young-Hyuck Im … (2012)

Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2), escalating, if tolerated, to 100 mg/m(2) every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688. Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1-55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6-38·5]; p=0·0141). 23 of 96 (24·0% [15·8-33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3-25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15-20 serious adverse events per group in 10-17% of patients) but lower in group C (four serious adverse events in 4% of patients). Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. F Hoffmann-La Roche. Copyright © 2012 Elsevier Ltd. All rights reserved.

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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).

A Schneeweiss, S. Chia, T Hickish … (2013)

Pertuzumab (P) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer. We assessed the tolerability, with particular focus on cardiac safety, of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients. The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.

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Author and article information

Contributors

Sandra M. Swain:

ORCID: http://orcid.org/0000-0002-1320-3830

sandra.swain@georgetown.edu

Journal

Journal ID (nlm-ta): Breast Cancer Res Treat

Journal ID (iso-abbrev): Breast Cancer Res Treat

Title: Breast Cancer Research and Treatment

Publisher: Springer US (New York )

ISSN (Print): 0167-6806

ISSN (Electronic): 1573-7217

Publication date (Electronic): 25 October 2022

Publication date PMC-release: 25 October 2022

Publication date (Print): 2022

Volume: 196

Issue: 3

Pages: 571-581

Affiliations

[1 ]GRID grid.213910.8, ISNI 0000 0001 1955 1644, Georgetown Lombardi Comprehensive Cancer Center, ; Washington, DC USA

[2 ]GRID grid.411663.7, ISNI 0000 0000 8937 0972, MedStar Georgetown University Hospital, ; Washington, DC USA

[3 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Breast Medical Oncology, , University of Texas MD Anderson Cancer Center, ; Houston, TX USA

[4 ]GRID grid.239835.6, ISNI 0000 0004 0407 6328, Hackensack University Medical Center, ; Hackensack, NJ USA

[5 ]GRID grid.411667.3, ISNI 0000 0001 2186 0438, Clinical Research Management Office, , Georgetown University Medical Center, ; Washington, DC USA

[6 ]GRID grid.415030.3, ISNI 0000 0000 9148 7539, Medstar Franklin Square Medical Center, ; Baltimore, MD USA

[7 ]GRID grid.65499.37, ISNI 0000 0001 2106 9910, Dana-Farber Cancer Institute, ; Boston, MA USA

[8 ]GRID grid.483500.a, ISNI 0000 0001 2154 2448, Present Address: FDA Center for Drug Evaluation and Research, ; Silver Spring, MD USA

[9 ]GRID grid.411667.3, ISNI 0000 0001 2186 0438, Department of Biostatistics, Bioinformatics, and Biomathematics, , Georgetown University Medical Center, ; Washington, DC USA

[10 ]GRID grid.415232.3, ISNI 0000 0004 0391 7375, MedStar Health, ; Washington, DC USA

Author information

Paula R. Pohlmann http://orcid.org/0000-0001-7914-5162

Deena Graham http://orcid.org/0000-0003-1111-6984

Tianmin Wu http://orcid.org/0000-0003-3279-3052

Filipa Lynce http://orcid.org/0000-0001-6615-7076

Asma Dilawari http://orcid.org/0000-0001-5706-9138

Candace Mainor http://orcid.org/0000-0002-4431-7101

Ming Tan http://orcid.org/0000-0003-2533-8246

Claudine Isaacs http://orcid.org/0000-0002-9646-1260

Sandra M. Swain http://orcid.org/0000-0002-1320-3830

Article

Publisher ID: 6743

DOI: 10.1007/s10549-022-06743-9

PMC ID: 9633499

PubMed ID: 36280642

SO-VID: dfb8add4-d737-4da4-b7b6-14f024df8df7

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 9 May 2022

Date accepted : 5 September 2022

Funding

Funded by: Genentech, Inc

Funded by: Napo Pharmaceuticals, Inc.

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: trastuzumab,pertuzumab,chemotherapy-induced diarrhea,taxane,crofelemer,her2-positive breast cancer

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: trastuzumab, pertuzumab, chemotherapy-induced diarrhea, taxane, crofelemer, her2-positive breast cancer

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

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Abstract

Purpose

Methods

Results

Conclusion

Trial registration

Supplementary Information

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Karger: Oncology

Most cited references 34

Stool form scale as a useful guide to intestinal transit time.

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.

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).

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