Incidence and Severity of Diarrhea in Patients With HER2 Positive Breast Cancer Treated With Trastuzumab and Neratinib

NCT03094052 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 167514NCI-2017-01443
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies the incidence and severity of diarrhea in patients with stage II-IIIC HER2 Positive breast cancer treated with trastuzumab and neratinib. Trastuzumab is a form of targeted therapy because it attaches itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body's immune system. Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving trastuzumab and neratinib may work better in treating patients with stage II-IIIC HER2 positive breast cancer.

Conditions

HER2-positive Breast Cancer; Breast Adenocarcinoma; Stage II Breast Cancer AJCC v6 and v7; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7

Keywords

Neratinib; Trastuzumab

Outcome Measures

Primary Outcomes (7)

• Percentage of Participants With Grade 3 or Greater Diarrhea

  Percentage of participants with clinically assessed grade 3 or greater diarrhea reported within the first 2 cycles (each cycle is 21 days) of neratinib while using anti-diarrheal strategies. Reports of diarrhea will be graded according to NCI CTCAE version 4.0.

  Up to 6 weeks

• Percentage of Participants Who Did Not Require Loperamide During Multiple Cycles of Treatment

  Percentage of participants who did not require loperamide during cancer treatment for at least 5 cycles will be reported.

  Up to 55 weeks

• Percentage of Participants Who Discontinued Anti-diarrheal Medications for Multiple Cycles of Treatment

  The percentage of participants who discontinued all anti-diarrheal medications during cancer treatment for at least 5 cycles will be reported.

  Up to 55 weeks

• Percentage of Participants With Treatment-related Adverse Events

  Percentage of participants with reported serious adverse events and adverse events of interest of any grade that have been determined to be related to the anti-diarrhea treatment will be reported by worst grade and associated toxicity.

  Up to 55 weeks

• Number of Participants With Neratinib Dose Holds

  The number of participants who experienced a dose hold of neratinib during the course of study therapy will be reported

  Up to 55 weeks

• Number of Participants Who Discontinued Neratinib Early

  The number of participants who discontinued neratinib earlier than expected during the course of study therapy will be reported

  Up to 55 weeks

• Number of Participants With Neratinib Dose-reductions

  The number of participants whose dose was reduced at any time during the course of therapy will be reported

  Up to 55 weeks

Study Arms (2)

Adjuvant Neratinib, Crofelemer, Loperamide

EXPERIMENTAL

Participants will receive 240mg neratinib to be taken continuously in 21-day cycles once a day for up to 55 weeks on study with no rest between cycles unless related to toxicity. Participants will receive Neratinib and may also be prescribed standard of care maintenance adjuvant trastuzumab (duration of maintenance trastuzumab is at the discretion of the treating physician), for up to 55 weeks. If applicable, after the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib may continue as monotherapy to complete a maximum of 55 weeks. Participants will also receive 125mg of prophylactic Crofelemer and 4 mg of prophylactic loperamide as needed in the first 2 cycles.

Drug: Neratinib; Biological: Trastuzumab; Drug: Loperamide; Drug: Crofelemer; Drug: Diphenoxylate/Atropine

Adjuvant Neratinib, Loperamide

EXPERIMENTAL

Participants will receive 120 mg of neratinib on days 1-7 with subsequent increase in dose by 40 mg every 7 days until the full dose of 240 mg a day is reached within the first cycle (up to 240mg) to be taken continuously in 21-day cycles once a day for up to 55 weeks on study with no rest between cycles unless related to toxicity. Participants will receive Neratinib and may also be prescribed standard of care maintenance adjuvant trastuzumab (duration of maintenance trastuzumab is at the discretion of the treating physician), for up to 55 weeks. If applicable, after the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib may continue as monotherapy to complete a maximum of 55 weeks. Participants will also receive 4 mg of prophylactic loperamide to be taken as needed.

Drug: Neratinib; Biological: Trastuzumab; Drug: Loperamide

Interventions

Neratinib DRUG

Given orally (PO)

Also known as: Nerlynx

Adjuvant Neratinib, Crofelemer, Loperamide; Adjuvant Neratinib, Loperamide

Trastuzumab BIOLOGICAL

Given Intravenously (IV)

Also known as: Herceptin, HER2 Monoclonal Antibody

Adjuvant Neratinib, Crofelemer, Loperamide; Adjuvant Neratinib, Loperamide

Loperamide DRUG

Given PO

Also known as: Imodium

Adjuvant Neratinib, Crofelemer, Loperamide; Adjuvant Neratinib, Loperamide

Crofelemer DRUG

Given PO

Also known as: Mytesi

Adjuvant Neratinib, Crofelemer, Loperamide

Diphenoxylate/Atropine DRUG

Allowed for participants experiencing refractory diarrhea

Also known as: Lomotil

Adjuvant Neratinib, Crofelemer, Loperamide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>= 18 years
• Histologically confirmed clinical or pathological stage 2 through stage 3c primary adenocarcinoma of the breast
• Documented human epidermal growth factor receptor 2 (HER2) overexpression or gene-amplified tumor by a validated approved method
• Patients can have hormone receptor (HR)+ or HR-negative disease
• Concurrent adjuvant endocrine therapy and bone-modifying agents is allowed
• Patients can be premenopausal or postmenopausal
• Completion of neoadjuvant or adjuvant chemotherapy
• Completion of adjuvant locoregional radiation, if indicated, is required prior to starting study treatment
• Histologically confirmed clinical or pathological stage 2 through stage 3c primary adenocarcinoma of the breast
• Documented HER2 overexpression or gene-amplified tumor by a validated approved method
• Patients can have hormone receptor (HR)+ or HR-negative disease
• Concurrent adjuvant endocrine therapy and bone-modifying agents is allowed
• Patients can be premenopausal or postmenopausal
• Completion of neoadjuvant or adjuvant chemotherapy
• Completion of adjuvant locoregional radiation, if indicated, is required prior to starting study treatment

You may not qualify if:

• Clinical or radiologic evidence of metastatic disease prior to or at the time of study entry. Locoregional recurrent disease that is resected is allowed
• Currently receiving chemotherapy, radiation therapy, investigational immunotherapy, or investigational biotherapy for breast cancer
• Major surgery (including breast surgery) within \< 30 days of starting treatment or received chemotherapy, investigational agents, or other cancer therapy \< 14 days prior to the initiation of investigational products (except adjuvant endocrine therapy)
• Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of \>= 2; including individuals who currently use digitalis, beta-blockers, or calcium channel blockers specifically for congestive heart failure), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia
• Corrected QT (QTc) interval \> 0.450 seconds (males) or \> 0.470 seconds (females), or known history of QTc prolongation or Torsade de Pointes (TdP)
• Absolute neutrophil count (ANC) =\< 1,000/microliter (uL)
• Platelets =\< 100,000/uL
• Hemoglobin =\< 9 g/dL
• Serum creatinine \>= 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance =\< 30 mL/min for patients with creatinine levels \> 1.5 x institutional ULN
• \* Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin \>= 1.5 x ULN OR direct bilirubin \>= ULN for patients with total bilirubin levels \> 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (\[SGOT)) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) \>= 2.5 x ULN
• Second malignancy for which the patient will be receiving active treatment during the time of study participation.
• Currently pregnant or breast-feeding
• Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or grade \>= 2 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v.4.0) diarrhea of any etiology at baseline)

Sponsors & Collaborators

• University of California, San Francisco: lead
• Puma Biotechnology, Inc.: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Related Publications (10)

• Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987 Jan 9;235(4785):177-82. doi: 10.1126/science.3798106.

  PMID: 3798106 BACKGROUND

• Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. doi: 10.1200/JCO.2014.55.5730. Epub 2014 Oct 20.

  PMID: 25332249 BACKGROUND

• Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, Gokmen E, von Minckwitz G, Ejlertsen B, Chia SKL, Mansi J, Barrios CH, Gnant M, Buyse M, Gore I, Smith J 2nd, Harker G, Masuda N, Petrakova K, Zotano AG, Iannotti N, Rodriguez G, Tassone P, Wong A, Bryce R, Ye Y, Yao B, Martin M; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):367-377. doi: 10.1016/S1470-2045(15)00551-3. Epub 2016 Feb 10.

  PMID: 26874901 BACKGROUND

• Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004 Jun 1;64(11):3958-65. doi: 10.1158/0008-5472.CAN-03-2868.

  PMID: 15173008 BACKGROUND

• Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, Awada A, Ranade A, Jiao S, Schwartz G, Abbas R, Powell C, Turnbull K, Vermette J, Zacharchuk C, Badwe R. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010 Mar 10;28(8):1301-7. doi: 10.1200/JCO.2009.25.8707. Epub 2010 Feb 8.

  PMID: 20142587 BACKGROUND

• Martin M, Bonneterre J, Geyer CE Jr, Ito Y, Ro J, Lang I, Kim SB, Germa C, Vermette J, Wang K, Wang K, Awada A. A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer. Eur J Cancer. 2013 Dec;49(18):3763-72. doi: 10.1016/j.ejca.2013.07.142. Epub 2013 Aug 15.

  PMID: 23953056 BACKGROUND

• Castro JG, Chin-Beckford N. Crofelemer for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on anti-retroviral therapy. Expert Rev Clin Pharmacol. 2015;8(6):683-90. doi: 10.1586/17512433.2015.1082424. Epub 2015 Aug 27.

  PMID: 26517110 BACKGROUND

• 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 Jan;77(1):69-78. doi: 10.1124/mol.109.061051. Epub 2009 Oct 6.

  PMID: 19808995 BACKGROUND

• Crutchley RD, Miller J, Garey KW. Crofelemer, a novel agent for treatment of secretory diarrhea. Ann Pharmacother. 2010 May;44(5):878-84. doi: 10.1345/aph.1M658. Epub 2010 Apr 13.

  PMID: 20388859 BACKGROUND

• 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 Nov-Dec;14(6):261-73. doi: 10.1310/hct1406-261.

  PMID: 24334179 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms

Interventions

neratinib; Trastuzumab; Loperamide; crofelemer; atropine sulfate-diphenoxylate hydrochloride drug combination

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

The study closed to enrollment earlier than expected due to a change in pharmaceutical sponsor priorities and treatment landscape.

Results Point of Contact

• Title: Dr. A. Jo Chien, MD
• Organization: University of California, San Francisco

Jo.Chien@ucsf.edu

(415) 885-7577

Study Officials

• Jo Chien, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Clinical Professor of Medicine

Study Record Dates

• First Submitted: March 14, 2017
• First Posted: March 29, 2017
• Study Start: October 9, 2018
• Primary Completion: October 31, 2022
• Study Completion: October 31, 2022
• Last Updated: June 26, 2025
• Results First Posted: November 18, 2023

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share

Locations

US (1)