HER2-positive Breast CancerPhase 2NCT03094052
Incidence and Severity of Diarrhea in Patients With HER2 Positive Breast Cancer Treated With Trastuzumab and Neratinib
A Phase 2 study testing Neratinib, Trastuzumab and Loperamide in people with HER2-positive Breast Cancer and Breast Adenocarcinoma, run by University of California, San Francisco at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HER2-positive Breast Cancer, Breast Adenocarcinoma, Stage II Breast Cancer AJCC v6 and v7
- What is being tested?
- Neratinib, Trastuzumab and Loperamide
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 1 siteUnited States
- Study dates
- 9 Oct 2018to 31 Oct 2022
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
- At the time of study enrollment, patients can still be receiving adjuvant trastuzumab monotherapy or be within 2 years of completing adjuvant trastuzumab +/- pertuzumab maintenance, or adjuvant T-DM1.
- Patients who are within 2 years of completing trastuzumab +/- pertuzumab or T-DM1 will receive neratinib monotherapy (and not neratinib + trastuzumab)
- Adjuvant T-DM1 is the standard of care for patients who have residual disease after neoadjuvant chemotherapy. Patients with residual disease after neoadjuvant chemotherapy should receive T-DM1 before enrolling on the study. If not, the option of T-DM1 should be discussed with the patient
- Clinically no evidence of metastatic disease at the time of study entry. Patients with fully resected locoregional recurrence with no evidence of disease are eligible
- Left ventricular ejection fraction (LVEF) >= 50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO)
- Eastern Cooperative Oncology Group (ECOG) status of 0 to 1
- Negative beta-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause; (women are considered postmenopausal if they are >= 12 months without menses, in the absence of endocrine or anti-endocrine therapies)
- Trastuzumab can cause embryo-fetal harm when administered during pregnancy and the effects of neratinib on the developing human fetus are unknown. Women of child-bearing potential must agree and commit to use of a highly effective double-barrier method of contraception (e.g., a combination of male condom with an intravaginal device such as the cervical cap, diaphragm, or vaginal sponge with spermicide) or a non-hormonal method, from the signing of informed consent until 28 days after the last dose of neratinib and 7 months after the last dose of trastuzumab, or consent to total sexual abstinence (abstinence must occur from randomization and continue for 28 days after the last dose of neratinib and 7 months after the last dose of trastuzumab). Men without confirmed vasectomy must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of investigational products, or consent to total sexual abstinence (abstinence must occur from randomization and continue for 3 months after the last dose of study medication)
- Recovery (i.e., to grade 1 or baseline) from all clinically significant adverse event (AE)s related to prior therapies (excluding alopecia, neuropathy, and nail changes)
- Provide written, informed consent to participate in the study and follow the study procedures
Who cannot join
- 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)
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- 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)
- Clinically active infection with hepatitis B or hepatitis C virus
- Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the investigator's judgment, make the patient inappropriate for this study
- Known hypersensitivity to any component of the investigational products
- Unable or unwilling to swallow tablets
Trial locations and contacts
1 site in 1 country.
United States1 site
University of California, San Francisco
San Francisco, California, 94143
About this study
Official title: An Open Label Study to Characterize the Incidence and Severity of Diarrhea in Patients With HER2+ Breast Cancer Treated With Neratinib With or Without Trastuzumab
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.
Read the detailed description
PRIMARY OBJECTIVE:
- To characterize the incidence and severity of diarrhea in patients with early stage breast cancer receiving adjuvant neratinib with or without trastuzumab in the setting of anti-diarrheal strategies.
SECONDARY OBJECTIVES:
- To evaluate the incidence of grade 3 or higher diarrhea using the dose-escalation strategy and anti-diarrhea medications as needed (prn) in patients who received prior trastuzumab emtansine (T-DM1).
II. To assess neratinib adherence, holds, delays, and early discontinuation throughout the course of study therapy which includes patients receiving neratinib for > 1 year.
III. To assess overall toxicity including constipation and cardiac toxicity with concomitant neratinib and trastuzumab.
OUTLINE: This is a dose-escalation study of neratinib. Patients receive one of the following treatment regimen:
NERATINIB MONOTHERAPY: Patients receive neratinib orally (PO) once daily (QD) on days 1-21. Cycles repeats every 21 days for up to 55 weeks in the absence of disease progression or unacceptable toxicity. Patients may receive loperamide and/or diphenoxylate hydrochloride/atropine sulfate as needed per physician discretion for symptom management.
NERATINIB AND TRASTUZUMAB: Patients receive neratinib PO QD on days 1-21. Patients also receive trastuzumab maintenance therapy as determined by treating physician. Treatment repeats every 21 days for up to 55 weeks in the absence of disease progression or unacceptable toxicity. After completion of trastuzumab treatment, patients may continue on neratinib monotherapy for the remainder of the 55 weeks. Patients may receive loperamide and/or diphenoxylate hydrochloride/atropine sulfate as needed per physician discretion for symptom management.
After completion of studies treatment, patients are followed up for 28 days.
- 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
- Being tested
- Neratinib, Trastuzumab, Loperamide, Crofelemer, Diphenoxylate/Atropine
- Keywords
- Neratinib, Trastuzumab
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NeratinibDrug
Also called Nerlynx
Given orally (PO)
TrastuzumabBiological
Also called Herceptin, HER2 Monoclonal Antibody
Given Intravenously (IV)
LoperamideDrug
Also called Imodium
Given PO
CrofelemerDrug
Also called Mytesi
Given PO
Diphenoxylate/AtropineDrug
Also called Lomotil
Allowed for participants experiencing refractory diarrhea
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Neratinib; Biological: Trastuzumab; Drug: Loperamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: Up to 55 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Mar 2017
- Study start9 Oct 2018
- Primary completion31 Oct 2022
- Study completion31 Oct 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for HER2-positive Breast CancerStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- Puma Biotechnology, Inc.
- Responsible party
- Principal investigator, Jo Chien, University of California, San Francisco
- Investigators
- Jo Chien, MD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03094052
- Sponsor's protocol ID
- 167514
- Other IDs
- NCI-2017-01443
- Status last verified
- Jun 2025
- First submitted
- 14 Mar 2017
- Last updated
- 26 Jun 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified datasets are available from the corresponding author on reasonable request.
Publications
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.
PubMed 3798106Perez 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.
PubMed 25332249Chan 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.
PubMed 26874901Rabindran 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.
PubMed 15173008Burstein 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.
PubMed 20142587Martin 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.
PubMed 23953056Castro 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.
PubMed 26517110Tradtrantip 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.
PubMed 19808995Crutchley 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.
PubMed 20388859Macarthur 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.
PubMed 24334179