- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03094052
Incidence and Severity of Diarrhea in Patients With HER2 Positive Breast Cancer Treated With Trastuzumab and Neratinib
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
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
PRIMARY OBJECTIVE:
I. 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:
I. 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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
California
-
San Francisco, California, United States, 94143
- University of California, San Francisco
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
INCLUSION CRITERIA:
- 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
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
EXCLUSION CRITERIA:
- 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)
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (Neratinib)
Patients will receive up to 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.
Patients 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.
|
Given orally (PO)
Other Names:
Given Intravenously (IV)
Other Names:
Given PO
Other Names:
Given PO
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percentage of Participants With Grade 3 or Greater Diarrhea
Time Frame: Up to 6 weeks
|
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 With Multiple Anti-diarrheal Medications
Time Frame: Up to 55 weeks
|
Percentage of patients requiring multiple anti-diarrheal medications will be reported
|
Up to 55 weeks
|
Percentage of Participants With Treatment-related Adverse Events
Time Frame: Up to 55 weeks
|
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
Time Frame: Up to 55 weeks
|
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
Time Frame: Up to 55 weeks
|
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
Time Frame: Up to 55 weeks
|
The number of participants whose dose was reduced at any time during the course of therapy will be reported
|
Up to 55 weeks
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Jo Chien, MD, University of California, San Francisco
Publications and helpful links
General 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Skin Diseases
- Neoplasms
- Neoplasms by Site
- Signs and Symptoms, Digestive
- Breast Diseases
- Breast Neoplasms
- Diarrhea
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Central Nervous System Depressants
- Parasympatholytics
- Autonomic Agents
- Peripheral Nervous System Agents
- Muscarinic Antagonists
- Cholinergic Antagonists
- Cholinergic Agents
- Analgesics
- Sensory System Agents
- Antineoplastic Agents
- Gastrointestinal Agents
- Antineoplastic Agents, Immunological
- Analgesics, Opioid
- Narcotics
- Adjuvants, Anesthesia
- Bronchodilator Agents
- Anti-Asthmatic Agents
- Respiratory System Agents
- Mydriatics
- Trastuzumab
- Atropine
- Loperamide
- Antidiarrheals
- Diphenoxylate
- Atropine sulfate-diphenoxylate hydrochloride drug combination
Other Study ID Numbers
- 167514
- NCI-2017-01443 (Registry Identifier: Clinical Trials Reporting Program (CTRP))
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on HER2-positive Breast Cancer
-
Mersana TherapeuticsRecruitingHER2-positive Breast Cancer | HER2-positive Gastric Cancer | HER2-positive Non-Small Cell Lung Cancer | HER2-positive Colorectal Cancer | HER2-positive Tumors | HER2 Low Breast CancerUnited States
-
QuantumLeap Healthcare CollaborativeRecruitingSolid Tumor | Metastatic Cancer | Metastatic Breast Cancer | Triple Negative Breast Cancer | HER2-positive Breast Cancer | Solid Tumor, Adult | Solid Carcinoma | HER2-positive Metastatic Breast Cancer | Progesterone Receptor-positive Breast Cancer | HER2-negative Breast Cancer | Estrogen Receptor Positive... and other conditionsUnited States
-
MacroGenicsApproved for marketingHER2-positive Breast Cancer | HER2-positive Carcinoma
-
Spanish Breast Cancer Research GroupSeagen Inc.RecruitingHER2-positive Metastatic Breast Cancer | Locally Advanced HER2 Positive Breast CarcinomaSpain
-
Cancer Trials IrelandCompletedBreast Cancer | HER2 Positive Breast Cancer | HER2 Negative Breast CancerIreland
-
Enliven TherapeuticsRecruitingColorectal Cancer | HER2-positive Breast Cancer | HER2-positive Gastric Cancer | HER2 Amplification | HER2 Positive Solid TumorsUnited States
-
Daiichi SankyoRecruitingBreast Cancer | Advanced Cancer | HER2-positive Breast Cancer | HER2-low Breast CancerChina
-
University of ArizonaPfizerCompletedBreast Cancer | Metastatic Breast Cancer | HER2-positive Breast Cancer | Recurrent Breast Cancer | HER2 Positive Breast Carcinoma | Breast Cancer StageUnited States
-
Clovis Oncology, Inc.TerminatedBreast Cancer | Metastatic Breast Cancer | Estrogen Receptor Positive | Triple Negative | HER2 | HER2 Positive | MBC | ERUnited States
-
Masonic Cancer Center, University of MinnesotaActive, not recruitingTriple Negative Breast Cancer | HER2-positive Breast Cancer | TN ER-/PR-/HER2- Breast Cancer | ERany/PRany/HER2+ Breast CancerUnited States
Clinical Trials on Neratinib
-
Puma Biotechnology, Inc.Completed
-
UNC Lineberger Comprehensive Cancer CenterNo longer available
-
Pierre Fabre MedicamentNot yet recruiting
-
Puma Biotechnology, Inc.Completed
-
Puma Biotechnology, Inc.Completed
-
Puma Biotechnology, Inc.Completed
-
Pierre Fabre Pharma GmbHiOMEDICO AG; Pierre Fabre Pharma Austria; Pierre Fabre Pharma AGActive, not recruiting
-
Puma Biotechnology, Inc.Completed
-
Puma Biotechnology, Inc.Completed
-
Puma Biotechnology, Inc.Withdrawn