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

HER2-positive Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03094052
• Other study ID #: 167514
• Secondary ID: NCI-2017-01443
• Status: Completed
• Phase: Phase 2
• Start date: October 9, 2018
• Est. completion date: October 31, 2022

Study information

• Verified date: October 2023
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: October 31, 2022
• Est. primary completion date: October 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Adenocarcinoma
• Breast Neoplasms
• Diarrhea
• HER2-positive Breast Cancer
• 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

Intervention

Drug:
• Neratinib
Given orally (PO)

Biological:
• Trastuzumab
Given Intravenously (IV)

Drug:
• Loperamide
Given PO
• Diphenoxylate Hydrochloride/Atropine Sulfate
Given PO

Locations

Country	Name	City	State
United States	University of California, San Francisco	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Francisco	Puma Biotechnology, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (10)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Percentage of Participants With Multiple Anti-diarrheal Medications	Percentage of patients requiring multiple anti-diarrheal medications will be reported	Up to 55 weeks
Primary	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
Primary	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
Primary	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
Primary	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