An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide

An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients with Early-Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide or other prophylactic measures.

Study Overview

• Status: Completed
• Conditions: Early Stage HER2+ Breast Cancer
• Intervention / Treatment: Drug: Neratinib; Drug: Loperamide; Drug: Budesonide; Drug: Colestipol

Detailed Description

This is an open-label, Phase 2 study that will investigate the incidence and severity of diarrhea in early-stage HER2+ breast cancer patients receiving neratinib with loperamide, alone and in combination with an anti-inflammatory treatment or a bile acid sequestrant treatment, or neratinib dose escalation, who have previously undergone a course of trastuzumab therapy in the adjuvant setting.

Patients will receive:

• Neratinib 240 mg orally once daily with food for thirteen 28-day cycles.
• Loperamide daily for two 28-day cycles and then as needed.
• Amendment 3, an anti-inflammatory treatment for one cycle and loperamide to be administered daily for two 28-day cycles and then as needed. Closed to enrollment.
• Amendment 4, colestipol for one cycle and loperamide to be administered one cycle and then as needed. Closed to enrollment.
• Amendment 5, colestipol for one cycle and loperamide as needed. Closed to enrollment.
• Amendment 6/6.1, 120 mg neratinib for Week 1 (C1D1-C1D7), followed by 160 mg neratinib for Week 2 (C1D8-C1D14), followed by 240 mg neratinib for Week 3 and thereafter (C1D15 to end of treatment). Loperamide as needed. Closed to enrollment.
• Amendment 7/7.1, 160 mg neratinib for the first 2 weeks (C1D1 - C1D14), followed by 200 mg neratinib for the next 2 weeks (C1D15 - C1D28), followed by 240 mg neratinib thereafter (C2D1 to end of treatment). Loperamide as needed.

• Study Type: Interventional
• Enrollment (Actual): 563
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Wahroonga, New South Wales, Australia
      • Sydney Adventist Hospital
  • South Australia
    • Kurralta Park, South Australia, Australia, 5037
      • Ashford Cancer Centre Research
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • BCRC-WA, Hollywood Private Hospital
• Austria
  • Graz, Austria, 8036
    • Univ. Klinik für Innere Medizin, Klin. Abt. Onkologie
  • Innsbruck, Austria, A-6020
    • Medical University of Innsbruck-Department of Gynecology
  • Salzburg, Austria, A-5020
    • Uniklinikum Salzburg, Landeskrankenhaus, Univ. Klinik fur Innere Medizin III der PMU
  • Vienna, Austria, 1090
    • Medical University of Vienna, Department of Oncology
  • Vienna, Austria, 1090
    • Medical University of Vienna,Department of Obstetrics and Gynecology
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N3M5
      • Sunnybrook Research Insitute
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre, Cedars Cancer Centre
• France
  • Paris, France, 5013
    • CHU Group Hospitalier Pitié-Salpêtrière, Service d'oncologie Médicale
  • Villejuif, France, 94800
    • Institut Gustave Roussy
• Germany
  • Freiburg, Germany, 79110
    • Praxis für interdisziplinäre Onkologie & Hämatologie
  • Hamburg, Germany, 20357
    • Mammazentrum HH am Krankenhaus Jerusalem
  • Kiel, Germany, 24105
    • Universitaetsklinikum Schleswig-Holstein
  • Kiel, Germany, D-24106
    • Universitaetsklinikum Schleswig-Holstein (UKSH), Klinik fuer Gynaekologie und Geburtshilfe, Studienzentrale Gynäkologische Onkologie (SGC) Kiel
  • Offenbach, Germany, 63069
    • Sana Klinikum Offenbach GmbH - Frauenklinik
• Spain
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen Del Rocio
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • Alabama Oncology
  • California
    • Corona, California, United States, 92879
      • Compassionate Care Research Group Inc.
    • Fullerton, California, United States, 92835
      • St. Joseph Heritage Healthcare
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
    • Redlands, California, United States, 92373
      • Emad Ibrahim, M.D., Inc.
    • Redondo Beach, California, United States, 90277
      • Torrance Memorial Physician Network Cancer Care Associates
    • Riverside, California, United States, 92501
      • Compassionate Care Research Group Inc.
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • Santa Ana, California, United States, 92705
      • The Oncology Institute of Hope and Innovation
    • Santa Barbara, California, United States, 93105
      • Cancer Center of Santa Barbara with Sansum Clinic
    • Santa Maria, California, United States, 93454
      • Central Coast Medical Oncology Corporation
  • Florida
    • Hollywood, Florida, United States, 33021
      • Memorial Healthcare System
    • Plantation, Florida, United States, 33324
      • Florida Cancer Research Institute, LLC
    • Port Saint Lucie, Florida, United States, 34952
      • Hematology-Oncology Associates of the Treasure Coast
    • Sunrise, Florida, United States, 33322
      • Baptist Health Urgent Care Sawgrass
  • Georgia
    • Newnan, Georgia, United States, 30265
      • Cancer Treatment Centers of America
  • Illinois
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital Cancer Care Specialists of Central Illinois
    • Harvey, Illinois, United States, 60426
      • Ingalls Memorial Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Norton Cancer Institute
  • Maine
    • Lewiston, Maine, United States, 04240
      • Central Maine Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland, Greenebaum Comprehensive Cancer Center
  • Mississippi
    • Tupelo, Mississippi, United States, 38801
      • North Mississippi Medical Center Hematology and Oncology Services
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • North Platte, Nebraska, United States, 69101
      • Great Plains Health (Callahan Cancer Center)
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
    • Neptune, New Jersey, United States, 07753
      • Jersey Shore University Medical Center
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
    • Voorhees, New Jersey, United States, 08035
      • MD Anderson Cancer Center at Cooper
  • New York
    • Lake Success, New York, United States, 11042
      • Clinical Research Alliance, Inc
  • Oregon
    • Corvallis, Oregon, United States, 97330
      • Good Samaritan Hospital Samaritan Pastega Regional Cancer Center
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee-Womens Hospital of UPMC
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • Charleston Hematology Oncology Associates
    • Hilton Head Island, South Carolina, United States, 29926
      • Saint Joseph / Candler SC Cancer Specialists
  • Texas
    • Corpus Christi, Texas, United States, 78412
      • Coastal Bend Cancer Center
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Utah
    • Ogden, Utah, United States, 84405
      • Community Cancer Trials of Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Schar Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥18; male or female
• Early breast cancer (stage I-3c)
• Documented HER2+ tumor: HER2 immunohistochemistry (IHC) 3+ or ISH+
• Prior course of adjuvant trastuzumab given >2 weeks and ≤1 year from enrollment
• No evidence of local/regional recurrence or metastatic disease
• Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
• Male patients with female partners of childbearing potential must agree and commit to use a condom and women of childbearing potential must not be pregnant and must agree and commit to the use of a highly effective non-hormonal method of contraception
• Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or ECHO

Exclusion Criteria:

• Major surgery < 30 days
• Chemotherapy, investigational agents, other cancer therapy (except hormonal therapy) < 14 days
• Corrected QT Interval (QTc) >0.450 seconds (males) or >0.470 (females) or other active cardiac disease
• Significant chronic GI disorder with diarrhea as a major symptom
• Active, unresolved infections
• Currently pregnant or breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Loperamide; 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed.	Drug: Neratinib; Other Names: Nerlynx; Drug: Loperamide
Experimental: Budesonide and Loperamide; 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter.	Drug: Neratinib; Other Names: Nerlynx; Drug: Loperamide; Drug: Budesonide; 9 mg extended release tablets once daily with or without food for 28 days
Experimental: Colestipol and Loperamide; 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter.	Drug: Neratinib; Other Names: Nerlynx; Drug: Loperamide; Drug: Colestipol; 2 g twice daily with or without food for one 28 day cycle
Experimental: Colestipol with Loperamide as needed; 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed.	Drug: Neratinib; Other Names: Nerlynx; Drug: Loperamide; Drug: Colestipol; 2 g twice daily with or without food for one 28 day cycle
Experimental: Neratinib Dose Escalation 1; 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed.	Drug: Neratinib; Other Names: Nerlynx; Drug: Loperamide
Experimental: Neratinib Dose Escalation 2; 160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only.	Drug: Neratinib; Other Names: Nerlynx; Drug: Loperamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.	The primary objective of this study is to characterize the percentage of patients with Grade 3 or higher diarrhea in patients with early-stage HER2 overexpressed/amplified (HER2+) breast cancer treated with neratinib when administered with intensive loperamide prophylaxis, after prior treatment with trastuzumab. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.	From first dose of investigational product through 28 days after last dose, up to 15.5 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Diarrhea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0.	Assess the percentage of patients with diarrhea after the administration of an anti-inflammatory agent, a bile acid sequestrant, or following two different dose-escalation regimens of neratinib, by maximum CTC grade. Grade 1: an increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline. Grade 2: Increase of 4 - 6 stools per day over baseline; moderate increase in ostomy output compared to baseline. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.	From first dose of investigational product through 28 days after last dose, up to 15.5 months.
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Assess the percentage of patients with serious adverse events (SAEs) and other adverse events of special interest (AESI). AESIs were selected based on the known safety profile of neratinib as well as typical key body system toxicity concerns generally reviewed for any new drug. These AESIs were grouped into the following categories: gastrointestinal toxicity (diarrhea and stomatitis), hepatotoxicity, pulmonary toxicity (interstitial lung disease), cardiac toxicity (LVEF decreased), and dermatologic toxicity (rash and nail disorders). The AESIs were analyzed by searching the clinical database for all TEAEs and SAEs using either Standardized MedDRA Queries (SMQs) or, if an applicable SMQ did not exist, a Sponsor-defined list of MedDRA preferred terms.	From first dose of investigational product through 28 days after last dose, up to 15.5 months.

Collaborators and Investigators

• Sponsor: Puma Biotechnology, Inc.

Publications and helpful links

General Publications

• Barcenas CH, Hurvitz SA, Di Palma JA, Bose R, Chien AJ, Iannotti N, Marx G, Brufsky A, Litvak A, Ibrahim E, Alvarez RH, Ruiz-Borrego M, Chan N, Manalo Y, Kellum A, Trudeau M, Thirlwell M, Garcia Saenz J, Hunt D, Bryce R, McCulloch L, Rugo HS, Tripathy D, Chan A; CONTROL Study Investigators. Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial. Ann Oncol. 2020 Sep;31(9):1223-1230. doi: 10.1016/j.annonc.2020.05.012. Epub 2020 May 25.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2015
• Primary Completion (Actual): April 22, 2021
• Study Completion (Actual): April 22, 2021

Study Registration Dates

• First Submitted: February 17, 2015
• First Submitted That Met QC Criteria: March 23, 2015
• First Posted (Estimate): March 27, 2015

Study Record Updates

• Last Update Posted (Actual): May 6, 2022
• Last Update Submitted That Met QC Criteria: April 12, 2022
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Breast Cancer; Neratinib; Nerlynx; Loperamide; Budesonide; HER2 +; Colestipol
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Signs and Symptoms, Digestive; Breast Diseases; Breast Neoplasms; Diarrhea; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antimetabolites; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Hypolipidemic Agents; Lipid Regulating Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Sequestering Agents; Budesonide; Loperamide; Antidiarrheals; Colestipol
• Other Study ID Numbers: PUMA-NER-6201; 2015-004374-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Puma Biotechnology is committed to sharing clinical trial data and information to help physicians and patients make informed treatment decisions, and to help qualified researchers advance scientific knowledge.

In accordance with legal and regulatory requirements, Puma publishes study protocol information and clinical study results on clinical trial registries, including ClinicalTrials.gov and EU Clinical Trials Register. Puma also publishes information about clinical studies in peer-reviewed scientific journals and shares data in scientific meetings.

Puma commits to safeguarding confidentiality and patient privacy throughout the clinical trial data and information sharing process. Any patient-level data will be anonymized to protect personally identifiable information.

Qualified researchers and study participants may submit requests for other study documentation and clinical trial data to clinicaltrials@pumabiotechnology.com for consideration.

• IPD Sharing Time Frame: Clinical study documents and clinical trial data may be requested by qualified researchers and study participants for studies that have been completed for at least 18 months, and for which the indication of the drug has been approved in the US and/or EU, as applicable. Requests will be accepted for up to 24 months after the criteria described in this section are met.

IPD Sharing Access Criteria

Requestors must provide organizational contact information; a detailed research plan, including outcomes; timeline for completion of the research; qualifications of the research team; funding source; and potential conflicts of interest.

Puma will not provide access to patient-level data if there is a reasonable likelihood that individual patients could be identified, or in cases where confidentiality or consent provisions prohibit transfer of data or information to third parties. Additionally, Puma will not disclose information that jeopardizes intellectual property rights or divulges confidential commercial information.

• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No