A Study to Characterize Colon Pathology in Patients With HER2 Amplified Breast Cancer Treated With Neratinib

An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients With HER2 Amplified Breast Cancer Treated With Neratinib

This study will investigate colon pathology in patients with HER2-positive breast cancer treated with neratinib. Colonoscopy will be performed after eligibility has been confirmed, prior to administration of the first dose of neratinib, and after 28 days of neratinib treatment.

Study Overview

• Status: Completed
• Conditions: HER2 Amplified Breast Cancer
• Intervention / Treatment: Drug: Neratinib; Drug: Capecitabine; Drug: Loperamide

Detailed Description

This is an open-label, phase 2 study that will investigate colon pathology in patients with HER2-positive breast cancer treated with neratinib as monotherapy.

All patients will receive neratinib for the first 28 days as a single daily dose of 240 mg.

Colonoscopy will be performed after eligibility has been confirmed, but prior to administration of the first dose of neratinib and at Day 30 (± 3 days) the conclusion of Cycle 1 (28 days).

Following the second study colonoscopy procedure:

• For patients being treated for stage 1 to 3c breast cancer in the extended adjuvant setting, neratinib will continue to be administered at a single daily dose of 240 mg until completion of one year of therapy from start of treatment, or until disease recurrence (as determined by the Investigator), death, unacceptable toxicity, or other specified withdrawal criterion.
• For patients being treated for metastatic breast cancer (mBC), capecitabine will be introduced after the second study colonoscopy procedure at a dose of 750mg/m2 twice daily for 14 days of each 21 day treatment cycle, with neratinib administered continuously throughout at 240 mg daily, until disease progression, death, unacceptable toxicity, or other specified withdrawal criterion.

All patients will receive loperamide diarrhea prophylaxis daily for one 28-day cycle and then as needed.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• Portugal
  • Lisboa, Portugal, 1998-018
    • Hospital Cuf Descobertas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

INCLUSION CRITERIA

1. Aged ≥18 years.
2. Histologically confirmed stage 1 through stage 4 primary adenocarcinoma of the breast.
3. Documented HER2 overexpression or gene-amplified tumor by a validated approved method.
4. Participants with confirmed stage 1 to stage 3c breast cancer receiving extended adjuvant treatment with neratinib monotherapy must have completed a course of prior adjuvant trastuzumab or experienced side effects that resulted in early discontinuation of trastuzumab that have since resolved.
5. Participants with mBC must have had at least 2 prior HER2-directed regimens.
6. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
7. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1.
8. Negative β-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.]
9. Women of childbearing potential must agree and commit to the use of a highly effective non-hormonal method of contraception, i.e., intrauterine device, bilateral tubal ligation, vasectomized partner, or abstinence (only when it is the preferred lifestyle of the participant), from the time of informed consent until 28 days after the last dose of the investigational products. Men (male participant) with a female partner of childbearing potential must agree and commit to use condom and the female partner must agree and commit to use a highly effective method of contraception (i.e., any of the above methods, or for females, hormonal contraception associated with inhibition of ovulation) while on treatment and for 3 months after last dose of investigational products.
10. Recovery (i.e., to Grade 1 or baseline) from all clinically significant adverse events related to prior therapies (excluding alopecia, neuropathy, and nail changes).
11. No major bleeding diathesis or use of anticoagulants that would pose a high risk for endoscopic procedure.
12. Provide written, informed consent to participate in the study and follow the study procedures.

EXCLUSION CRITERIA:

1. Participants with confirmed stage 1 to stage 3c currently receiving chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer.
2. Participants with mBC who have received prior capecitabine or HER2 directed tyrosine kinase inhibitor (TKI) therapy.
3. Currently using drugs that have been implicated as causing microscopic colitis/watery diarrhea, such as acarbose, aspirin, proton pump inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), histamine H2 receptor antagonists, selective serotonin reuptake inhibitors, and ticlopidine (Pardi, 2017).
4. Major surgery within <28 days of starting treatment or received chemotherapy, investigational agents, or other cancer therapy, except hormonal therapy (e.g., tamoxifen, aromatase inhibitors), <14 days prior to the initiation of investigational products.
5. 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.
6. Corrected QT Interval (QTc) interval >0.450 seconds (males) or >0.470 (females), or known history of QTc prolongation or Torsade de Pointes (TdP).
7. Diagnosis of inflammatory bowel disease

8. Screening laboratory assessments outside the following limits:

   Laboratory Parameters Required Limit for Exclusion Absolute neutrophil count (ANC) <1,000/µl (<1.0 x 109/L) Platelet count <50,000/µl (<100 x 109/L) Hemoglobin <8 g/dL (transfusions allowed) Transfusions must be at least 14 days prior to initiation of treatment Total bilirubin >1.5 x institutional upper limit of normal (ULN) (in case of known Gilbert's syndrome, <2 x ULN is allowed) Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x institutional ULN (>5 x ULN if liver metastases are present) Creatinine Creatinine clearance <30 mL/min (as calculated by Cockcroft-Gault formula A or Modification of Diet in Renal Disease formula B) International Normalized Ratio (INR) >1.5 a Cockcroft and Gault, 1976 b Levey et al, 1999

9. Active, unresolved infections.
10. Participants with a second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Participants with other non-mammary malignancies must have been disease free for at least 5 years.
11. Currently pregnant or breast-feeding.
12. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, 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).
13. Clinically active infection with hepatitis B or hepatitis C virus.
14. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the Investigator's judgment, make the person inappropriate for this study.
15. Known hypersensitivity to any component of the investigational products; known allergies to any of the medications or components of medications used in the trial.
16. Unable or unwilling to swallow tablets

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Neratinib; Neratinib with loperamide prophylaxis, and capecitabine for participants treated for metastatic breast cancer	Drug: Neratinib; Administered orally once daily as a single daily dose of 240 mg; Other Names: Nerlynx; Drug: Capecitabine; Administered orally twice daily at 750 mg/m^2 for 14 days of each 21 day treatment cycle; Drug: Loperamide; Administered orally for prophylaxis for 28 days and then as needed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Colon Pathology	The primary endpoint is to describe the changes in colon pathology between the baseline colonoscopy and the second colonoscopy.	From baseline to second colonoscopy, which is 88 days after start of neratinib treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and Severity of Diarrhea	Incidence and severity of treatment emergent (TEAE) diarrhea will be summarized according to the NCI-CTCAE version 4.0 in the first cycle of neratinib treatment, which is from the time of the first colonoscopy to the second colonoscopy, or 28 days for subjects with only one colonoscopy. Incidence is defined as the number of patients experiencing diarrhea divided by the number of patients at risk.	From baseline to second colonoscopy, which is 88 days after start of neratinib treatment.

Collaborators and Investigators

• Sponsor: Puma Biotechnology, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 30, 2020
• Primary Completion (ACTUAL): December 28, 2021
• Study Completion (ACTUAL): December 28, 2021

Study Registration Dates

• First Submitted: March 23, 2020
• First Submitted That Met QC Criteria: April 24, 2020
• First Posted (ACTUAL): April 29, 2020

Study Record Updates

• Last Update Posted (ACTUAL): February 10, 2023
• Last Update Submitted That Met QC Criteria: January 13, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Breast Cancer; Colonoscopy; HER2-Positive; Colon Pathology
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Gastrointestinal Agents; Capecitabine; Loperamide; Antidiarrheals
• Other Study ID Numbers: PUMA-NER-6203; 2019-001896-35 (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; SAP; ICF; 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