Evaluation of Diarrhea-Related Discontinuations in Early-Stage HER2+/HR+ Breast Cancer with Neratinib, Loperamide, and Colesevelam Prophylaxis

Trial ID: 2024-514630-21-00
Protocol: GEICAM/2018-06
Sponsor: Fundacion Grupo Espanol De Investigacion En Cancer De Mama

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Diseases & Conditions

Hormone receptor positive breast cancer HER2 positive breast cancer

Objectives

The primary objective of this study is to evaluate the **incidence** of neratinib discontinuations due to **diarrhoea** within the first three cycles (1 cycle = 28 days) in patients with early-stage HER2-positive (HER2+), hormone receptor-positive (HR+) breast cancer who have completed neoadjuvant/adjuvant trastuzumab-based therapy. This is clinically relevant as it aims to assess the tolerability of neratinib, a critical factor in ensuring adherence to treatment regimens and optimizing therapeutic outcomes in this patient population.

Secondary objectives include:

Incidence and time of neratinib discontinuations due to any treatment-emergent adverse event (TEAE).
Diarrhoea due to neratinib: incidence, duration, severity, and treatment interventions.
Incidence of neratinib discontinuation due to any reason.
Incidence of hospitalisations (overall and for diarrhoea).
Incidence of TEAEs and serious adverse events (SAEs) and adverse events of special interest (AESIs, i.e., hepatic, cardiac, pulmonary, reproductive, and developmental).
Neratinib exposure assessment.
Determine the effect of study treatment on quality of life, as measured by patient-reported outcomes, in all treatment arms.

Participants

The clinical trial involves participants diagnosed with **HER2 positive (HER2+), Hormone Receptor positive (HR+) Early-stage Breast Cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have completed prior neoadjuvant or adjuvant trastuzumab-based therapy. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants must have a left ventricular ejection fraction of at least 50% and an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1. Lifestyle considerations include the use of highly effective contraception methods for both male and female participants of childbearing potential. The trial population was selected based on specific inclusion criteria, such as histologically confirmed Stage IB through Stage IIIC primary adenocarcinoma of the breast and documented HER2-positive and hormone receptor-positive disease. The trial does not focus on any specific dietary or physical activity requirements.

Plans and Procedures

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the incidence of discontinuations due to diarrhea in patients with early-stage **HER2-positive**, hormone receptor-positive breast cancer. The trial involves the administration of **neratinib** in combination with **loperamide** prophylaxis, with variations in dosing and additional prophylactic measures. The study aims to assess the primary endpoint of neratinib discontinuations due to diarrhea over three cycles, each cycle lasting 28 days. Secondary endpoints include the incidence and time to discontinuations due to any treatment-emergent adverse event (TEAE), the incidence of hospitalizations, and the incidence of dose modifications.

Participants will be involved in the trial for a maximum treatment period of 12 months. The trial includes a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, completion of prior trastuzumab-based therapy, and left ventricular ejection fraction. Follow-up visits will occur regularly to monitor the incidence of diarrhea, adverse events, and overall health status. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment.

Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The trial is estimated to conclude by November 2030, with recruitment having commenced in January 2022. The study is conducted under strict adherence to ethical guidelines, ensuring the safety and well-being of all participants throughout the trial duration.

Treatment

The clinical trial involves the administration of **NERATINIB**, an experimental medication, in the form of a film-coated tablet. The active substance, neratinib, is administered orally. The maximum daily dose is 240 mg, with a total maximum dose of 2880 mg over the treatment period. The treatment duration is set for a maximum of 12 cycles, with each cycle lasting 28 days. The medication used in the trial is identical to the commercial version, except for the number of tablets included in the bottle, which is 210 compared to the standard 180. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

In addition to neratinib, the trial includes the administration of **LOPERAMIDE HYDROCHLORIDE** as a non-experimental treatment. This medication is provided in the form of hard capsules, marketed under the name Sindiar 2 mg capsules. Loperamide hydrochloride is also administered orally, with a maximum daily dose of 16 mg and a total maximum dose of 192 mg over the treatment period. The medication is relabeled specifically for the clinical trial. The use of loperamide hydrochloride is intended as a prophylactic measure to manage potential side effects associated with neratinib, particularly diarrhea. Compliance with the administration of loperamide is similarly monitored to ensure proper prophylactic coverage throughout the trial duration.

Efficacy

The efficacy of the clinical trial will be assessed primarily by evaluating the **incidence of neratinib discontinuations due to diarrhoea** at the end of three cycles of treatment. This primary endpoint will provide insight into the tolerability of the treatment regimen in patients with early-stage HER2-positive, hormone receptor-positive breast cancer. Secondary endpoints include the incidence and time to neratinib discontinuations due to any treatment-emergent adverse event (TEAE), the incidence, cumulative duration, and time to the first episode of any diarrhoea and grade 3 or higher diarrhoea, and the incidence and time to neratinib discontinuation due to any reason. Additionally, the incidence of hospitalisations due to any reason and diarrhoea, the incidence of TEAEs and serious adverse events (SAEs) including adverse events of special interest (AESIs) such as hepatic, cardiac, pulmonary, reproductive, and developmental events, and the incidence of neratinib dose modifications and dose intensity will be evaluated. Patient-reported outcomes will be assessed using the FACT B and EQ5D-5L questionnaires.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female patient ≥18 years of age at signing of informed consent.
Histologically confirmed Stage IB through Stage IIIC primary adenocarcinoma of the breast according to the 8th edition of the TNM Classification of Breast Cancer, by the UICC (Union for International Cancer Control). (Clarification note: in patients with surgery as their first treatment approach, the pathological stage will be used; in patients receiving neoadjuvant therapy, the higher staging will be used).
Documented HER2-positive disease based on local laboratory determination according to ASCO/CAP 2018 criteria.
Documented hormone receptor-positive (HR+) disease, defined as oestrogen receptor (ER) and/or progesterone receptor (PR) ≥1% based on local laboratory determination.
Patients must have completed prior neoadjuvant/adjuvant trastuzumab-based therapy (eg, trastuzumab-based treatments including trastuzumab-emtansine [T-DM1]) or experienced side effects that resulted in early discontinuation of trastuzumab-based therapy that have since resolved (pertuzumab therapy is accepted but not mandatory).
The last dose of trastuzumab-based therapy must have been given to the patient >2 weeks and ≤1 year (365 days) before first dose of neratinib.
Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
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].
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 male partner, or abstinence (only when it is the preferred lifestyle of the patient), from the time of informed consent until 30 days after the last dose of the medicinal products. Male patient with female partner of childbearing potential must agree and commit with his female partner 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 medicinal products.
Recovery (i.e., to Grade 1 or baseline) from all clinically significant adverse events (AEs) related to prior therapies (excluding alopecia, neuropathy, and nail changes).
Provide written, informed consent to participate in the study and follow the study procedures.

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Exclusion Criteria

Clinical or radiologic evidence of local or regional recurrence of disease or metastatic disease prior to or at the time of study entry.
Currently receiving chemotherapy, radiation therapy, immunotherapy, or biological therapy for breast cancer (adjuvant endocrine therapy is allowed).
Major 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.
Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrolment, or ventricular arrhythmia.
QTc interval >0.450 seconds (males) or >0.470 (females) or known history of QTc prolongation or Torsade de Pointes (TdP).
Screening laboratory assessments outside the following limits: Laboratory Parameters/ Required Limit for Exclusion. Absolute neutrophil count (ANC): < or =1,000/µl (< or =1.0 x 109/L). Platelet count: < or =100,000/µl (< or =100 x 109/L). Hemoglobin: < or =9 g/dL. 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. Creatinine: Creatinine clearance <30 mL/min (as calculated by Cockcroft-Gault formulaa or Modification of Diet in Renal Disease [MDRD] formulab). a: Cockcroft and Gault, 1976. b: Levey et al, 1999
Active, unresolved infections.
Patients with a second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Patients with other non-mammary malignancies must have been disease free for at least 5 years.
Currently pregnant or breast-feeding.
Significant chronic gastrointestinal disorder with diarrhoea as a major symptom (eg, Crohn’s disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 5.0 [CTCAE v.5.0] diarrhoea of any aetiology at baseline); or gastroparesis, dysphagia, or swallowing disorder.
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; known allergies to any of the medications or components of medications used in the trial.
Unable or unwilling to swallow tablets.