Three Antidiarrheal Strategies in HER2+/HR+ Early Breast Cancer Patients Treated With Extended Adjuvant Neratinib

NCT05252988 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: GEICAM/2018-062019-001559-38
• Study Type: interventional
• Target: 177
• Locations: 1 country
• Sites: 55

Brief Summary

A Randomized Phase II Study to Evaluate the Incidence of Discontinuations due to Diarrhoea at 3 Cycles in patients with Early-stage HER2-positive (HER2+), Hormone Receptor-positive (HR+) Breast Cancer treated with Neratinib plus Loperamide prophylaxis versus Neratinib with Initial Dose Escalation plus PRN Loperamide prophylaxis versus Neratinib plus Loperamide plus Colesevelam prophylaxis.

Conditions

Early-stage Breast Cancer; HER2 Positive Breast Cancer; Hormone Receptor Positive

Keywords

Early-stage Breast Cancer; HER2 positive; Hormone Receptor positive; Neratinib; Loperamide prophylaxis; Colesevelam prophylaxis; Incidence of Discontinuations due to Diarrhoea

Outcome Measures

Primary Outcomes (1)

• The incidence of neratinib discontinuations due to diarrhoea at the end of 3 cycles (1 cycle= 28 days) of neratinib treatment.

  The proportion of patients who discontinue the treatment with neratinib due to diarrhoea within this time period.

  Up to 3 months

Secondary Outcomes (15)

• Incidence of neratinib discontinuations due to any TEAE (treatment-emergent adverse event).

  Up to 13 months

• Time to neratinib discontinuations due to any TEAE (treatment-emergent adverse event).

  Up to 13 months

• Incidence of diarrhoea of any grade/grade 3 or higher.

  Up to 13 months

• Cumulative duration of diarrhoea (Grade 2/3/4).

  Up to 13 months

• Time to first episode of diarrhoea.

  Up to 13 months

Other Outcomes (1)

• Minimal residual disease (MRD)

  Up to 13 months

Study Arms (3)

Arm A

EXPERIMENTAL

1. Neratinib 240 mg (six 40mg tablets) orally once daily for 13 cycles (C) (1 C = 28 days), unless patient discontinues earlier. 2. Mandatory loperamide 4 mg (2 tablets/capsules) orally, 3 times a day (total 12 mg a day) starting Day (D) 1 of neratinib and for the first 14 days. Then, 4 mg (2 tablets/capsules) orally, 2 times a day (total 8 mg a day) until the end of C2 (D56); thereafter, loperamide will be administered PRN (without exceeding 16 mg per day).

Drug: Neratinib; Drug: Loperamide

Arm B

EXPERIMENTAL

1. Neratinib 120 mg 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 for 13 cycles inclusive, until cycle 13 day 28 (unless patient discontinues earlier). 2. Loperamide to be administered PRN only (without exceeding 16 mg per day).

Drug: Neratinib; Drug: Loperamide

Arm C

EXPERIMENTAL

1. Neratinib 240 mg (six 40-mg tablets) orally once daily for 13 C, unless patient discontinues earlier. 2. Mandatory loperamide 4 mg (2 tablets/capsules) orally, 3 times a day (total 12 mg a day) for the first 14 days. After the first 14 days, 4 mg (2 tablets/capsules) orally, 2 times a day (total 8 mg a day) to complete a total of 28 days. 3. Mandatory colesevelam 1,875 mg (three 625-mg capsules orally), 2 times a day for the first month (28 days). After day 28, any prophylaxis or treatment for diarrhoea could be administered PRN, if loperamide not to exceed 16 mg per day.

Drug: Neratinib; Drug: Loperamide; Drug: Colesevelam

Interventions

Neratinib DRUG

Neratinib orally once daily for 13 cycles, unless patient discontinues earlier.

Also known as: Nerlynx

Arm A; Arm B; Arm C

Loperamide DRUG

Loperamide orally.

Also known as: Sindiar

Arm A; Arm B; Arm C

Colesevelam DRUG

Colesevelam capsules orally, 2 times a day for the first month (28 days).

Also known as: Cholestagel

Arm C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients are eligible to be enrolled in the study only if they meet all of the following criteria:
• Male or female patient ≥18 years of age at signing of informed consent.
• Histologically confirmed Stage I B through Stage III C primary adenocarcinoma of the breast.
• Documented HER2-positive disease based on local laboratory determination according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2018 criteria.
• Documented 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, ie, intrauterine device, bilateral tubal ligation, vasectomized 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 to use condom, and the female partner must agree and commit to use a highly effective method of contraception (ie, 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 (ie, to Grade 1 or baseline) from all clinically significant 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.

You may not qualify if:

• Patients will be excluded from the study if they meet any of the following 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.
• Corrected QT interval (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:
• Absolute neutrophil count (ANC) ≤1,000/μl (≤1.0 x 109/L), Platelet count ≤100,000/μl (≤100 x 109/L), Hemoglobin ≤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 clearance \<30 mL/min (as calculated by Cockcroft-Gault formula a or Modification of Diet in Renal Disease (MDRD) formula).
• 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 etiology 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.

Sponsors & Collaborators

• Spanish Breast Cancer Research Group: lead
• Puma Biotechnology, Inc.: collaborator
• Pierre Fabre Laboratories: collaborator

Study Sites (55)

Hospital General Universitario de Elche

Elche, Alicante, 03203, Spain

Location

Hospital Costa del Sol

Málaga, Andalusia, 29603, Spain

Location

Hospital Clínico Universitario Lozano Blesa

Zaragoza, Aragon, 50009, Spain

Location

Institut Català d'Oncología (ICO) L'Hospitalet

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

Location

Althaia Xarxa Asistencial de Manresa

Manresa, Barcelona, 08243, Spain

Location

Hospital de Mataró

Mataró, Barcelona, 08304, Spain

Location

Consorcio Hospitalario Provincial de Castellón

Castellon, Castellón, 12002, Spain

Location

Hospital Clínico Universitario de Valladolid

Valladolid, Castille and León, 47003, Spain

Location

Hospital Universitario Puerta del Mar

Cadiz, Cádiz, 11009, Spain

Location

Hospital Universitario de Jerez de la Frontera

Jerez de la Frontera, Cádiz, 11407, Spain

Location

Centro Oncologico de Galicia

A Coruña, Galicia, 15009, Spain

Location

Hospital Universitario Fundación Alcorcón

Alcorcón, Madrid, 28922, Spain

Location

Hospital Universitario de Fuenlabrada

Fuenlabrada, Madrid, 28942, Spain

Location

Hospital Universitario Severo Ochoa

Leganés, Madrid, 28911, Spain

Location

Hospital Universitario Puerta de Hierro Majadahonda

Majadahonda, Madrid, 28222, Spain

Location

Hospital Universitario de Móstoles

Móstoles, Madrid, 28935, Spain

Location

Hospital Universitario Infanta Cristina

Parla, Madrid, 28981, Spain

Location

Hospital Universitario Infanta Sofía

San Sebastián de los Reyes, Madrid, 28702, Spain

Location

Hospital Universitario Son Espases

Palma de Mallorca, Mallorca, 07120, Spain

Location

Hospital Clínico Universitario Virgen de la Arrixaca

El Palmar, Murcia, 30120, Spain

Location

Hospital Álvaro Cunqueiro

Vigo, Pontevedra, 36213, Spain

Location

Hospital Universitario San Joan de Reus

Reus, Tarragona, 43204, Spain

Location

Hospital General Universitario Dr. Balmis

Alicante, Valencia, 03010, Spain

Location

Hospital Universitario Cruces

Barakaldo, Vizcaya, 48903, Spain

Location

OSI Barrualde-Galdakao (Hospital Galdakao-Usansolo)

Usansolo, Vizcaya, 48960, Spain

Location

Complejo Hospitalario Universitario A Coruña

A Coruña, 15006, Spain

Location

Compejo Hospitalario Universitario de Albacete

Albacete, 02006, Spain

Location

Hospital Universitario de Badajoz

Badajoz, 06080, Spain

Location

Hospital del Mar

Barcelona, 08003, Spain

Location

Hospital Universitario Santa Creu i Sant Pau

Barcelona, 08025, Spain

Location

Hospital Clinic de Barcelona

Barcelona, 08036, Spain

Location

Hospital Universitario Basurto

Bilbao, 48013, Spain

Location

Hospital Universitario de Burgos

Burgos, 09006, Spain

Location

Hospital Universitario San Pedro de Alcántara

Cáceres, 10003, Spain

Location

Institut Català d'Oncología (ICO) Girona

Girona, 17007, Spain

Location

Hospital Universitario Virgen de las Nieves

Granada, 18014, Spain

Location

Hospital Universitario Clínico San Cecilio

Granada, 18016, Spain

Location

Complejo Hospitalario de Jaén

Jaén, 23007, Spain

Location

Hospital General Universitario Gregorio Marañón

Madrid, 28007, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Clínico San Carlos

Madrid, 28040, Spain

Location

Hospital Universitario Fundación Jiménez Díaz

Madrid, 28040, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Hospital Universitario Nuestra Señora De Candelaria

Santa Cruz de Tenerife, 38010, Spain

Location

Hospital Universitario Virgen de la Macarena

Seville, 41009, Spain

Location

Hospital Quirónsalud Sagrado Corazón

Seville, 41013, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

Hospital Universitario de Toledo

Toledo, 45007, Spain

Location

Fundación Instituto Valenciano de Oncología

Valencia, 46009, Spain

Location

Hospital Clinico Universitario de Valencia

Valencia, 46010, Spain

Location

Hospital Universitario Arnau de Vilanova de Valencia

Valencia, 46015, Spain

Location

Consorcio Hospital General Universitario de Valencia

Valencia, 46018, Spain

Location

Hospital Universitario y Politécnico La Fe

Valencia, 46026, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, 50009, Spain

Location

Related Links

• Spanish Breast Cancer Research Group (GEICAM) is a Spanish Breast Cancer Research Group

MeSH Terms

Conditions

Breast Neoplasms

Interventions

neratinib; Loperamide; Colesevelam Hydrochloride

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Allylamine; Amines; Organic Chemicals; Allyl Compounds; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons

Study Officials

• Study Director Study Director

  Hospital General Universitario Gregorio Marañón

  STUDY DIRECTOR

• Study Director Study Director

  Insititut Català d'Oncologia de L'Hospitalet

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 2, 2022
• First Posted: February 23, 2022
• Study Start: August 31, 2022
• Primary Completion: October 28, 2024
• Study Completion (Estimated): January 1, 2030
• Last Updated: April 1, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

ES (55)