Clinical trial NCT05252988: Three Antidiarrheal Strategies in HER2+/HR+ Early Breast Cancer Patients Treated With Extended Adjuvant Neratinib
Official title: 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 "DIANER Study"
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
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
Lead sponsor: Spanish Breast Cancer Research Group
Sponsor class: OTHER
Collaborators: name: Puma Biotechnology, Inc.
name: Pierre Fabre Laboratories
First posted: 2022-02-23
Enrollment: 177
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Detailed description: This is an international, multicenter, prospective, controlled, randomized, adaptative, phase II study to evaluate the incidence of discontinuations due to diarrhoea within the first 3 cycles in patients with early-stage HER2+ and HR+ breast cancer treated with neratinib plus loperamide prophylaxis for the first 2 cycles versus neratinib with initial 2-week dose escalation plus PRN loperamide versus neratinib and loperamide plus colesevelam prophylaxis for 28 days.

After the preplanned therapy, prophylaxis or treatment for diarrhoea will be given as clinically indicated following the standard of care by the treating physician.

Approximately 315 patients will be enrolled in the study.

All enrolled patients will receive neratinib orally once daily for 13 cycles, continuously. Eligible patients will be randomly assigned in a 1:1:1 ratio to one of the diarrhoea prophylaxis arms, using an interactive response technology (IRT) module within the electronic data capture (EDC) system. Patients will be stratified according to menopausal status (premenopausal versus postmenopausal) and prior anti-HER2 therapy (trastuzumab only versus trastuzumab plus pertuzumab).

Baseline assessments will be performed prior to C1D1 dosing. During the first 3 cycles of treatment, safety data will be collected during the cycle visits. After the first 3 cycles, all patients will enter in a follow-up period to complete approximately 1 year of neratinib treatment. During this follow-up period, safety data will be collected every 3 months. An End-of-Treatment (EOT) Visit is planned on cycle 13 day 28 for all treatment arms (unless patient discontinues earlier), followed by a Safety Follow-up Visit (30 +/-5 days after the last dose of neratinib). This will be the core phase of the study.

After this safety follow-up visit, long term outcome data will be collected for 5 years to address the exploratory objectives. This will be the extended phase of the study. Archived primary tumor tissue (at baseline) and whole blood samples (at baseline, during the treatment and follow-up period, and at disease relapse) will be collected for the exploratory analyses.

Patients are anticipated to participate in the core phase of the study for approximately 1 year to address primary and secondary objectives (28 days for screening, approximately 12 months to complete neratinib treatment, and 30 days for a safety follow-up visit after the last dose of neratinib). Later on patients will continue in the extended phase of the study and will be followed-up for at least 5 years to collect long term outcome data to conduct the exploratory analyses. The approximate duration of the full study is 8 years.

The objectives of the study are indicated below:

Primary objectives:

To evaluate the incidence of neratinib discontinuations due to diarrhoea within the first 3 cycles (1 cycle = 28 days) in patients with early-stage HER2 overexpressed/amplified (HER2+), hormone receptor-positive (HR+) breast cancer who have completed adjuvant trastuzumab-based therapy.

Primary End-point:

Incidence of neratinib discontinuations due to diarrhoea at the end of 3 cycles of neratinib treatment.

Secondary Objectives:

* 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, ie, 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.

Secondary End-points:

* Incidence and time to neratinib discontinuations due to any TEAE.
* Incidence, cumulative duration and time to first episode of any diarrhoea and grade 3 or higher diarrhoea.
* Incidence and time to neratinib discontinuation due to any reason.
* Incidence of hospitalisations due to any reason and diarrhoea.
* Incidence of TEAEs and SAEs that included AESIs (i.e. hepatic, cardiac, pulmonary, reproductive and developmental).
* Incidence of Neratinib dose modifications (reductions and dose holds), and dose intensity.
* Systemic therapy-induced diarrhea Assessment Tool (STIDAT), Functional Assessment of Cancer Therapy Questionnaire for Breast Cancer (FACT B) and EuroQol 5 Dimensions 5 Levels (EQ5D-5L) questionnaires.

Exploratory Objectives:

Evaluate minimal residual disease (MRD) and molecular alterations associated with patient outcome, and/or the development of diarrhoea with neratinib.

Exploratory End-points:

Correlation of biomarkers data with patient outcome and safety data.

Eligibility criteria: Inclusion Criteria:

Patients are eligible to be enrolled in the study only if they meet all of the following criteria:

1. Male or female patient ≥18 years of age at signing of informed consent.
2. Histologically confirmed Stage I B through Stage III C primary adenocarcinoma of the breast.
3. Documented HER2-positive disease based on local laboratory determination according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2018 criteria.
4. Documented HR+ disease, defined as oestrogen receptor (ER) and/or progesterone receptor (PR) ≥1% based on local laboratory determination.
5. 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).
6. 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.
7. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
8. Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
9. 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. \[Women are considered postmenopausal if they are ≥ 12 months without menses, in the absence of endocrine or anti-endocrine therapies\].
10. 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.
11. Recovery (ie, to Grade 1 or baseline) from all clinically significant AEs related to prior therapies (excluding alopecia, neuropathy, and nail changes).
12. Provide written, informed consent to participate in the study and follow the study procedures.

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

1. Clinical or radiologic evidence of local or regional recurrence of disease or metastatic disease prior to or at the time of study entry.
2. Currently receiving chemotherapy, radiation therapy, immunotherapy, or biological therapy for breast cancer (adjuvant endocrine therapy is allowed).
3. 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.
4. 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.
5. Corrected QT interval (QTc) interval \>0.450 seconds (males) or \>0.470 (females), or known history of QTc prolongation or Torsade de Pointes (TdP).
6. 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).
7. Active, unresolved infections.
8. 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.
9. Currently pregnant or breast-feeding.
10. 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.
11. Clinically active infection with hepatitis B or hepatitis C virus.
12. 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.
13. Known hypersensitivity to any component of the investigational products; known allergies to any of the medications or components of medications used in the trial.
14. Unable or unwilling to swallow tablets.

Primary outcomes:
measure: The incidence of neratinib discontinuations due to diarrhoea at the end of 3 cycles (1 cycle= 28 days) of neratinib treatment.
timeFrame: Up to 3 months
Secondary outcomes:
measure: Incidence of neratinib discontinuations due to any TEAE (treatment-emergent adverse event).
timeFrame: Up to 13 months
measure: Time to neratinib discontinuations due to any TEAE (treatment-emergent adverse event).
timeFrame: Up to 13 months
measure: Incidence of diarrhoea of any grade/grade 3 or higher.
timeFrame: Up to 13 months
measure: Cumulative duration of diarrhoea (Grade 2/3/4).
timeFrame: Up to 13 months
measure: Time to first episode of diarrhoea.
timeFrame: Up to 13 months
measure: Incidence of neratinib discontinuation (for any reason).
timeFrame: Up to 13 months
measure: Time to neratinib discontinuation/neratinib treatment duration.
timeFrame: Up to 13 months
measure: Incidence of hospitalisations due to any reason and diarrhoea.
timeFrame: Up to 13 months
measure: Incidence of TEAEs and SAEs that include AESIs (ie, hepatic, cardiac, pulmonary, reproductive and developmental).
timeFrame: Up to 13 months
measure: Cumulative dose of neratinib.
timeFrame: Up to 13 months
measure: Neratinib dose intensity.
timeFrame: Up to 13 months
measure: Neratinib relative dose intensity.
timeFrame: Up to 13 months
measure: Patient reported outcomes (PRO) of health related quality of life measured by FACT B.
timeFrame: Up to 13 months
measure: Patient reported outcomes (PRO) of health related quality of life measured by EQ5D-5L
timeFrame: Up to 13 months
measure: Patient reported outcomes (PRO) of health related quality of life measured by Systemic Therapy-Induced Diarrhea Assessment Test (STIDAT)
timeFrame: Up to 13 months
Other outcomes:
measure: Minimal residual disease (MRD)
timeFrame: Up to 13 months
Locations:
city: Elche
country: Spain
facility: Hospital General Universitario de Elche
state: Alicante
city: Málaga
country: Spain
facility: Hospital Costa del Sol
state: Andalucía
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario Lozano Blesa
state: Aragón
city: Hospitalet de Llobregat
country: Spain
facility: Institut Català d'Oncología (ICO) L'Hospitalet
state: Barcelona
city: Manresa
country: Spain
facility: Althaia Xarxa Asistencial de Manresa
state: Barcelona
city: Mataró
country: Spain
facility: Hospital de Mataró
state: Barcelona
city: Castellón De La Plana
country: Spain
facility: Consorcio Hospitalario Provincial de Castellón
state: Castellón
city: Valladolid
country: Spain
facility: Hospital Clínico Universitario de Valladolid
state: Castilla-León
city: Alicante
country: Spain
facility: Hospital General Universitario Dr. Balmis
state: Comunidad Valenciana
city: Cadiz
country: Spain
facility: Hospital Universitario Puerta del Mar
state: Cádiz
city: Jerez De La Frontera
country: Spain
facility: Hospital Universitario de Jerez de la Frontera
state: Cádiz
city: A Coruña
country: Spain
facility: Centro Oncologico de Galicia
state: Galicia
city: Alcorcón
country: Spain
facility: Hospital Universitario Fundación Alcorcón
state: Madrid
city: Fuenlabrada
country: Spain
facility: Hospital Universitario de Fuenlabrada
state: Madrid
city: Leganés
country: Spain
facility: Hospital Universitario Severo Ochoa
state: Madrid
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
state: Madrid
city: Móstoles
country: Spain
facility: Hospital Universitario de Móstoles
state: Madrid
city: Parla
country: Spain
facility: Hospital Universitario Infanta Cristina
state: Madrid
city: San Sebastián de los Reyes
country: Spain
facility: Hospital Universitario Infanta Sofía
state: Madrid
city: Palma De Mallorca
country: Spain
facility: Hospital Universitario Son Espases
state: Mallorca
city: El Palmar
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
state: Murcia
city: Vigo
country: Spain
facility: Hospital Álvaro Cunqueiro
state: Pontevedra
city: Reus
country: Spain
facility: Hospital Universitario San Joan de Reus
state: Tarragona
city: Baracaldo
country: Spain
facility: Hospital Universitario Cruces
state: Vizcaya
city: Usansolo
country: Spain
facility: OSI Barrualde-Galdakao (Hospital Galdakao-Usansolo)
state: Vizcaya
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
city: Albacete
country: Spain
facility: Compejo Hospitalario Universitario de Albacete
city: Badajoz
country: Spain
facility: Hospital Universitario de Badajoz
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitario Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Bilbao
country: Spain
facility: Hospital Universitario Basurto
city: Burgos
country: Spain
facility: Hospital Universitario de Burgos
city: Cáceres
country: Spain
facility: Hospital Universitario San Pedro de Alcántara
city: Girona
country: Spain
facility: Institut Català d'Oncología (ICO) Girona
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: Granada
country: Spain
facility: Hospital Universitario Clínico San Cecilio
city: Jaen
country: Spain
facility: Complejo Hospitalario de Jaén
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Santa Cruz De Tenerife
country: Spain
facility: Hospital Universitario Nuestra Señora De Candelaria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de la Macarena
city: Sevilla
country: Spain
facility: Hospital Quirónsalud Sagrado Corazón
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Toledo
country: Spain
facility: Hospital Universitario de Toledo
city: Valencia
country: Spain
facility: Fundación Instituto Valenciano de Oncología
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitario Arnau de Vilanova de Valencia
city: Valencia
country: Spain
facility: Consorcio Hospital General Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Hospital General Universitario Gregorio Marañón
name: Study Director Study Director
role: STUDY_DIRECTOR
affiliation: Insititut Català d'Oncologia de L'Hospitalet
name: Study Director Study Director
role: STUDY_DIRECTOR
References: