Early-stage Breast CancerPhase 2DIANERNCT05252988
Three Antidiarrheal Strategies in HER2+/HR+ Early Breast Cancer Patients Treated With Extended Adjuvant Neratinib
A Phase 2 study testing Neratinib, Loperamide and Colesevelam in people with Early-stage Breast Cancer and HER2 Positive Breast Cancer, run by Spanish Breast Cancer Research Group at 55 sites in Spain.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Early-stage Breast Cancer, HER2 Positive Breast Cancer, Hormone Receptor Positive
- What is being tested?
- Neratinib, Loperamide and Colesevelam
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 177 participants
- Where
- 55 sitesSpain
- Study dates
- 31 Aug 2022to Jan 2030
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
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- 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.
Who cannot join
- 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).
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- 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.
- Unable or unwilling to swallow tablets.
Trial locations and contacts
55 sites in 1 country.
55 sites in 1 country
Spain55 sites
Centro Oncologico de Galicia
A Coruña, Galicia, 15009
Complejo Hospitalario Universitario A Coruña
A Coruña, 15006
Compejo Hospitalario Universitario de Albacete
Albacete, 02006
Hospital Universitario Fundación Alcorcón
Alcorcón, Madrid, 28922
Hospital General Universitario Dr. Balmis
Alicante, Valencia, 03010
Hospital Universitario de Badajoz
Badajoz, 06080
Hospital Universitario Cruces
Barakaldo, Vizcaya, 48903
Hospital del Mar
Barcelona, 08003
Hospital Universitario Santa Creu i Sant Pau
Barcelona, 08025
Hospital Clinic de Barcelona
Barcelona, 08036
Hospital Universitario Basurto
Bilbao, 48013
Hospital Universitario de Burgos
Burgos, 09006
Hospital Universitario San Pedro de Alcántara
Cáceres, 10003
Hospital Universitario Puerta del Mar
Cadiz, Cádiz, 11009
Consorcio Hospitalario Provincial de Castellón
Castellon, Castellón, 12002
Hospital Clínico Universitario Virgen de la Arrixaca
El Palmar, Murcia, 30120
Hospital General Universitario de Elche
Elche, Alicante, 03203
Hospital Universitario de Fuenlabrada
Fuenlabrada, Madrid, 28942
Institut Català d'Oncología (ICO) Girona
Girona, 17007
Hospital Universitario Virgen de las Nieves
Granada, 18014
Hospital Universitario Clínico San Cecilio
Granada, 18016
Complejo Hospitalario de Jaén
Jaén, 23007
Hospital Universitario de Jerez de la Frontera
Jerez de la Frontera, Cádiz, 11407
Institut Català d'Oncología (ICO) L'Hospitalet
L'Hospitalet de Llobregat, Barcelona, 08908
Hospital Universitario Severo Ochoa
Leganés, Madrid, 28911
Hospital General Universitario Gregorio Marañón
Madrid, 28007
Hospital Universitario Ramón y Cajal
Madrid, 28034
Hospital Clínico San Carlos
Madrid, 28040
Hospital Universitario Fundación Jiménez Díaz
Madrid, 28040
Hospital Universitario La Paz
Madrid, 28046
Hospital Universitario Puerta de Hierro Majadahonda
Majadahonda, Madrid, 28222
Hospital Costa del Sol
Málaga, Andalusia, 29603
Althaia Xarxa Asistencial de Manresa
Manresa, Barcelona, 08243
Hospital de Mataró
Mataró, Barcelona, 08304
Hospital Universitario de Móstoles
Móstoles, Madrid, 28935
Hospital Universitario Son Espases
Palma de Mallorca, Mallorca, 07120
Hospital Universitario Infanta Cristina
Parla, Madrid, 28981
Hospital Universitario San Joan de Reus
Reus, Tarragona, 43204
Hospital Universitario de Salamanca
Salamanca, 37007
Hospital Universitario Infanta Sofía
San Sebastián de los Reyes, Madrid, 28702
Hospital Universitario Nuestra Señora De Candelaria
Santa Cruz de Tenerife, 38010
Hospital Universitario Virgen de la Macarena
Seville, 41009
Hospital Quirónsalud Sagrado Corazón
Seville, 41013
Hospital Universitario Virgen del Rocío
Seville, 41013
Hospital Universitario de Toledo
Toledo, 45007
OSI Barrualde-Galdakao (Hospital Galdakao-Usansolo)
Usansolo, Vizcaya, 48960
Fundación Instituto Valenciano de Oncología
Valencia, 46009
Hospital Clinico Universitario de Valencia
Valencia, 46010
Hospital Universitario Arnau de Vilanova de Valencia
Valencia, 46015
Consorcio Hospital General Universitario de Valencia
Valencia, 46018
Hospital Universitario y Politécnico La Fe
Valencia, 46026
Hospital Clínico Universitario de Valladolid
Valladolid, Castille and León, 47003
Hospital Álvaro Cunqueiro
Vigo, Pontevedra, 36213
Hospital Clínico Universitario Lozano Blesa
Zaragoza, Aragon, 50009
Hospital Universitario Miguel Servet
Zaragoza, 50009
About this study
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"
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.
Read the 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.
- Being tested
- Neratinib, Loperamide, Colesevelam
- Keywords
- Early-stage Breast Cancer, HER2 positive, Hormone Receptor positive, Neratinib, Loperamide prophylaxis, Colesevelam prophylaxis, Incidence of Discontinuations due to Diarrhoea
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NeratinibDrug
Also called Nerlynx
Neratinib orally once daily for 13 cycles, unless patient discontinues earlier.
LoperamideDrug
Also called Sindiar
Loperamide orally.
ColesevelamDrug
Also called Cholestagel
Colesevelam capsules orally, 2 times a day for the first month (28 days).
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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). Receives: 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. Receives: Drug: Neratinib; Drug: Loperamide; Drug: Colesevelam |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 3 months
Secondary outcomes (15)
Incidence of neratinib discontinuations due to any TEAE (treatment-emergent adverse event).
The proportion of patients who discontinue the treatment of neratinib at any time due to any TEAE. TEAE are undesirable events not present prior to medical treatment, or an already present event that worsens either in intensity or frequency following the treatment.
Measured: Up to 13 months
Time to neratinib discontinuations due to any TEAE (treatment-emergent adverse event).
The time from the start of neratinib therapy to the discontinuation due to any TEAE.
Measured: Up to 13 months
Incidence of diarrhoea of any grade/grade 3 or higher.
The proportion of patients with at least one TEAE of diarrhoea of any grade/grade 3 or higher coded and graded by the investigator according to the NCI-CTCAE version 5.0.
Measured: Up to 13 months
Cumulative duration of diarrhoea (Grade 2/3/4).
The time from the diagnosis of each of the different diarrhoea Grades 2 or 3 or 4 coded and graded by the investigator according to the NCI-CTCAE version 5.0 to the time of change to a different grade of this adverse event.
Measured: Up to 13 months
Time to first episode of diarrhoea.
The time from the start of neratinib therapy to the first episode of diarrhoea of any grade, whichever occurs first.
Measured: Up to 13 months
Incidence of neratinib discontinuation (for any reason).
The proportion of patients who discontinued neratinib early (before 1 year of therapy).
Measured: Up to 13 months
Time to neratinib discontinuation/neratinib treatment duration.
The time from the start of neratinib to the last dose of neratinib.
Measured: Up to 13 months
Incidence of hospitalisations due to any reason and diarrhoea.
The proportion of patients who have a hospitalisation during the treatment with neratinib or 30 days after the last dose.
Measured: Up to 13 months
Incidence of TEAEs and SAEs that include AESIs (ie, hepatic, cardiac, pulmonary, reproductive and developmental).
The proportion of patients in which those events are observed.
Measured: Up to 13 months
Cumulative dose of neratinib.
The total dose of neratinib administered during the study.
Measured: Up to 13 months
Neratinib dose intensity.
The cumulative dose of neratinib divided by the neratinib treatment duration.
Measured: Up to 13 months
Neratinib relative dose intensity.
The dose intensity divided by 240 mg.
Measured: Up to 13 months
Patient reported outcomes (PRO) of health related quality of life measured by FACT B.
PRO of health related quality of life will be assessed using the FACT-B questionnaire.
The FACT-B is a 36-item questionnaire composed of five multi-item functional subscales: physical well-being, social/family well-being, emotional well-being, functional well-being and a subscale related with the breast cancer and its treatment. The questionnaire employs 5 points Likert scales with responses from "not at all" to "very much". The total score is obtained from the sum of the score on each subscale.
Patients will complete a questionnaire at cycle 1 day 1 (before the first dose of neratinib and anti-diarrhoeal therapy), on day 1 of cycles 2, 3, 4, 7 and 10 and at the End of Treatment Visit.
Measured: Up to 13 months
Patient reported outcomes (PRO) of health related quality of life measured by EQ5D-5L
To be assessed using the EQ5D-5L questionnaire, a standardized instrument for measuring generic health status. It has 2 components:
- health state description: measured in terms of 5 dimensions; mobility (person's walking ability), self-care (ability to wash or dress by oneself), usual activities (work, study, housework, family or leisure activities), pain/discomfort (how much pain or discomfort they have), and anxiety/depression (how anxious or depressed they are). The number of levels of severity is 5; having no problems, slight problems, moderate problems, severe problems and being unable to do/extreme problems. The respondents self-rate their level of severity for each dimension.
- Evaluation: It also includes a visual analogue scale, EQ VAS, which records patient's self-rated health on a scale from 0 (worst imaginable) to 100 (best imaginable).
To be completed at day 1 of cycles 1, 2, 3, 4, 7 and 10 and at the End of Treatment Visit.
Measured: Up to 13 months
Patient reported outcomes (PRO) of health related quality of life measured by Systemic Therapy-Induced Diarrhea Assessment Test (STIDAT)
PRO of health related quality of life will be assessed using the STIDAT questionnaire.
The STIDAT is a questionnaire that was developed using the FDA iterative process for patient-reported outcomes in which patients define diarrhoea based on presence of watery stool. The STIDAT assess patient's perception of having diarrhoea, daily number of bowel movements, daily number of diarrhoea episodes, antidiarrheal medication use, the presence of urgency, abdominal pain, abdominal spasms or fecal incontinence, patient's perception of diarrhoea severity, and QoL.
Patients will complete the instrument at cycle 1 day 1 (before the first dose of neratinib and anti-diarrhoeal therapy), on day 1 of cycles 2, 3, 4, 7, 10 and at the End of Treatment Visit.
Measured: Up to 13 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Feb 2022
- Study start31 Aug 2022
- Primary completion28 Oct 2024
- Study completionJan 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Early-stage Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 177 participants (actual)
Sponsor and investigators
- Lead sponsor
- Spanish Breast Cancer Research Group
- Sponsor type
- University, hospital or other
- Collaborators
- Puma Biotechnology, Inc., Pierre Fabre Laboratories
- Responsible party
- Sponsor
- Investigators
- Study Director Study Director, Study director, Hospital General Universitario Gregorio MarañonStudy Director Study Director, Study director, Insititut Català d'Oncologia de L'Hospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05252988
- Sponsor's protocol ID
- GEICAM/2018-06
- Other IDs
- 2019-001559-38, 2019
- Acronym
- DIANER
- Status last verified
- Mar 2025
- First submitted
- 2 Feb 2022
- Last updated
- 1 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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"
- ClinicalTrials.gov ID
- NCT05252988
- Acronym / sponsor ID
- DIANER / GEICAM/2018-06
- Keywords
- Early-stage Breast Cancer, HER2 positive, Hormone Receptor positive, Neratinib, Loperamide prophylaxis, Colesevelam prophylaxis, Incidence of Discontinuations due to Diarrhoea
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 177 participants (actual)
- Lead sponsor
- Spanish Breast Cancer Research GroupUniversity, hospital or other
- Collaborators
- Puma Biotechnology, Inc., Pierre Fabre Laboratories
- Study start
- 31 Aug 2022 (actual)
- Primary completion
- 28 Oct 2024 (actual)
- Study completion
- Jan 2030 (estimated)
- First posted
- 23 Feb 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Arm A | Experimental | Drug: Neratinib, Drug: Loperamide1. 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). |
| Arm B | Experimental | Drug: Neratinib, Drug: Loperamide1. 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). |
| Arm C | Experimental | Drug: Neratinib, Drug: Loperamide, Drug: Colesevelam1. 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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.
Key exclusion criteria (16 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NeratinibAlso: NerlynxNeratinib orally once daily for 13 cycles, unless patient discontinues earlier. | Drug | Arm A, Arm B, Arm C |
| LoperamideAlso: SindiarLoperamide orally. | Drug | Arm A, Arm B, Arm C |
| ColesevelamAlso: CholestagelColesevelam capsules orally, 2 times a day for the first month (28 days). | Drug | Arm C |
Primary outcome
The incidence of neratinib discontinuations due to diarrhoea at the end of 3 cycles (1 cycle= 28 days) of neratinib treatment.
Time frame: Up to 3 months
The proportion of patients who discontinue the treatment with neratinib due to diarrhoea within this time period.
15 secondary outcomes
Incidence of neratinib discontinuations due to any TEAE (treatment-emergent adverse event).
Time frame: Up to 13 months
Time to neratinib discontinuations due to any TEAE (treatment-emergent adverse event).
Time frame: Up to 13 months
Incidence of diarrhoea of any grade/grade 3 or higher.
Time frame: Up to 13 months
Cumulative duration of diarrhoea (Grade 2/3/4).
Time frame: Up to 13 months
Time to first episode of diarrhoea.
Time frame: Up to 13 months
Incidence of neratinib discontinuation (for any reason).
Time frame: Up to 13 months
Time to neratinib discontinuation/neratinib treatment duration.
Time frame: Up to 13 months
Incidence of hospitalisations due to any reason and diarrhoea.
Time frame: Up to 13 months
Incidence of TEAEs and SAEs that include AESIs (ie, hepatic, cardiac, pulmonary, reproductive and developmental).
Time frame: Up to 13 months
Cumulative dose of neratinib.
Time frame: Up to 13 months
Neratinib dose intensity.
Time frame: Up to 13 months
Neratinib relative dose intensity.
Time frame: Up to 13 months
Patient reported outcomes (PRO) of health related quality of life measured by FACT B.
Time frame: Up to 13 months
Patient reported outcomes (PRO) of health related quality of life measured by EQ5D-5L
Time frame: Up to 13 months
Patient reported outcomes (PRO) of health related quality of life measured by Systemic Therapy-Induced Diarrhea Assessment Test (STIDAT)
Time frame: Up to 13 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Apr 2025.
- Spanish Breast Cancer Research Group (GEICAM) is a Spanish Breast Cancer Research GroupLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Study Director Study Director study director
Hospital General Universitario Gregorio Marañon
Study Director Study Director study director
Insititut Català d'Oncologia de L'Hospitalet
55 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Neratinib, Loperamide and Colesevelam in people with Early-stage Breast Cancer and HER2 Positive Breast Cancer, run by Spanish Breast Cancer Research Group at 55 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 1 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 55 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The incidence of neratinib discontinuations due to diarrhoea at the end of 3 cycles (1 cycle= 28 days) of neratinib treatment. (time frame: Up to 3 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Apr 2025.