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

Early-stage Breast Cancer Clinical Trial

— DIANER  

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"

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05252988
• Other study ID #: GEICAM/2018-06
• Secondary ID: 2019-001559-38
• Status: Recruiting
• Phase: Phase 2
• Start date: August 31, 2022
• Est. completion date: January 2030

Study information

• Verified date: December 2023
• Source: Spanish Breast Cancer Research Group
• Contact: Study Project Manager Study Project Manager
• Phone: +34916592870
• Email: inicio_ensayos[@]geicam.org
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 prophylaxis versus Neratinib plus Loperamide plus Colesevelam prophylaxis.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 315
• Est. completion date: January 2030
• Est. primary completion date: March 25, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ß-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.

Related Conditions & MeSH terms

• Breast Neoplasms
• Early-stage Breast Cancer
• HER2 Positive Breast Cancer
• Hormone Receptor Positive

Intervention

Drug:
• Neratinib
Neratinib orally once daily for 13 cycles, unless patient discontinues earlier.
• Loperamide
Loperamide orally.
• Colesevelam
Colesevelam capsules orally, 2 times a day for the first month (28 days).

Locations

Country	Name	City	State
Spain	Centro Oncologico de Galicia	A Coruña	Galicia
Spain	Complejo Hospitalario Universitario A Coruña	A Coruña
Spain	Compejo Hospitalario Universitario de Albacete	Albacete
Spain	Hospital Universitario Fundación Alcorcón	Alcorcón	Madrid
Spain	Hospital General Universitario Dr. Balmis	Alicante	Comunidad Valenciana
Spain	Hospital Universitario de Badajoz	Badajoz
Spain	Hospital Universitario Cruces	Baracaldo	Vizcaya
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitario Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitario Basurto	Bilbao
Spain	Hospital Universitario de Burgos	Burgos
Spain	Hospital Universitario San Pedro de Alcántara	Cáceres
Spain	Hospital Universitario Puerta del Mar	Cadiz	Cádiz
Spain	Consorcio Hospitalario Provincial de Castellón	Castellón De La Plana	Castellón
Spain	Hospital Clínico Universitario Virgen de la Arrixaca	El Palmar	Murcia
Spain	Hospital General Universitario de Elche	Elche	Alicante
Spain	Hospital Universitario de Fuenlabrada	Fuenlabrada	Madrid
Spain	Institut Català d'Oncología (ICO) Girona	Girona
Spain	Hospital Universitario Clínico San Cecilio	Granada
Spain	Hospital Universitario Virgen de las Nieves	Granada
Spain	Institut Català d'Oncología (ICO) L'Hospitalet	Hospitalet de Llobregat	Barcelona
Spain	Complejo Hospitalario de Jaén	Jaen
Spain	Hospital Universitario de Jerez de la Frontera	Jerez De La Frontera	Cádiz
Spain	Hospital Universitario Severo Ochoa	Leganés	Madrid
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario Fundación Jiménez Díaz	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda	Madrid
Spain	Hospital Costa del Sol	Málaga	Andalucía
Spain	Althaia Xarxa Asistencial de Manresa	Manresa	Barcelona
Spain	Hospital de Mataró	Mataró	Barcelona
Spain	Hospital Universitario de Móstoles	Móstoles	Madrid
Spain	Hospital Universitario Son Espases	Palma De Mallorca	Mallorca
Spain	Hospital Universitario Infanta Cristina	Parla	Madrid
Spain	Hospital Universitario San Joan de Reus	Reus	Tarragona
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Infanta Sofía	San Sebastián de los Reyes	Madrid
Spain	Hospital Universitario Nuestra Señora De Candelaria	Santa Cruz De Tenerife
Spain	Hospital Quirónsalud Sagrado Corazón	Sevilla
Spain	Hospital Universitario Virgen de la Macarena	Sevilla
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital Universitario de Toledo	Toledo
Spain	OSI Barrualde-Galdakao (Hospital Galdakao-Usansolo)	Usansolo	Vizcaya
Spain	Consorcio Hospital General Universitario de Valencia	Valencia
Spain	Fundación Instituto Valenciano de Oncología	Valencia
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital Universitario Arnau de Vilanova de Valencia	Valencia
Spain	Hospital Universitario y Politécnico La Fe	Valencia
Spain	Hospital Clínico Universitario de Valladolid	Valladolid	Castilla-León
Spain	Hospital Álvaro Cunqueiro	Vigo	Pontevedra
Spain	Hospital Clínico Universitario Lozano Blesa	Zaragoza	Aragón
Spain	Hospital Universitario Miguel Servet	Zaragoza

Sponsors (3)

Lead Sponsor	Collaborator
Spanish Breast Cancer Research Group	Pierre Fabre Laboratories, Puma Biotechnology, Inc.

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Minimal residual disease (MRD)	Correlation of biomarkers data with patient outcome and safety data These analysis will be performed in the biomarker population. Given a relapse rate of around 10%, we anticipate that approximately 150-200 patients would be sufficient to explore the prognostic value of the MRD assessed on circulating tumor DNA and the correlation of the molecular and clinical relapse.	Up to 13 months
Primary	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	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.	Up to 13 months
Secondary	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.	Up to 13 months
Secondary	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.	Up to 13 months
Secondary	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.	Up to 13 months
Secondary	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.	Up to 13 months
Secondary	Incidence of neratinib discontinuation (for any reason).	The proportion of patients who discontinued neratinib early (before 1 year of therapy).	Up to 13 months
Secondary	Time to neratinib discontinuation/neratinib treatment duration.	The time from the start of neratinib to the last dose of neratinib.	Up to 13 months
Secondary	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.	Up to 13 months
Secondary	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.	Up to 13 months
Secondary	Cumulative dose of neratinib.	The total dose of neratinib administered during the study.	Up to 13 months
Secondary	Neratinib dose intensity.	The cumulative dose of neratinib divided by the neratinib treatment duration.	Up to 13 months
Secondary	Neratinib relative dose intensity.	The dose intensity divided by 240 mg.	Up to 13 months
Secondary	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.	Up to 13 months
Secondary	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.	Up to 13 months
Secondary	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.	Up to 13 months

External Links

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