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

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ClinicalTrials.gov Identifier: NCT05252988
Recruitment Status : Recruiting
First Posted : February 23, 2022
Last Update Posted : December 15, 2023
Sponsor:
Collaborators:
Puma Biotechnology, Inc.
Pierre Fabre Laboratories
Information provided by (Responsible Party):
Spanish Breast Cancer Research Group

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.

Condition or disease Intervention/treatment Phase
Early-stage Breast Cancer HER2 Positive Breast Cancer Hormone Receptor Positive Drug: Neratinib Drug: Loperamide Drug: Colesevelam Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 315 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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"
Actual Study Start Date : August 31, 2022
Estimated Primary Completion Date : March 25, 2025
Estimated Study Completion Date : January 2030

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A
  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
Neratinib orally once daily for 13 cycles, unless patient discontinues earlier.
Other Name: Nerlynx

Drug: Loperamide
Loperamide orally.
Other Name: Sindiar

Experimental: Arm B
  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
Neratinib orally once daily for 13 cycles, unless patient discontinues earlier.
Other Name: Nerlynx

Drug: Loperamide
Loperamide orally.
Other Name: Sindiar

Experimental: Arm C
  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
Neratinib orally once daily for 13 cycles, unless patient discontinues earlier.
Other Name: Nerlynx

Drug: Loperamide
Loperamide orally.
Other Name: Sindiar

Drug: Colesevelam
Colesevelam capsules orally, 2 times a day for the first month (28 days).
Other Name: Cholestagel




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Incidence of neratinib discontinuations due to any TEAE (treatment-emergent adverse event). [ Time Frame: Up to 13 months ]
    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.

  2. Time to neratinib discontinuations due to any TEAE (treatment-emergent adverse event). [ Time Frame: Up to 13 months ]
    The time from the start of neratinib therapy to the discontinuation due to any TEAE.

  3. Incidence of diarrhoea of any grade/grade 3 or higher. [ Time Frame: Up to 13 months ]
    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.

  4. Cumulative duration of diarrhoea (Grade 2/3/4). [ Time Frame: Up to 13 months ]
    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.

  5. Time to first episode of diarrhoea. [ Time Frame: Up to 13 months ]
    The time from the start of neratinib therapy to the first episode of diarrhoea of any grade, whichever occurs first.

  6. Incidence of neratinib discontinuation (for any reason). [ Time Frame: Up to 13 months ]
    The proportion of patients who discontinued neratinib early (before 1 year of therapy).

  7. Time to neratinib discontinuation/neratinib treatment duration. [ Time Frame: Up to 13 months ]
    The time from the start of neratinib to the last dose of neratinib.

  8. Incidence of hospitalisations due to any reason and diarrhoea. [ Time Frame: Up to 13 months ]
    The proportion of patients who have a hospitalisation during the treatment with neratinib or 30 days after the last dose.

  9. Incidence of TEAEs and SAEs that include AESIs (ie, hepatic, cardiac, pulmonary, reproductive and developmental). [ Time Frame: Up to 13 months ]
    The proportion of patients in which those events are observed.

  10. Cumulative dose of neratinib. [ Time Frame: Up to 13 months ]
    The total dose of neratinib administered during the study.

  11. Neratinib dose intensity. [ Time Frame: Up to 13 months ]
    The cumulative dose of neratinib divided by the neratinib treatment duration.

  12. Neratinib relative dose intensity. [ Time Frame: Up to 13 months ]
    The dose intensity divided by 240 mg.

  13. Patient reported outcomes (PRO) of health related quality of life measured by FACT B. [ Time Frame: Up to 13 months ]

    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.


  14. Patient reported outcomes (PRO) of health related quality of life measured by EQ5D-5L [ Time Frame: Up to 13 months ]

    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.


  15. 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 ]

    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.



Other Outcome Measures:
  1. Minimal residual disease (MRD) [ Time Frame: Up to 13 months ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05252988


Contacts
Layout table for location contacts
Contact: Study Project Manager Study Project Manager +34916592870 inicio_ensayos@geicam.org
Contact: Start-Up Unit Manager Start-Up Unit Manager +34916592870 inicio_ensayos@geicam.org

Locations
Show Show 55 study locations
Sponsors and Collaborators
Spanish Breast Cancer Research Group
Puma Biotechnology, Inc.
Pierre Fabre Laboratories
Investigators
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Study Director: Study Director Study Director Hospital General Universitario Gregorio Marañón
Study Director: Study Director Study Director Insititut Català d'Oncologia de L'Hospitalet
Additional Information:
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Responsible Party: Spanish Breast Cancer Research Group
ClinicalTrials.gov Identifier: NCT05252988    
Other Study ID Numbers: GEICAM/2018-06
2019-001559-38 ( EudraCT Number )
First Posted: February 23, 2022    Key Record Dates
Last Update Posted: December 15, 2023
Last Verified: December 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Spanish Breast Cancer Research Group:
Early-stage Breast Cancer
HER2 positive
Hormone Receptor positive
Neratinib
Loperamide prophylaxis
Colesevelam prophylaxis
Incidence of Discontinuations due to Diarrhoea
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Loperamide
Antidiarrheals
Colesevelam Hydrochloride
Neratinib
Tyrosine Kinase Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Agents
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents