Phase II study to evaluate diarrhoea discontinuations at 3 cycles in patients with early-stage HER2 positive, hormone receptor positive breast cancer treated with neratinib plus loperamide versus neratinib dose escalation plus loperamide administered as needed versus neratinib plus loperamide plus colesevelam.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Grupo Espanol De Investigacion En Cancer De Mama

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Aug 2022 → ongoing

Decision date (initial)

2024-12-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

PUMA BIOTECHNOLOGY, INC

External identifiers

EU CT number

2024-514630-21-00

EudraCT number

2019-001559-38

ClinicalTrials.gov

NCT05252988

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety

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

Secondary objectives 7

1. Incidence and time of neratinib discontinuations due to any treatment-emergent adverse event (TEAE).
2. Diarrhoea due to neratinib: incidence, duration, severity, and treatment interventions.
3. Incidence of neratinib discontinuation due to any reason.
4. Incidence of hospitalisations (overall and for diarrhoea).
5. Incidence of TEAEs and serious adverse events (SAEs) and adverse events of special interest (AESIs, i.e. hepatic, cardiac, pulmonary, reproductive and developmental).
6. Neratinib exposure assessment.
7. Determine the effect of study treatment on quality of life, as measured by patient reported outcomes, in all treatment arms.

Conditions and MedDRA coding

HER2 positive (HER2+), Hormone Receptor positive (HR+) Early-stage Breast Cancer.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Male or female patient ≥18 years of age at signing of informed consent.
2. Histologically confirmed Stage IB through Stage IIIC primary adenocarcinoma of the breast according to the 8th edition of the TNM Classification of Breast Cancer, by the UICC (Union for International Cancer Control). (Clarification note: in patients with surgery as their first treatment approach, the pathological stage will be used; in patients receiving neoadjuvant therapy, the higher staging will be used).
3. Documented HER2-positive disease based on local laboratory determination according to ASCO/CAP 2018 criteria.
4. Documented hormone receptor-positive (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, i.e., intrauterine device, bilateral tubal ligation, vasectomized male 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 with his female partner to use a highly effective method of contraception (i.e., 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 (i.e., to Grade 1 or baseline) from all clinically significant adverse events (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 14

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. 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: Laboratory Parameters/ Required Limit for Exclusion. Absolute neutrophil count (ANC): < or =1,000/µl (< or =1.0 x 109/L). Platelet count: < or =100,000/µl (< or =100 x 109/L). Hemoglobin: < or =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: Creatinine clearance <30 mL/min (as calculated by Cockcroft-Gault formulaa or Modification of Diet in Renal Disease [MDRD] formulab). a: Cockcroft and Gault, 1976. b: Levey et al, 1999
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 aetiology 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 7

1. Incidence and time to neratinib discontinuations due to any TEAE.
2. Incidence, cumulative duration and time to first episode of any diarrhoea and grade 3 or higher diarrhoea.
3. Incidence and time to neratinib discontinuation due to any reason.
4. Incidence of hospitalisations due to any reason and diarrhoea.
5. Incidence of TEAEs and SAEs that included AESIs (i.e. hepatic, cardiac, pulmonary, reproductive and developmental).
6. Incidence of Neratinib dose modifications (reductions and dose holds), and dose intensity.
7. FACT B and EQ5D-5L questionnaires.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Grupo Espanol De Investigacion En Cancer De Mama

Sponsor organisation

Fundacion Grupo Espanol De Investigacion En Cancer De Mama

Address

Avenida De Los Pirineos 7 Oficina 1-14, Industrial Zona Sur Industrial Zona Sur

City

San Sebastian De Los Reyes

Postcode

28703

Country

Spain

Scientific contact point

Organisation

Fundacion Grupo Espanol De Investigacion En Cancer De Mama

Contact name

Clinical Operations Department

Public contact point

Organisation

Fundacion Grupo Espanol De Investigacion En Cancer De Mama

Contact name

Clinical Operations Department

Third parties 2

Locations

4 EU/EEA countries · 66 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications