Neratinib Dose Escalation Regimen for HER2 Positive Early Breast Cancer

Study Overview
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Brief Summary
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This is a prospective study on the prevention of Neratinib-related diarrhea in a Chinese population, exploring the best options for reducing the incidence of neratinib-related diarrhea through either pharmacologic intervention (prophylactic antidiarrheal therapy) or non-pharmacologic intervention (dose escalation program).

Detailed Description
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This is A prospective, randomized, single-center clinical trial, divided into 3 groups (experimental group: group A and group B, control group: group C), planned sixty patients were enrolled, with 20 patients in each group. Experimental group: Group A (n=20) and group B (n=20) were given neratinib dose escalation regimen foranti-HER2 adjuvant therapy.In group A, the dose of neratinib climbed up to 240mg within 2 weeks, and in group B, the dose climbed up to 240mg within 4 weeks. Control group: Group C (n=20) was given 240mg neratinib initially, but prophylactic loperamide antidiarrhea treatment was given at the same time within 2 months. Diarrhea caused by neratinib often occurred within 1-2 months of initial treatment, so small dose of neratinib was used in both group A and group B at the time of initial treatment. The incidence and severity of neratinib-related diarrhea in the three groups were observed, and DFS and other neratinib-related adverse events were followed up for a long time. The study is to evaluate the safety and efficacy of neratinib dose escalation regimen and conventional dose combined with loperamide regimen in enhanced anti-HER2 adjuvant therapy for early HER2-positive breast cancer.

Official Title
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Neratinib Dose Escalation Regimen for HER2 Positive Early Breast Cancer

Conditions
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HER2-positive Breast Cancer

Intervention / Treatment
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* Drug: Neratinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 75 year-old women； ECOG score: 0-1； HER2 positive breast cancer diagnosed histologically is defined as HER2 (3+) by immunohistochemistry or HER2 (2+) with positive FISH test； Postoperative pathological stage ⅱ → ⅲ, or initial stage (before neoadjuvant therapy) ⅱ → ⅲ, radiographic assessment showed no metastasis; Complete 1 year of anti-HER2 therapy with trastuzumab, prior use of pertuzumab neoadjuvant + adjuvant therapy or T-DM1 adjuvant therapy is permitted; No major organ dysfunction, contraception; The patients have good compliance to the therapy and follow-up to be scheduled and are able to understand the study protocol and sign the Informed Consent Form. Exclusion Criteria: Patients who are allergic to the study drug, cannot take the drug orally, or refuse the medication regimen; Prior treatment with TKI anti-HER-2 drugs (e.g. Lapatinib, Pyrotinib, etc.); Patients were enrolled in other studies or stopped taking other drugs within 4 weeks; Patients with serious dysfunction of important organs (heart, liver and kidney); Patients with other malignancies, other than cured non-melanoma skin cancer, carcinoma in situ of the cervix and other tumors that have been cured for at least 5 years; In pregnancy, lactation patients; In the active stage of other acute or chronic infectious diseases; The patients have uncontrollable mental illness; There is a known history of human immunodeficiency virus; There are other circumstances in which the investigator suggested that the patient should not participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neratinib escalation 2 weeks（group A）<br>Neratinib: 120mg/ day for days 1-7, 160mg/ day for days 8-14, and then 240mg/ day to complete 1-year treatment, or to tumor recurrence and metastasis, new breast cancer, or unacceptable adverse reactions within 1 year. | Drug: Neratinib<br>* Patients with her2-positive early breast cancer were treated with a dose escalation regimen of neratinib or a routine dose of neratinib combined with loperamide<br>* Other names: Loperamide prophylaxis;|
| Experimental: Neratinib escalation 4 weeks（group B）<br>Neratinib: 160mg/ day for days 1-14, 200mg/ day for days 15-28, and then 240mg/ day for 1 year, or to tumor recurrence and metastasis, new breast cancer, or unacceptable adverse reactions within 1 year. | Drug: Neratinib<br>* Patients with her2-positive early breast cancer were treated with a dose escalation regimen of neratinib or a routine dose of neratinib combined with loperamide<br>* Other names: Loperamide prophylaxis;|
| Placebo Comparator: Neratinib standard dose control （group C）<br>Neratinib: 240mg/ day for 1 year, or to tumor recurrence and metastasis, new breast cancer or unacceptable adverse reactions within 1 year. Loperamide prophylaxis: 4mg three times daily on days 1-14 and 4mg twice daily on days 15-56, followed by as needed, not exceeding 16mg/ day. | Drug: Neratinib<br>* Patients with her2-positive early breast cancer were treated with a dose escalation regimen of neratinib or a routine dose of neratinib combined with loperamide<br>* Other names: Loperamide prophylaxis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Endpoint | Incidence of grade ≥3 diarrhea in patients with her2-positive early breast cancer treated with neratinib dose escalation versus neratinib conventional dose combined with loperamide | up to 3 year after the last patient enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Endpoint | 3-year invasive disease-free survival (iDFS%) and other safety events | up to 3 year after the last patient enrolled |