Incidence and Severity of Diarrhea in Patients With HER2 Positive Breast Cancer Treated With Trastuzumab and Neratinib

Phase 2

Completed

Conditions: HER2-positive Breast Cancer
Stage II Breast Cancer AJCC v6 and v7
Breast Adenocarcinoma
Stage IIA Breast Cancer AJCC v6 and v7
Stage IIIC Breast Cancer AJCC v7
Stage IIIB Breast Cancer AJCC v7
Stage IIB Breast Cancer AJCC v6 and v7
Stage III Breast Cancer AJCC v7
Stage IIIA Breast Cancer AJCC v7

Interventions: Drug: Neratinib
Biological: Trastuzumab
Drug: Loperamide
Drug: Crofelemer
Drug: Diphenoxylate/Atropine

Registration Number: NCT03094052

Lead Sponsor: University of California, San Francisco

Brief Summary: This phase II trial studies the incidence and severity of diarrhea in patients with stage II-IIIC HER2 Positive breast cancer treated with trastuzumab and neratinib. Trastuzumab is a form of targeted therapy because it attaches itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body's immune system. Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving trastuzumab and neratinib may work better in treating patients with stage II-IIIC HER2 positive breast cancer.

Detailed Description: PRIMARY OBJECTIVE:

I. To characterize the incidence and severity of diarrhea in patients with early stage breast cancer receiving adjuvant neratinib with or without trastuzumab in the setting of anti-diarrheal strategies.

SECONDARY OBJECTIVES:

I. To evaluate the incidence of grade 3 or higher diarrhea using the dose-escalation strategy and anti-diarrhea medications as needed (prn) in patients who received prior trastuzumab emtansine (T-DM1).

II. To assess neratinib adherence, holds, delays, and early discontinuation throughout the course of study therapy which includes patients receiving neratinib for \> 1 year.

III. To assess overall toxicity including constipation and cardiac toxicity with concomitant neratinib and trastuzumab.

OUTLINE: This is a dose-escalation study of neratinib. Patients receive one of the following treatment regimen:

NERATINIB MONOTHERAPY: Patients receive neratinib orally (PO) once daily (QD) on days 1-21. Cycles repeats every 21 days for up to 55 weeks in the absence of disease progression or unacceptable toxicity. Patients may receive loperamide and/or diphenoxylate hydrochloride/atropine sulfate as needed per physician discretion for symptom management.

NERATINIB AND TRASTUZUMAB: Patients receive neratinib PO QD on days 1-21. Patients also receive trastuzumab maintenance therapy as determined by treating physician. Treatment repeats every 21 days for up to 55 weeks in the absence of disease progression or unacceptable toxicity. After completion of trastuzumab treatment, patients may continue on neratinib monotherapy for the remainder of the 55 weeks. Patients may receive loperamide and/or diphenoxylate hydrochloride/atropine sulfate as needed per physician discretion for symptom management.

After completion of studies treatment, patients are followed up for 28 days.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 11

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Adjuvant Neratinib, Crofelemer, Loperamide	Neratinib	Participants will receive 240mg neratinib to be taken continuously in 21-day cycles once a day for up to 55 weeks on study with no rest between cycles unless related to toxicity. Participants will receive Neratinib and may also be prescribed standard of care maintenance adjuvant trastuzumab (duration of maintenance trastuzumab is at the discretion of the treating physician), for up to 55 weeks. If applicable, after the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib may continue as monotherapy to complete a maximum of 55 weeks. Participants will also receive 125mg of prophylactic Crofelemer and 4 mg of prophylactic loperamide as needed in the first 2 cycles.
Adjuvant Neratinib, Crofelemer, Loperamide	Trastuzumab	Participants will receive 240mg neratinib to be taken continuously in 21-day cycles once a day for up to 55 weeks on study with no rest between cycles unless related to toxicity. Participants will receive Neratinib and may also be prescribed standard of care maintenance adjuvant trastuzumab (duration of maintenance trastuzumab is at the discretion of the treating physician), for up to 55 weeks. If applicable, after the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib may continue as monotherapy to complete a maximum of 55 weeks. Participants will also receive 125mg of prophylactic Crofelemer and 4 mg of prophylactic loperamide as needed in the first 2 cycles.
Adjuvant Neratinib, Crofelemer, Loperamide	Loperamide	Participants will receive 240mg neratinib to be taken continuously in 21-day cycles once a day for up to 55 weeks on study with no rest between cycles unless related to toxicity. Participants will receive Neratinib and may also be prescribed standard of care maintenance adjuvant trastuzumab (duration of maintenance trastuzumab is at the discretion of the treating physician), for up to 55 weeks. If applicable, after the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib may continue as monotherapy to complete a maximum of 55 weeks. Participants will also receive 125mg of prophylactic Crofelemer and 4 mg of prophylactic loperamide as needed in the first 2 cycles.
Adjuvant Neratinib, Crofelemer, Loperamide	Crofelemer	Participants will receive 240mg neratinib to be taken continuously in 21-day cycles once a day for up to 55 weeks on study with no rest between cycles unless related to toxicity. Participants will receive Neratinib and may also be prescribed standard of care maintenance adjuvant trastuzumab (duration of maintenance trastuzumab is at the discretion of the treating physician), for up to 55 weeks. If applicable, after the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib may continue as monotherapy to complete a maximum of 55 weeks. Participants will also receive 125mg of prophylactic Crofelemer and 4 mg of prophylactic loperamide as needed in the first 2 cycles.
Adjuvant Neratinib, Crofelemer, Loperamide	Diphenoxylate/Atropine	Participants will receive 240mg neratinib to be taken continuously in 21-day cycles once a day for up to 55 weeks on study with no rest between cycles unless related to toxicity. Participants will receive Neratinib and may also be prescribed standard of care maintenance adjuvant trastuzumab (duration of maintenance trastuzumab is at the discretion of the treating physician), for up to 55 weeks. If applicable, after the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib may continue as monotherapy to complete a maximum of 55 weeks. Participants will also receive 125mg of prophylactic Crofelemer and 4 mg of prophylactic loperamide as needed in the first 2 cycles.
Adjuvant Neratinib, Loperamide	Neratinib	Participants will receive 120 mg of neratinib on days 1-7 with subsequent increase in dose by 40 mg every 7 days until the full dose of 240 mg a day is reached within the first cycle (up to 240mg) to be taken continuously in 21-day cycles once a day for up to 55 weeks on study with no rest between cycles unless related to toxicity. Participants will receive Neratinib and may also be prescribed standard of care maintenance adjuvant trastuzumab (duration of maintenance trastuzumab is at the discretion of the treating physician), for up to 55 weeks. If applicable, after the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib may continue as monotherapy to complete a maximum of 55 weeks. Participants will also receive 4 mg of prophylactic loperamide to be taken as needed.
Adjuvant Neratinib, Loperamide	Trastuzumab	Participants will receive 120 mg of neratinib on days 1-7 with subsequent increase in dose by 40 mg every 7 days until the full dose of 240 mg a day is reached within the first cycle (up to 240mg) to be taken continuously in 21-day cycles once a day for up to 55 weeks on study with no rest between cycles unless related to toxicity. Participants will receive Neratinib and may also be prescribed standard of care maintenance adjuvant trastuzumab (duration of maintenance trastuzumab is at the discretion of the treating physician), for up to 55 weeks. If applicable, after the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib may continue as monotherapy to complete a maximum of 55 weeks. Participants will also receive 4 mg of prophylactic loperamide to be taken as needed.
Adjuvant Neratinib, Loperamide	Loperamide	Participants will receive 120 mg of neratinib on days 1-7 with subsequent increase in dose by 40 mg every 7 days until the full dose of 240 mg a day is reached within the first cycle (up to 240mg) to be taken continuously in 21-day cycles once a day for up to 55 weeks on study with no rest between cycles unless related to toxicity. Participants will receive Neratinib and may also be prescribed standard of care maintenance adjuvant trastuzumab (duration of maintenance trastuzumab is at the discretion of the treating physician), for up to 55 weeks. If applicable, after the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib may continue as monotherapy to complete a maximum of 55 weeks. Participants will also receive 4 mg of prophylactic loperamide to be taken as needed.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Grade 3 or Greater Diarrhea	Up to 6 weeks	Percentage of participants with clinically assessed grade 3 or greater diarrhea reported within the first 2 cycles (each cycle is 21 days) of neratinib while using anti-diarrheal strategies. Reports of diarrhea will be graded according to NCI CTCAE version 4.0.
Percentage of Participants Who Did Not Require Loperamide During Multiple Cycles of Treatment	Up to 55 weeks	Percentage of participants who did not require loperamide during cancer treatment for at least 5 cycles will be reported.
Percentage of Participants Who Discontinued Anti-diarrheal Medications for Multiple Cycles of Treatment	Up to 55 weeks	The percentage of participants who discontinued all anti-diarrheal medications during cancer treatment for at least 5 cycles will be reported.
Percentage of Participants With Treatment-related Adverse Events	Up to 55 weeks	Percentage of participants with reported serious adverse events and adverse events of interest of any grade that have been determined to be related to the anti-diarrhea treatment will be reported by worst grade and associated toxicity.
Number of Participants With Neratinib Dose Holds	Up to 55 weeks	The number of participants who experienced a dose hold of neratinib during the course of study therapy will be reported
Number of Participants Who Discontinued Neratinib Early	Up to 55 weeks	The number of participants who discontinued neratinib earlier than expected during the course of study therapy will be reported
Number of Participants With Neratinib Dose-reductions	Up to 55 weeks	The number of participants whose dose was reduced at any time during the course of therapy will be reported

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (1): University of California, San Francisco
🇺🇸
San Francisco, California, United States
University of California, San Francisco
🇺🇸San Francisco, California, United States