Diarrhea Prophylaxis in Patients With HER2+ Breast Cancer Treated With Neratinib, With or Without Trastuzumab
Keywords
Abstract
Description
This is an open-label adjuvant/post neoadjuvant single arm phase 2 trial.
Patients will receive:
Neratinib 240 mg orally once a day for up to 52 weeks while receiving concurrent trastuzumab. After the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib will continue as monotherapy for 12 months. Neratinib is to be taken continuously in 21-day cycles with no rest between cycles unless related to toxicity.
Intensive daily loperamide prophylaxis for the first 2 cycles and then as needed.
Crofelemer 125 mg bid for the first two cycles then as needed.
Each cycle is 21 days. Clinic visits and laboratory studies are planned on day 1 of every cycle for the first 4 cycles, then q4 cycles thereafter. An end of treatment visit will occur 28 days after the last dose of neratinib. Patients who permanently discontinue treatment due to unacceptable toxicity will be followed-up for 28 days after the last dose of neratinib.
Dates
| Last Verified: | 12/31/2019 |
| First Submitted: | 03/13/2017 |
| Estimated Enrollment Submitted: | 03/21/2017 |
| First Posted: | 03/28/2017 |
| Last Update Submitted: | 01/16/2020 |
| Last Update Posted: | 01/21/2020 |
| Actual Study Start Date: | 01/03/2017 |
| Estimated Primary Completion Date: | 11/30/2020 |
| Estimated Study Completion Date: | 12/01/2022 |
Condition or disease
Intervention/treatment
Drug: Neratinib
Drug: Neratinib, Trastuzumab, Crofelemer, and Loperamide
Drug: Crofelemer
Drug: Loperamide
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Experimental: Neratinib, Crofelemer, and Loperamide Neratinib 240 mg orally once a day for up to 2 years. Neratinib is to be taken continuously in 21-day cycles with no rest between cycles unless related to toxicity.
Intensive daily loperamide prophylaxis for the first 2 cycles (42 days) and then as needed. Days 1-14: 4 mg 3 times daily. Days 15-42: 4 mg twice per day.
Crofelemer 125 mg bid for the first 2 cycles then as needed. | |
| Experimental: Neratinib, Trastuzumab, Crofelemer, and Loperamide Neratinib and Trastuzumab: Neratinib and at a dose of 240 mg orally while receiving maintenance adjuvant trastuzumab (duration of maintenance trastuzumab up to the treating physician). After the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib will continue as monotherapy for 52 weeks. Neratinib is to be taken continuously in 21-day cycles with no rest between cycles unless related to toxicity.
Intensive daily loperamide prophylaxis for the first 2 cycles (42 days) and then as needed. Days 1-14: 4 mg 3 times daily. Days 15-42: 4 mg twice per day.
Crofelemer 125 mg bid for the first 2 cycles then as needed. | Drug: Neratinib, Trastuzumab, Crofelemer, and Loperamide Intravenously administered as determined by the treating physician for up to 52 weeks with neratinib. |
Eligibility Criteria
| Ages Eligible for Study | 18 Years To 18 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | Inclusion Criteria: A patient will be eligible for this study if she/he meets any of the following criteria. 1. Aged ≥18 years at signing of informed consent. 2. Histologically confirmed clinical or pathological stage 2 through stage 3c primary adenocarcinoma of the breast. 3. Documented HER2 overexpression or gene-amplified tumor by a validated approved method. 4. Patients can have hormone receptor (HR)+ or HR-negative disease. 5. Concurrent adjuvant endocrine therapy and bone-modifying agents is allowed 6. Patients can be premenopausal or postmenopausal 7. Completion of neoadjuvant or adjuvant chemotherapy 8. Completion of adjuvant locoregional radiation, if indicated, is required prior to starting study treatment. 9. At the time of study enrollment, can still be receiving adjuvant trastuzumab or be within 1 year of completing adjuvant trastuzumab monotherapy maintenance. 10. Clinically no evidence of metastatic disease at the time of study entry 11. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO). 12. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1. 13. 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]. 14. Trastuzumab can cause embryo-fetal harm when administered during pregnancy and the effects of neratinib on the developing human fetus are unknown. Women of child-bearing potential must agree and commit to use of a highly effective double-barrier method of contraception (e.g., a combination of male condom with an intravaginal device such as the cervical cap, diaphragm, or vaginal sponge with spermicide) or a non-hormonal method, from the signing of informed consent until 28 days after the last dose of neratinib and 7 months after the last dose of trastuzumab, or consent to total sexual abstinence (abstinence must occur from randomization and continue for 28 days after the last dose of neratinib and 7 months after the last dose of trastuzumab). Men without confirmed vasectomy must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of investigational products, or consent to total sexual abstinence (abstinence must occur from randomization and continue for 3 months after the last dose of study medication). 15. Recovery (i.e., to Grade 1 or baseline) from all clinically significant AEs related to prior therapies (excluding alopecia, neuropathy, and nail changes). 16. Provide written, informed consent to participate in the study and follow the study procedures. Exclusion Criteria: A patient will be excluded from this study if she/he meets any of the following criteria. 1. Clinical or radiologic evidence of metastatic disease prior to or at the time of study entry. 2. Currently receiving chemotherapy, radiation therapy, investigational immunotherapy, or investigational biotherapy for breast cancer. 3. Major surgery (including breast 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 (except adjuvant endocrine therapy). 4. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2; including individuals who currently use digitalis, beta-blockers, or calcium channel blockers specifically for congestive heart failure), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia. 5. Corrected QT interval (QTc) interval >0.450 seconds (males) or >0.470 seconds (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 Platelets: ≤100,000 /μL Hemoglobin: ≤9 g/dL Serum creatinine or calculated creatinine clearance†: ≥1.5 x upper limit of normal (ULN) OR ≤30 mL/min for patients with creatinine levels >1.5 x institutional ULN Serum total bilirubin: ≥1.5 x ULN OR direct bilirubin ≥ ULN for patients with total bilirubin levels >1.5 x ULN aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT): ≥2.5 x ULN † Creatinine clearance should be calculated per institutional standard. 7. 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. 8. Currently pregnant or breast-feeding. 9. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any etiology at baseline). 10. Clinically active infection with hepatitis B or hepatitis C virus. 11. 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. 12. Known hypersensitivity to any component of the investigational products. 13. Unable or unwilling to swallow tablets. |
Outcome
Primary Outcome Measures
1. Incidence of Grade 3 or Greater Diarrhea with 2 Cycles (6 Weeks) of Prophylactic Loperamide and Crofelemer, According to NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [2 cycles (6 weeks)]
Secondary Outcome Measures
1. Activity of crofelemer as a rescue anti-diarrheal medication as determined by...... [From Day 1 through the end of study treatment, up to 2 years]
2. Assess neratinib dose adherence as determined by .......(percentage of prescribed doses taken?) [From Day 1 through the end of study treatment, up to 2 years]
3. Number of Patients with Neratinib Dose Holds [From Day 1 through the end of study treatment, up to 2 years]
4. Number of Patients Who Discontinued Neratinib Early [From Day 1 through the end of study treatment, up to 2 years]
5. Number of Patients With Dose-Reductions [From Day 1 through the end of study treatment, up to 2 years]
6. Incidence of Adverse Events for the Combination of Neratinib and Trastuzumab, Assessed by CTCAE Version 4.0 [From Day 1 until 28 days after the last dose of neratinib, up to about 2 years]
