A Study to Characterize Colon Pathology in Patients With HER2 Amplified Breast Cancer Treated With Neratinib

Sponsor

Puma Biotechnology, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT04366713

Collaborator

(none)

Enrollment

Location

Arm

17.9

Actual Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will investigate colon pathology in patients with HER2-positive breast cancer treated with neratinib. Colonoscopy will be performed after eligibility has been confirmed, prior to administration of the first dose of neratinib, and after 28 days of neratinib treatment.

Condition or Disease	Intervention/Treatment	Phase
HER2 Amplified Breast Cancer	Drug: Neratinib Drug: Capecitabine Drug: Loperamide	Phase 2

Detailed Description

This is an open-label, phase 2 study that will investigate colon pathology in patients with HER2-positive breast cancer treated with neratinib as monotherapy.

All patients will receive neratinib for the first 28 days as a single daily dose of 240 mg.

Colonoscopy will be performed after eligibility has been confirmed, but prior to administration of the first dose of neratinib and at Day 30 (± 3 days) the conclusion of Cycle 1 (28 days).

Following the second study colonoscopy procedure:

For patients being treated for stage 1 to 3c breast cancer in the extended adjuvant setting, neratinib will continue to be administered at a single daily dose of 240 mg until completion of one year of therapy from start of treatment, or until disease recurrence (as determined by the Investigator), death, unacceptable toxicity, or other specified withdrawal criterion.
For patients being treated for metastatic breast cancer (mBC), capecitabine will be introduced after the second study colonoscopy procedure at a dose of 750mg/m2 twice daily for 14 days of each 21 day treatment cycle, with neratinib administered continuously throughout at 240 mg daily, until disease progression, death, unacceptable toxicity, or other specified withdrawal criterion.

All patients will receive loperamide diarrhea prophylaxis daily for one 28-day cycle and then as needed.

Study Design

Study Type:

Interventional

Actual Enrollment :

6 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients With HER2 Amplified Breast Cancer Treated With Neratinib

Actual Study Start Date :

Jun 30, 2020

Actual Primary Completion Date :

Dec 28, 2021

Actual Study Completion Date :

Dec 28, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Neratinib Neratinib with loperamide prophylaxis, and capecitabine for participants treated for metastatic breast cancer	Drug: Neratinib Administered orally once daily as a single daily dose of 240 mg Other Names: Nerlynx Drug: Capecitabine Administered orally twice daily at 750 mg/m^2 for 14 days of each 21 day treatment cycle Drug: Loperamide Administered orally for prophylaxis for 28 days and then as needed

Arm

Intervention/Treatment

Experimental: Neratinib

Neratinib with loperamide prophylaxis, and capecitabine for participants treated for metastatic breast cancer

Drug: Neratinib

Administered orally once daily as a single daily dose of 240 mg

Other Names:

Nerlynx

Drug: Capecitabine

Administered orally twice daily at 750 mg/m^2 for 14 days of each 21 day treatment cycle

Drug: Loperamide

Administered orally for prophylaxis for 28 days and then as needed

Outcome Measures

Primary Outcome Measures

Changes in Colon Pathology [From baseline to 28 days after neratinib treatment]
The primary endpoint is to describe the changes in colon pathology observed over the first 28 days of neratinib therapy. The clinical study report will be a descriptive summary of these changes using listings and narratives.

Secondary Outcome Measures

Incidence and Severity of Diarrhea [From baseline to 28 days after neratinib treatment]
Incidence and severity of diarrhea will be summarized according to the NCI-CTCAE version 4.0 in the first 28-day cycle of neratinib treatment.
Change in Erythrocyte Sedimentation Rate (ESR) [From the first baseline colonoscopy to the second colonoscopy, up to 33 days]
Change in the serological inflammatory marker erythrocyte sedimentation rate (ESR) will be assessed from baseline at the time of the first colonoscopy to the second colonoscopy. The unit of measurement is mm/hr.
Change in C-reactive protein (CRP) [From the first baseline colonoscopy to the second colonoscopy, up to 33 days]
Change in the serological inflammatory marker C-reactive protein (CRP) will be assessed from baseline at the time of the first colonoscopy to the second colonoscopy. The unit of measurement is mg/L.
Change in Fecal Calprotectin [From the first baseline colonoscopy to the second colonoscopy, up to 33 days]
Change in the stool inflammatory marker fecal calprotectin will be assessed from baseline at the time of the first colonoscopy to the second colonoscopy. The unit of measurement is mcg/g.
Change in Fecal Elastase [From the first baseline colonoscopy to the second colonoscopy, up to 33 days]
Change in the stool inflammatory marker fecal elastase will be assessed from baseline at the time of the first colonoscopy to the second colonoscopy. The unit of measurement is mcg/g.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

INCLUSION CRITERIA

Aged ≥18 years.
Histologically confirmed stage 1 through stage 4 primary adenocarcinoma of the breast.
Documented HER2 overexpression or gene-amplified tumor by a validated approved method.
Participants with confirmed stage 1 to stage 3c breast cancer receiving extended adjuvant treatment with neratinib monotherapy must have completed a course of prior adjuvant trastuzumab or experienced side effects that resulted in early discontinuation of trastuzumab that have since resolved.
Participants with mBC must have had at least 2 prior HER2-directed regimens.
Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
Eastern Cooperative Oncology Group (ECOG) status of 0 to 1.
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.]
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 partner, or abstinence (only when it is the preferred lifestyle of the participant), from the time of informed consent until 28 days after the last dose of the investigational products. Men (male participant) with a 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 (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 investigational products.
Recovery (i.e., to Grade 1 or baseline) from all clinically significant adverse events related to prior therapies (excluding alopecia, neuropathy, and nail changes).
No major bleeding diathesis or use of anticoagulants that would pose a high risk for endoscopic procedure.
Provide written, informed consent to participate in the study and follow the study procedures.

EXCLUSION CRITERIA:

Participants with confirmed stage 1 to stage 3c currently receiving chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer.
Participants with mBC who have received prior capecitabine or HER2 directed tyrosine kinase inhibitor (TKI) therapy.
Currently using drugs that have been implicated as causing microscopic colitis/watery diarrhea, such as acarbose, aspirin, proton pump inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), histamine H2 receptor antagonists, selective serotonin reuptake inhibitors, and ticlopidine (Pardi, 2017).
Major surgery within <28 days of starting treatment or received chemotherapy, investigational agents, or other cancer therapy, except hormonal therapy (e.g., tamoxifen, aromatase inhibitors), <14 days prior to the initiation of investigational products.
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.
Corrected QT Interval (QTc) interval >0.450 seconds (males) or >0.470 (females), or known history of QTc prolongation or Torsade de Pointes (TdP).
Diagnosis of inflammatory bowel disease
Screening laboratory assessments outside the following limits:

Laboratory Parameters Required Limit for Exclusion Absolute neutrophil count (ANC) <1,000/µl (<1.0 x 109/L) Platelet count <50,000/µl (<100 x 109/L) Hemoglobin <8 g/dL (transfusions allowed) Transfusions must be at least 14 days prior to initiation of treatment 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 (>5 x ULN if liver metastases are present) Creatinine Creatinine clearance <30 mL/min (as calculated by Cockcroft-Gault formula A or Modification of Diet in Renal Disease formula B) International Normalized Ratio (INR) >1.5 a Cockcroft and Gault, 1976 b Levey et al, 1999

Active, unresolved infections.
Participants with a second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Participants with other non-mammary malignancies must have been disease free for at least 5 years.
Currently pregnant or breast-feeding.
Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, 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).
Clinically active infection with hepatitis B or hepatitis C virus.
Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the Investigator's judgment, make the person inappropriate for this study.
Known hypersensitivity to any component of the investigational products; known allergies to any of the medications or components of medications used in the trial.
Unable or unwilling to swallow tablets