Neratinib in Treating Older Patients With Stage IV HER2-Positive Breast Cancer

Study Overview
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Brief Summary
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This phase II trial studies the side effects of and how well neratinib works in treating older patients with stage IV HER2-positive breast cancer. Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the safety and tolerability of neratinib in adults age 60 or older with locally advanced or metastatic HER2 over-expressing breast cancer. SECONDARY OBJECTIVES: I. To describe the full toxicity profile including all grade toxicities measured by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0. II. To estimate the rate of all grades of gastrointestinal (GI) toxicities such as diarrhea, nausea, and vomiting. III. To estimate the rate of dose reduction, delays and discontinuation related to study drug. IV. To describe pharmacokinetic parameters of neratinib in adults 60 and older. V. To estimate overall response rate (ORR) and clinical benefit rate (CBR) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. VI. To estimate event free survival (EFS), progression-free survival (PFS) and overall survival (OS). VII. To evaluate the role of cancer-specific geriatric assessment tool in predicting treatment toxicities. VIII. To estimate adherence rate to neratinib in older adults (percentage of doses of neratinib taken). IX. To explore the association of pharmacokinetic (PK) parameters and geriatric assessment findings. X. To explore if serum biomarkers of aging (interleukin [IL]-6, C-reactive protein [CRP], and D-dimer) are associated with treatment toxicities. OUTLINE: Patients receive neratinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days and then periodically thereafter.

Official Title
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Phase II Study of Neratinib in Patients 60 and Older With HER2 Positive Metastatic Breast Cancer

Conditions
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HER2 Positive Breast Carcinoma, Stage IV Breast Cancer AJCC v6 and v7

Intervention / Treatment
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* Other: Comprehensive Geriatric Assessment
* Other: Laboratory Biomarker Analysis
* Drug: Neratinib
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance 0-2 Life expectancy of greater than 12 weeks Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) Both measurable as well as non-measurable disease will be allowed Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration Total bilirubin within normal institutional limits within 4 weeks of pre-registration Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: Prior treatment with neratinib Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) Any major surgery =< 28 days prior to the initiation of investigational products Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes Inability to take oral medication Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas 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 [CTCAE] v.4.0 diarrhea of any etiology at baseline) Known clinically active infection with hepatitis B or hepatitis C virus Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s judgment, makes the patient inappropriate for this study

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (neratinib)<br>Patients receive neratinib 240mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Other: Comprehensive Geriatric Assessment<br>* Ancillary studies<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Neratinib<br>* Given PO<br>* Other names: PB-272;Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With Grade 2 or Higher Toxicities | Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Tables will be created to summarize the toxicities and side effects by organ system, attribution and severity for all participants that receive at least one dose of neratinib. Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for grade 2 or higher toxicities attributed to neratinib. | On treatment, 28 days per cycle up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Count of Participants With Grade 3 or Higher Gastrointestinal (GI) Toxicities Such as Diarrhea, Nausea and Vomiting | Will be graded according to the NCI CTCAE version 4.0. Tables will be created to summarize the toxicities and side effects by organ system, attribution and severity for all participants that receive at least one dose of neratinib. | On treatment, 28 days per cycle up to 1 year | 
| Rate of Participants With a Dose Reduction | Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for dose reduction. | On treatment, up to 48 months | 
| Rate of Participants Requiring Hospitalizations | Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for hospitalizations. | On treatment, up to 48 months | 
| Tumor Response Using Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response (CR): Disappearance of all target lesions. Lymph node CR is when the lymph node has decreased to less than 10mm in the short axis. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started (including the baseline scan if that is the smallest), and at least a 5mm increase or the appearance of new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | Participants are evaluated every 12 weeks, up to 48 months | 
| Median Progression-free Survival (PFS) in Months | Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for PFS. PFS will be estimated using the product limit method of Kaplan and Meier. | From the date treatment begins until the first date on which recurrence, progression or death due to any cause, assessed up to 48 months | 
| Median Overall Survival (OS) | OS will be estimated using the product limit method of Kaplan and Meier. | Time from start of treatment to death due to any cause, assessed up to 48 months | 
| Cancer-specific Geriatric Assessment Score | The cancer specific geriatric assessment score includes an evaluation of functional status, co-morbidity, cognition, psychological stats, social functioning and support, and nutritional status. It assesses a patient's age, gender, height, weight, cancer type, dosage, number of chemotherapy agents, hemoglobin, hearing, number of falls in past 6 months, able to take own medicine, whether walking is limited, have physical or emotional problems interfered with social activities and serum creatinine. Scores can range from 0 to to 1, with a higher score indicating higher risk of chemotherapy toxicity. Generalized linear models and graphical methods will be used to explore factors as identified by a cancer-specific geriatric assessment. | At day 0 of treatment | 
| Pharmacokinetics of Steady State Neratinib Concentration Transformed Using a Logarithm Base 2 | Least squares regression was used to assess the relationship between steady state neratinib concentration, transformed using a logarithm base 2 transformation, and age | Day 0 to day 15 |