HER2 Positive Breast Carcinoma, Stage IV Breast Cancer AJCC v6 and v7
Conditions
Brief summary
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
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.
Interventions
OTHERComprehensive Geriatric Assessment
Ancillary studies
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGNeratinib
Given PO
OTHERPharmacological Study
Correlative studies
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Grade 2 or Higher Toxicities | On treatment, 28 days per cycle up to 1 year | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Participants With a Dose Reduction | On treatment, up to 48 months | Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for dose reduction. |
| Rate of Participants Requiring Hospitalizations | On treatment, up to 48 months | Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for hospitalizations. |
| Tumor Response Using Response Evaluation Criteria in Solid Tumors (RECIST) | Participants are evaluated every 12 weeks, up to 48 months | 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. |
| Count of Participants With Grade 3 or Higher Gastrointestinal (GI) Toxicities Such as Diarrhea, Nausea and Vomiting | On treatment, 28 days per cycle up to 1 year | 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. |
| Median Overall Survival (OS) | Time from start of treatment to death due to any cause, assessed up to 48 months | OS will be estimated using the product limit method of Kaplan and Meier. |
| Cancer-specific Geriatric Assessment Score | At day 0 of treatment | 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. |
| Pharmacokinetics of Steady State Neratinib Concentration Transformed Using a Logarithm Base 2 | Day 0 to day 15 | Least squares regression was used to assess the relationship between steady state neratinib concentration, transformed using a logarithm base 2 transformation, and age |
| Median Progression-free Survival (PFS) in Months | From the date treatment begins until the first date on which recurrence, progression or death due to any cause, assessed up to 48 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Neratinib) Patients receive neratinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Comprehensive Geriatric Assessment: Ancillary studies
Laboratory Biomarker Analysis: Correlative studies
Neratinib: Given PO
Pharmacological Study: Correlative studies | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | Treatment (Neratinib) |
|---|---|
| Age, Continuous | 66 years |
| ECOG performance status 0 = Fully active, able to carry on all pre-disease performance without restriction | 8 Participants |
| ECOG performance status 1 = Restricted in physically strenuous activity but ambulatory and able to do work of a light nature | 17 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Hormone receptor status Negative | 6 Participants |
| Hormone receptor status Positive | 19 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 16 / 25 |
| other Total, other adverse events | 23 / 25 |
| serious Total, serious adverse events | 10 / 25 |
Outcome results
Primary
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.
Time frame: On treatment, 28 days per cycle up to 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Neratinib) | Percent of Participants With Grade 2 or Higher Toxicities | 80 percentage of participants |
Secondary
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.
Time frame: At day 0 of treatment
Population: 3 participants did not have complete geriatric assessment data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment (Neratinib) | Cancer-specific Geriatric Assessment Score | 0.34 scores on a scale |
Comparison: Student's t-test was used to assess if geriatric risk score differed depending on whether or not a participant had a dose reduction (mean difference log2 risk = no dose modification - dose modification).p-value: 0.0595% CI: [-0.82, 0.01]t-test, 2 sided
Comparison: Linear regression was used to assess whether log2 geriatric toxicity risk score was a risk factor for the number of course completed.p-value: 0.39Regression, Linear
Secondary
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.
Time frame: On treatment, 28 days per cycle up to 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Neratinib) | Count of Participants With Grade 3 or Higher Gastrointestinal (GI) Toxicities Such as Diarrhea, Nausea and Vomiting | Diarrhea | 5 Participants |
| Treatment (Neratinib) | Count of Participants With Grade 3 or Higher Gastrointestinal (GI) Toxicities Such as Diarrhea, Nausea and Vomiting | Vomiting | 2 Participants |
| Treatment (Neratinib) | Count of Participants With Grade 3 or Higher Gastrointestinal (GI) Toxicities Such as Diarrhea, Nausea and Vomiting | Abdominal pain | 2 Participants |
| Treatment (Neratinib) | Count of Participants With Grade 3 or Higher Gastrointestinal (GI) Toxicities Such as Diarrhea, Nausea and Vomiting | Nausea | 1 Participants |
Secondary
Median Overall Survival (OS)
OS will be estimated using the product limit method of Kaplan and Meier.
Time frame: Time from start of treatment to death due to any cause, assessed up to 48 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Neratinib) | Median Overall Survival (OS) | 17.4 months |
Secondary
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.
Time frame: From the date treatment begins until the first date on which recurrence, progression or death due to any cause, assessed up to 48 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Neratinib) | Median Progression-free Survival (PFS) in Months | 2.6 months |
Secondary
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
Time frame: Day 0 to day 15
Population: Only 20 participants had PK data available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Neratinib) | Pharmacokinetics of Steady State Neratinib Concentration Transformed Using a Logarithm Base 2 | 4.7 log2(ng/mL) | Standard Deviation 1.09 |
Comparison: Least squares regression was used to assess the relationship between steady state neratinib concentration and agep-value: 0.03Regression, Linear
Comparison: Least squares regression was used to determine if geriatric toxicity risk score at baseline was predictive of steady state neratinib concentration.p-value: 0.57Regression, Linear
Secondary
Rate of Participants Requiring Hospitalizations
Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for hospitalizations.
Time frame: On treatment, up to 48 months
Population: 4 of 25 patients (16%) were hospitalized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Neratinib) | Rate of Participants Requiring Hospitalizations | 16 percentage of participants |
Secondary
Rate of Participants With a Dose Reduction
Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for dose reduction.
Time frame: On treatment, up to 48 months
Population: 9 of 25 patients 36% had a dose reduction.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Neratinib) | Rate of Participants With a Dose Reduction | 36 percentage of participants |
Secondary
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.
Time frame: Participants are evaluated every 12 weeks, up to 48 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Neratinib) | Tumor Response Using Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Remission | 1 Participants |
| Treatment (Neratinib) | Tumor Response Using Response Evaluation Criteria in Solid Tumors (RECIST) | Stable Disease | 11 Participants |
| Treatment (Neratinib) | Tumor Response Using Response Evaluation Criteria in Solid Tumors (RECIST) | Progressive Disease | 12 Participants |
| Treatment (Neratinib) | Tumor Response Using Response Evaluation Criteria in Solid Tumors (RECIST) | Not assessed | 1 Participants |