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

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ClinicalTrials.gov Identifier: NCT02673398
Recruitment Status : Active, not recruiting
First Posted : February 3, 2016
Last Update Posted : June 21, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

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.

Condition or disease Intervention/treatment Phase
HER2 Positive Breast Carcinoma Stage IV Breast Cancer AJCC v6 and v7 Other: Comprehensive Geriatric Assessment Other: Laboratory Biomarker Analysis Drug: Neratinib Other: Pharmacological Study Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Neratinib in Patients 60 and Older With HER2 Positive Metastatic Breast Cancer
Actual Study Start Date : October 27, 2016
Estimated Primary Completion Date : October 22, 2019
Estimated Study Completion Date : October 22, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Neratinib

Arm Intervention/treatment
Experimental: 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.
Other: Comprehensive Geriatric Assessment
Ancillary studies

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Neratinib
Given PO
Other Names:
  • (2E)-N-(4-((3-chloro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide
  • HKI 272
  • HKI-272
  • PB 272
  • PB-272

Other: Pharmacological Study
Correlative studies




Primary Outcome Measures :
  1. Incidence of grade 2 or higher toxicities [ Time Frame: Up to 30 days after the completion of study treatment ]
    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 Outcome Measures :
  1. Incidence of all toxicities [ Time Frame: Up to 30 days after the completion of study treatment ]
    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.

  2. Incidence of gastrointestinal (GI) toxicities such as diarrhea, nausea and vomiting [ Time Frame: Up to 30 days after the completion of study treatment ]
    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. Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for all grade GI toxicities (diarrhea, nausea and vomiting).

  3. Rate of dose reduction [ Time Frame: Up to 48 months ]
    Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for dose reduction.

  4. Rate of holds [ Time Frame: Up to 48 months ]
    Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for holds.

  5. Rate of hospitalizations [ Time Frame: Up to 48 months ]
    Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for hospitalizations.

  6. Clearance [ Time Frame: Day 15 of course 1 and day 1 of courses 3-4 ]
    Clearance will be estimated using population pharmacokinetic (PK) methods.

  7. Volume of distribution [ Time Frame: Day 15 of course 1 and day 1 of courses 3-4 ]
    Volume of distribution will be estimated using population PK methods.

  8. Overall response rate [ Time Frame: Up to 48 months ]
    Will be measured by Response Evaluation Criteria in Solid Tumors (RECIST). Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for objective response (complete response [CR] + partial response [PR]).

  9. Clinical benefit rate [ Time Frame: Up to 48 months ]
    Clinical benefit rate is defined as the proportion of patients who achieved overall tumor response (CR or PR) or stable disease (SD) for at least 24 weeks, measured by RECIST. Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for clinical benefit (CR+PR+SD).

  10. Event free survival (EFS) [ Time Frame: Up to 48 months ]
    EFS will be estimated using the product limit method of Kaplan and Meier.

  11. Progression-free survival (PFS) [ Time Frame: From the date of randomization until the first date on which recurrence, progression or death due to any cause, assessed up to 16 weeks ]
    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.

  12. Overall survival (OS) [ Time Frame: Time from randomization to death due to any cause, assessed up to 48 months ]
    OS will be estimated using the product limit method of Kaplan and Meier.

  13. Geriatric assessment score [ Time Frame: Up to 48 months ]
    Generalized linear models and graphical methods will be used to explore factors as identified by a cancer-specific geriatric assessment.

  14. Adherence, as defined by pill count [ Time Frame: Up to 48 months ]
    Descriptive statistics will be provided for drug adherence and participant demographics.

  15. IL-6, CRP, and D-dimer analysis [ Time Frame: Baseline to up to 48 months ]
    Will be measured and descriptive statistics provided. Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.



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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02673398


Locations
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United States, California
City of Hope Corona
Corona, California, United States, 92879
City of Hope Comprehensive Cancer Center
Duarte, California, United States, 91010
City of Hope Antelope Valley
Lancaster, California, United States, 93534
City of Hope Mission Hills
Mission Hills, California, United States, 91345
City of Hope Rancho Cucamonga
Rancho Cucamonga, California, United States, 91730
City of Hope South Pasadena
South Pasadena, California, United States, 91030
City of Hope West Covina
West Covina, California, United States, 91790
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Yuan Yuan City of Hope Comprehensive Cancer Center

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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02673398     History of Changes
Other Study ID Numbers: 15342
NCI-2015-02282 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
15342 ( Other Identifier: City of Hope Comprehensive Cancer Center )
K12CA001727 ( U.S. NIH Grant/Contract )
P30CA033572 ( U.S. NIH Grant/Contract )
First Posted: February 3, 2016    Key Record Dates
Last Update Posted: June 21, 2019
Last Verified: May 2019
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases