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

NCT ID: NCT02673398

Last Updated: 2023-06-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-02
• Study Completion Date: 2022-09-22

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.

Conditions

HER2 Positive Breast Carcinoma; Stage IV Breast Cancer AJCC v6 and v7

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (neratinib)

Patients receive neratinib 240mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Comprehensive Geriatric Assessment

Intervention Type: OTHER

Ancillary studies

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Neratinib

Intervention Type: DRUG

Given PO

Pharmacological Study

Intervention Type: OTHER

Correlative studies

Interventions

Comprehensive Geriatric Assessment

Ancillary studies

Intervention Type: OTHER

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Neratinib

Given PO

Intervention Type: DRUG

Pharmacological Study

Correlative studies

Intervention Type: OTHER

Other Intervention 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

Eligibility 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

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

City of Hope Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mina Sedrak, MD

Role: PRINCIPAL_INVESTIGATOR

City of Hope Medical Center

Locations

City of Hope Corona

Corona, California, United States

City of Hope Medical Center

Duarte, California, United States

City of Hope Antelope Valley

Lancaster, California, United States

City of Hope Mission Hills

Mission Hills, California, United States

City of Hope Rancho Cucamonga

Rancho Cucamonga, California, United States

City of Hope South Pasadena

South Pasadena, California, United States

City of Hope West Covina

West Covina, California, United States

Countries

United States

References

Wong CW, Yost SE, Lee JS, Gillece JD, Folkerts M, Reining L, Highlander SK, Eftekhari Z, Mortimer J, Yuan Y. Analysis of Gut Microbiome Using Explainable Machine Learning Predicts Risk of Diarrhea Associated With Tyrosine Kinase Inhibitor Neratinib: A Pilot Study. Front Oncol. 2021 Mar 10;11:604584. doi: 10.3389/fonc.2021.604584. eCollection 2021.

Reference Type: DERIVED

PMID: 33796451 (View on PubMed)

Yuan Y, Lee JS, Yost SE, Stiller T, Blanchard MS, Padam S, Katheria V, Kim H, Sun C, Tang A, Martinez N, Patel ND, Sedrak MS, Waisman J, Li D, Sanani S, Presant CA, Mortimer J. Phase II study of neratinib in older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer. J Geriatr Oncol. 2021 Jun;12(5):752-758. doi: 10.1016/j.jgo.2021.02.020. Epub 2021 Mar 2.

Reference Type: DERIVED

PMID: 33663941 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2015-02282

Identifier Type: REGISTRY

Identifier Source: secondary_id

15342

Identifier Type: OTHER

Identifier Source: secondary_id

K12CA001727

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA033572

Identifier Type: NIH

Identifier Source: secondary_id

View Link

15342

Identifier Type: -

Identifier Source: org_study_id