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

• ClinicalTrials.gov Identifier: NCT02673398
• Recruitment Status: Active, not recruiting
• First Posted: February 3, 2016
• Last Update Posted: December 17, 2020
• Sponsor: City of Hope Medical Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): City of Hope Medical Center

Tracking Information

• First Submitted Date: January 21, 2016
• First Posted Date: February 3, 2016
• Last Update Posted Date: December 17, 2020
• Actual Study Start Date: December 2, 2016
• Estimated Primary Completion Date: October 22, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 23, 2019)

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.

Original Primary Outcome Measures (submitted: February 1, 2016)

Incidence of grade 2 or higher toxicities, graded according to the NCI CTCAE v4.0 [ Time Frame: Up to 30 days after the completion of study treatment ]

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.

Current Secondary Outcome Measures (submitted: May 23, 2019)

• 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.
• 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).
• 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.
• 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.
• 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.
• Clearance [ Time Frame: Day 15 of course 1 and day 1 of courses 3-4 ]
  Clearance will be estimated using population pharmacokinetic (PK) methods.
• 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.
• 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]).
• 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).
• Event free survival (EFS) [ Time Frame: Up to 48 months ]
  EFS will be estimated using the product limit method of Kaplan and Meier.
• 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.
• 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.
• 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.
• Adherence, as defined by pill count [ Time Frame: Up to 48 months ]
  Descriptive statistics will be provided for drug adherence and participant demographics.
• 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.

Original Secondary Outcome Measures (submitted: February 1, 2016)

• Adherence, as defined by pill count [ Time Frame: Up to 48 months ]
  Descriptive statistics will be provided for drug adherence and participant demographics.
• CBR, 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 [ Time Frame: Up to 48 months ]
  Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for clinical benefit (CR+PR+SD).
• IL-6 (interleukin-6), CRP (C reactive protein ), and D-dimer will be measured and descriptive statistics provided. [ Time Frame: Baseline to up to 48 months ]
  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.
• EFS [ Time Frame: Up to 48 months ]
  EFS will be estimated using the product limit method of Kaplan and Meier.
• 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.
• Incidence of all toxicities, graded according to the NCI CTCAE v4.0 [ Time Frame: Up to 30 days after the completion of study treatment ]
  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.
• Incidence of GI toxicities such as diarrhea, nausea and vomiting, graded according to the NCI CTCAE v4.0 [ Time Frame: Up to 30 days after the completion of study treatment ]
  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).
• ORR, measured by RECIST [ Time Frame: From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 48 months ]
  Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for objective response (complete remission [CR] + partial remission [PR]).
• 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.
• 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.
• Clearance will be estimated using population PK methods. [ Time Frame: Day 15 of course 1 and day 1 of courses 3-4 ]
• Volume of distribution will be estimated using population PK methods. [ Time Frame: Day 15 of course 1 and day 1 of courses 3-4 ]
• 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.
• 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.
• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Neratinib in Treating Older Patients With Stage IV HER2-Positive Breast Cancer
• Official Title: Phase II Study of Neratinib in Patients 60 and Older With HER2 Positive Metastatic Breast Cancer
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• 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

Study Arms

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.

Interventions:

• Other: Comprehensive Geriatric Assessment
• Other: Laboratory Biomarker Analysis
• Drug: Neratinib
• Other: Pharmacological Study

• Publications *: 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: February 1, 2016): 40
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 22, 2021
• Estimated Primary Completion Date: October 22, 2021 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02673398
• 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 )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: City of Hope Medical Center
• Study Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Yuan Yuan; City of Hope Comprehensive Cancer Center

• PRS Account: City of Hope Medical Center
• Verification Date: December 2020