Trial of Pre-operative Neratinib and Endocrine Therapy With Trastuzumab in ER-Positive, HER-2 Positive Breast Cancers

Breast Cancer Clinical Trial

Official title:

An Open Label, Phase II Trial of Pre-operative Neratinib and Endocrine Therapy With Trastuzumab in ER-Positive, HER-2 Positive Cancers Hoosier Cancer Research Network BRE17-141

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04886531
• Other study ID #: HCRN BRE17-141
• Status: Recruiting
• Phase: Phase 2
• Start date: July 21, 2022
• Est. completion date: May 2024

Study information

• Verified date: March 2024
• Source: Hoosier Cancer Research Network
• Contact: Ruth O'Regan, MD
• Phone: 608-265-9701
• Email: ruth_oregan[@]urmc.rochester.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patient will be treated with neratinib, an aromatase inhibitor and trastuzumab for 24 weeks prior to surgery, following an initial 3 weeks of neratinib alone, aromatase inhibitor alone or the combination of neratinib and an aromatase inhibitor. A breast biopsy will be performed prior to Day 1 of week 4 of treatment. Following surgery, patients will receive standard of care HER2-directed and endocrine therapy at the treating physician's discretion.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 48
• Est. completion date: May 2024
• Est. primary completion date: May 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

• Age = 18 years at the time of consent.

• Postmenopausal females. NOTE: Postmenopausal status defined as: prior bilateral oophorectomy, Age = 60 years, or Age < 60 years and amenorrhea for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) or an estradiol level in postmenopausal ranges per local reference range.

• ECOG Performance Status of 0-2 within 28 days prior to registration.

• Anatomic, clinical stage I-III, invasive breast cancer, greater than 10mm

• HER2-positive (by the most recent ASCO-CAP criteria)

• ER positive (= 10%). NOTE: There is no requirement for PR status; PR positive or negative allowed.

• Resectable breast cancer in which pre-operative therapy is appropriate (T > 10mm and/or node-positive).

• Archival tissue from the diagnostic pre-treatment biopsy is required. This sample should be identified at screening and shipped by Week 4. If archival tissue is not available, the subject is not eligible for the study.

• Agreeable to repeat breast biopsy at 3 weeks after initiation of treatment.

• Candidate for either letrozole or anastrozole, as determined by the treating physician

• Left ventricular ejection fraction (LVEF) = 50% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) documented within 4 weeks prior to the study treatment.

• Demonstrate adequate organ function as defined below; all screening labs to be obtained within 28 days prior to registration.

• Hematological

• Platelet count =100,000/uL

• Absolute Neutrophil Count (ANC) =1500/uL

• Hemoglobin (Hgb) =10 g/dL

• Renal

---Calculated creatinine clearance: CrCl =60 mL/min using the Cockcroft-Gault formula

• Hepatic

• Bilirubin =1.5 x upper limit of normal (ULN)

• Aspartate aminotransferase (AST) = 2.5 × ULN

• Alanine aminotransferase (ALT) = 2.5 × ULN

• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.

• For patients with known serologic evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial.

• Ability of the subject to understand and comply with study procedures for the entire length of the study, as determined by the enrolling physician or protocol designee.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

• Locally advanced or inflammatory breast cancer.

• Evidence of metastatic disease. Systemic imaging is not required.

• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial: exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years.

• Active infection requiring systemic therapy.

• Requirement for use of a moderate or stonr CYP3A4 inhibitor or inducer during the study (see protocol).

• Treatment with any investigational drug within 14 days prior to registration or within 5 half-lives of the investigational product, whichever is longer.

• Subject has had major surgery within 14 days prior to registration or has not recovered from major side effects of the surgery (tumor biopsy is not considered as major surgery).

• Any impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) or significantly impair the ability to swallow capsules/tablets.

• Known history of myelodysplastic syndrome or acute myeloid leukemia.

• Subjects with any of the following conditions:

• History of abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within 28 days prior to registration.

• Any history of cerebrovascular accident (CVA) or transient ischemic attack within 12 months prior to registration.

• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to registration.

• Symptomatic congestive heart failure (New York Heart Association III-IV) or documented current cardiomyopathy with left ventricular ejection fraction (LVEF) <50%.

• Clinically significant cardiac ventricular arrhythmias (e.g. sustained ventricular tachycardia/ventricular fibrillation) or high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block) unless a pacemaker is in place.

• Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.

• Any concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate subject participation in the clinical study or compromise compliance with the protocol.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• ER Positive Breast Cancer
• HER2-positive Breast Cancer
• PR-Positive Breast Cancer

Intervention

Drug:
• Neratinib
120mg for 7 days; 160mg for 7 days ; 240mg for 7 days. 240 mg (up to a maximum of 24 weeks) orally daily*.
• Letrozole (L) or Anastrozole (A)
L: (2.5 mg) OR A: (1 mg) orally daily (up to a maximum of 24 weeks)*
• Trastuzumab
All Arms 8mg/kg loading dose followed by 6mg/kg every 3 weeks administered every 3 weeks by IV starting wk 4. Trastuzumab biosimilars may be used per institutional guidelines.

Locations

Country	Name	City	State
United States	University of Illinois Cancer Center	Chicago	Illinois
United States	Penn State Cancer Institute	Hershey	Pennsylvania
United States	University of Wisconsin	Madison	Wisconsin
United States	University of Rochester Medical Center	Rochester	New York

Sponsors (3)

Lead Sponsor	Collaborator
Ruth O'Regan	Puma Biotechnology, Inc., University of Rochester

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathologic Complete Response (pCR)	pCR is defined as the lack of all signs of invasive cancer in the breast removed during surgery	24 weeks
Secondary	Assess Adverse Events	Assess the adverse events of neratinib in combination with NSAI in subjects	24 weeks
Secondary	Pathological Complete Response (pCR)	Estimate the pCR (ypT0/Tis ypN0) in the breast tissue and lymph nodes	24 weeks
Secondary	Measure Residual Disease	Estimate residual disease in the breast tissue	24 weeks