Neratinib with or without Fulvestrant in Treating Patients with HER2 and Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer That Cannot Be Removed by Surgery
This randomized phase II trial studies how well neratinib with or without fulvestrant works in treating patients with HER2 and estrogen receptor positive breast cancer that has spread to other places in the body or cannot be removed by surgery. Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include HER2. Drugs used in chemotherapy, such as fulvestrant, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving neratinib with or without fulvestrant will work better in treating patients with breast cancer.
- Participants must have histologically or cytologically confirmed inoperable locally advanced or metastatic ER+ breast cancer; to fulfill the requirement for ER+ disease, a breast cancer must express, by immunohistochemistry (IHC), ER in >= 10% of cells, on the most recent biopsy; central confirmation of ER status is not required
- Participants must have documented HER2+ disease by overexpression and/or gene amplification on the most recent biopsy, per current ASCO-CAP (American Society of Clinical Oncology – College of American Pathologists) 2013 guidelines; central confirmation of HER2 status is not required
- Participants must have received prior therapy with the following agents in any combination, and in setting (i.e., neoadjuvant, adjuvant, metastatic, etc.); these therapies do not need to be the most recent line of therapy * Trastuzumab * Pertuzumab * Ado-trastuzumab emtansine (T-DM1)
- Participants must agree to undergo a research biopsy of a reasonably accessible metastatic lesion (chest wall, skin, subcutaneous tissue, lymph nodes, skin, breast, bones, lung, and liver metastases); if a reasonably accessible metastatic lesion is not available, the patient may go on study provided that archived tissue is available; however, if a reasonably accessible site is available for biopsy, the patient must agree to biopsy; any patients not undergoing biopsy must be approved for study enrollment by the overall principal investigator at Dana-Farber Cancer Institute (DFCI); biopsies may be done with local anesthesia or intravenous conscious sedation, according to institutional guideline; if a biopsy requires general anesthesia, then it is only allowed if acquisition of tissue is clinically indicated, and excess tissue may be collected for research purposes; patients without sites available for biopsy must have available tissue (archived formalin-fixed paraffin embedded blocks [FFPB], blocks from which slides can be created, or fresh frozen tissue from original diagnosis or metastatic setting) for correlative studies; tissue needs to be located and available at the time of registration
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Absolute neutrophil count >= 1,000/uL
- Platelets >= 75,000/uL
- Hemoglobin >= 8 g/dL
- Total bilirubin =< 1.5 X institutional upper limit of normal (ULN); in case of known Gilbert’s syndrome, < 2 x ULN is allowed
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 X institutional ULN without liver metastases, or =< 5 X institutional ULN with liver metastases
- Creatinine clearance >= 50 mL/min
- Left ventricular ejection fraction >= 50%, as determined by radionuclide ventriculogram (RVG) (multigated acquisition [MUGA]) or echocardiogram (ECHO) within 60 days prior to initiation of protocol therapy
- Participants may have received any number of prior therapies as long as they have adequate performance status and meet all other eligibility criteria
- Women of childbearing potential (including premenopausal women and women less than 12 months after menopause) must have a negative beta-human chorionic gonadotropin (hCG) urine pregnancy test within 4 weeks of registration
- Women of child-bearing potential must agree to be abstinent, or to use a highly effective double barrier method of contraception (e.g, a combination of male condom with an intravaginal device such as the cervical cap, diaphragm, or vaginal sponge with spermicide) or a non-hormonal method, while enrolled in the study, until at least 28 days after the last dose of neratinib or 1 year after the last dose of fulvestrant; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately; if a woman is of childbearing potential, she must agree to use adequate contraception prior to the study, for the duration of study participation, and for one year after completion of the study drug
- Ability to understand and willingness to sign a written informed consent document
- Participants who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to neratinib or fulvestrant
- Participants who have known hypersensitivity to any component of loperamide or budesonide
- Participants who have received previous therapy with neratinib or fulvestrant
- Participants who have received anti-cancer therapy (including chemotherapy, biological therapy, investigational agents, hormonal therapy, or other anti-cancer therapy) or radiotherapy within =< 14 days prior to the planned initiation of investigational products, or those who have not recovered to grade =< 1 from adverse events due to their most recent therapy (excepting alopecia)
- Participants who have had any major surgery =< 28 days prior to the planned initiation of study therapy, or those who have not recovered from adverse events due to agents/surgery administered more than 4 weeks earlier
- Participants who are receiving any other investigational agents
- Participants with symptomatic or progressive brain metastases, or requiring steroids to control symptoms of brain metastases
- Participant has active, uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia
- Participant has a corrected QT (QTc) interval > 470 ms or known history of QTc prolongation or Torsade de Pointes
- Participant has an active infection or unexplained fever > 38.5 degrees Celsius (C) (101.3 degrees Fahrenheit [F])
- Participant has had another malignancy within the past 5 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the breast, cervix or vulva; or 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
- Participant has 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) version (v.) 4.0] diarrhea of any etiology at screening)
- Participant has known active infection with hepatitis B or hepatitis C virus; hepatitis B and C serology testing is not required, unless active infection is suspected
- Participant is unable or unwilling to swallow tablets
- Participant has evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that would, in the investigator’s judgment, limit compliance with study requirements
- Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with neratinib and/or fulvestrant
Locations & Contacts
Contact: Tarah J. Ballinger
Contact: Sarah J. Sinclair
Contact: Heather A. Parsons
Contact: Heather A. Parsons
Contact: Michael Joseph DeLeo
Contact: Frederick M. Briccetti
Contact: Robert Wesolowski
Contact: Barbara Jean B. Haley
Trial Objectives and Outline
I. To estimate the efficacy, as measured by progression free survival (PFS), of neratinib combined with fulvestrant compared with neratinib alone in patients with inoperable locally advanced or metastatic HER2-positive, estrogen receptor (ER)-positive breast cancer.
I. To estimate the efficacy, as measured by overall survival (OS) of neratinib combined with fulvestrant compared with neratinib alone in patients with inoperable locally advanced or metastatic HER2-positive, ER-positive breast cancer.
II. To estimate the clinical activity, as measured by overall response rate (ORR) of neratinib combined with fulvestrant compared with neratinib alone in patients with inoperable locally advanced or metastatic HER2-positive, ER-positive breast cancer.
III. To estimate the clinical activity, as measured by duration of response, of neratinib combined with fulvestrant compared with neratinib alone in patients with inoperable locally advanced or metastatic HER2-positive, ER-positive breast cancer.
I. To determine the proportion of patients with ESR1 gene mutations in baseline tumor tissue.
II. To determine the proportion of patients with PIK3CA gene mutations and loss of PTEN expression in baseline tumor tissue.
III. To determine the proportion of patients with PIK3CA gene mutations in circulating tumor deoxyribonucleic acid (DNA) (ctDNA) from blood obtained at study baseline.
IV. To determine concordance of PIK3CA mutation status assessed in circulating free tumor DNA and distant metastasis specimens (i.e. liquid and solid biopsies).
V. To determine concordance of ESR1 mutation status assessed in circulating free tumor DNA and distant metastasis specimens (i.e. liquid and solid biopsies).
VI. To perform molecular characterization of potential resistance mechanisms, predictive biomarkers, and immunological function by collecting blood and tumor specimens.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive neratinib orally (PO) once daily (QD) on days 1-28 and fulvestrant intramuscularly (IM) on days 1 and 15 of course 1 and day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive neratinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 5 years.
Trial Phase & Type
Dana-Farber Harvard Cancer Center
Heather A. Parsons
Secondary IDs NCI-2017-02356
Clinicaltrials.gov ID NCT03289039