Neoadjuvant Neratinib for the Treatment of Stage I-III HER2-Mutated Lobular Breast Cancers
Neoadjuvant Neratinib for the Treatment of Stage I-III HER2-Mutated Lobular Breast Cancers
This phase II trial tests how well neratinib prior to the primary treatment (neoadjuvant) works in treating patients with stage I-III HER2 mutated lobular breast cancers. Neratinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving neratinib in addition to normal therapy may work better in treating cancer than the endocrine therapy patients would normally receive.
Not Available
Phase II
Adults
Not Available
Not Available
Not Available
National
Baylor Breast Center, Duke University Medical Center, Emory University, Houston Methodist Hospital, M.D. Anderson Cancer Center, Houston, UT Southwestern Medical Center, University of Pittsburgh, Vanderbilt University
05-30-2024
Eligibility
18 Years
BOTH
NO
Inclusion Criteria:
Subjects aged 18 years or older at signing of informed consent
New diagnosis of clinical stage I-III hormone receptor (HR)+ histologically-proven (i.e. absent or decreased e-cadherin expression) invasive lobular carcinoma
Synchronous breast tumors are permitted as long as the synchronous tumor is estrogen receptor (ER)+ and HER2-negative
ER+ disease defined as >= 1% estrogen receptor (ER) positive consistent with current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or European Society of Medical Oncology (ESMO) guidelines)
At the time of screening, histologically confirmed cancers in patients with previously documented activating HER2 mutation confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent laboratory
Archival tissue availability (if not available a fresh tumor biopsy will be required) and subject must agree to submission of sample for central testing
Minimum tumor size of >= 5 cm by ultrasound (US), mammogram, magnetic resonance imaging (MRI) imaging, or clinical breast exam
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Estimated glomerular filtration rate of >= 50 mL/min (Cockcroft-Gault formula) (obtained within 1 month of study entry)
Albumin >= 2.5 g/dL (obtained within 1 month of study entry)
Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained within 1 month of study entry)
Platelet count >= 100,000/mm^3 (obtained within 1 month of study entry)
Hemoglobin (HgB) >= 9 g/dL (obtained within 1 month of study entry)
Total serum bilirubin = 1.5 x upper limit of normal (ULN) (in patients with known Gilbert Syndrome, a total bilirubin = 3.0 x ULN, with direct bilirubin = 1.5 x ULN) (obtained within 1 month of study entry)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3 x ULN (obtained within 1 month of study entry)
Pre-, peri-, or post-menopausal, confirmed by history or laboratory testing as needed
Diagnostic biopsy tissue availability with sufficient tumor to permit next generation sequencing (NGS) (if not available, a fresh biopsy will be required)
No prior treatment for current diagnosis of breast cancer
For patients who are not postmenopausal (women) or surgically sterile (absence of ovaries and/or uterus or vasectomy), agreement to remain abstinent or to use two adequate methods of contraception (e.g., condoms, diaphragm, vasectomy/vasectomized partner, tubal ligation), during the treatment period and for at least 30 days after the last dose of study treatment. Hormone based oral contraceptives are not allowed on study. Postmenopausal is defined as: * Age >= 55 years * Age = 55 years and amenorrheic for 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression; or follicle stimulating hormone and estradiol in the postmenopausal range
Female participants of childbearing potential are eligible to participate if they agree to use a highly effective method of contraception that has a lo used dependency consistently and correctly. Note: The effects of neratinib of the developing fetus are unknown and endocrine therapy is contraindicated in pregnancy. For this reason and because teratogenic effects have been observed in nonclinical studies and neratinib, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstenence) prior to study entry and for the duration of the study participation, and for 1 month after the last dose of study medication. Should a woman become pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation and 3.5 months after completion of study treatment
Exclusion Criteria:
Evidence of distant metastatic disease
Synchronous breast cancer that is estrogen receptor negative OR HER2-amplified OR requires treatment with neoadjuvant chemotherapy per the judgement of the treating physician
Patients harboring ineligible somatic HER2 mutations, such as those that are subclonal in nature or those resulting in the expression of truncated proteins including alterations that result in premature stop codon or a change in reading frame (ie, frame shift mutations)
Prior endocrine therapy for breast cancer within the last 2 years
Women who are pregnant, are planning to become pregnant, or are breast-feeding
Any investigational treatment for the current diagnosis of breast cancer
HER2 amplification by fluorescence in situ hybridization (FISH) (HER2:CEP17 ratio >2.0) or immunohistochemistry (IHC) (HER2 3+)
Hepatic function impairment as defined by AST or ALT > 3x ULN OR total serum bilirubin > 1.5 (in patients with known Gilbert syndrome, a total bilirubin of > 3.0 x ULN or direct bilirubin > 1.5 x ULN)
Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohns disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE version 4.0] diarrhea of any etiology at baseline
Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the Investigators judgment, make the patient inappropriate for this study
Known hypersensitivity to any component of the investigational product, required combination therapy, or loperamide
Unable or unwilling to swallow tablets
Unable or unwilling to complete study procedures such as research biopsies or imaging
Any medical condition that in the judgement of the co-investigator would impair the patients ability to complete the planned study therapy
Subjects aged 18 years or older at signing of informed consent
New diagnosis of clinical stage I-III hormone receptor (HR)+ histologically-proven (i.e. absent or decreased e-cadherin expression) invasive lobular carcinoma
Synchronous breast tumors are permitted as long as the synchronous tumor is estrogen receptor (ER)+ and HER2-negative
ER+ disease defined as >= 1% estrogen receptor (ER) positive consistent with current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or European Society of Medical Oncology (ESMO) guidelines)
At the time of screening, histologically confirmed cancers in patients with previously documented activating HER2 mutation confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent laboratory
Archival tissue availability (if not available a fresh tumor biopsy will be required) and subject must agree to submission of sample for central testing
Minimum tumor size of >= 5 cm by ultrasound (US), mammogram, magnetic resonance imaging (MRI) imaging, or clinical breast exam
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Estimated glomerular filtration rate of >= 50 mL/min (Cockcroft-Gault formula) (obtained within 1 month of study entry)
Albumin >= 2.5 g/dL (obtained within 1 month of study entry)
Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained within 1 month of study entry)
Platelet count >= 100,000/mm^3 (obtained within 1 month of study entry)
Hemoglobin (HgB) >= 9 g/dL (obtained within 1 month of study entry)
Total serum bilirubin = 1.5 x upper limit of normal (ULN) (in patients with known Gilbert Syndrome, a total bilirubin = 3.0 x ULN, with direct bilirubin = 1.5 x ULN) (obtained within 1 month of study entry)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3 x ULN (obtained within 1 month of study entry)
Pre-, peri-, or post-menopausal, confirmed by history or laboratory testing as needed
Diagnostic biopsy tissue availability with sufficient tumor to permit next generation sequencing (NGS) (if not available, a fresh biopsy will be required)
No prior treatment for current diagnosis of breast cancer
For patients who are not postmenopausal (women) or surgically sterile (absence of ovaries and/or uterus or vasectomy), agreement to remain abstinent or to use two adequate methods of contraception (e.g., condoms, diaphragm, vasectomy/vasectomized partner, tubal ligation), during the treatment period and for at least 30 days after the last dose of study treatment. Hormone based oral contraceptives are not allowed on study. Postmenopausal is defined as: * Age >= 55 years * Age = 55 years and amenorrheic for 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression; or follicle stimulating hormone and estradiol in the postmenopausal range
Female participants of childbearing potential are eligible to participate if they agree to use a highly effective method of contraception that has a lo used dependency consistently and correctly. Note: The effects of neratinib of the developing fetus are unknown and endocrine therapy is contraindicated in pregnancy. For this reason and because teratogenic effects have been observed in nonclinical studies and neratinib, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstenence) prior to study entry and for the duration of the study participation, and for 1 month after the last dose of study medication. Should a woman become pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation and 3.5 months after completion of study treatment
Exclusion Criteria:
Evidence of distant metastatic disease
Synchronous breast cancer that is estrogen receptor negative OR HER2-amplified OR requires treatment with neoadjuvant chemotherapy per the judgement of the treating physician
Patients harboring ineligible somatic HER2 mutations, such as those that are subclonal in nature or those resulting in the expression of truncated proteins including alterations that result in premature stop codon or a change in reading frame (ie, frame shift mutations)
Prior endocrine therapy for breast cancer within the last 2 years
Women who are pregnant, are planning to become pregnant, or are breast-feeding
Any investigational treatment for the current diagnosis of breast cancer
HER2 amplification by fluorescence in situ hybridization (FISH) (HER2:CEP17 ratio >2.0) or immunohistochemistry (IHC) (HER2 3+)
Hepatic function impairment as defined by AST or ALT > 3x ULN OR total serum bilirubin > 1.5 (in patients with known Gilbert syndrome, a total bilirubin of > 3.0 x ULN or direct bilirubin > 1.5 x ULN)
Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohns disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE version 4.0] diarrhea of any etiology at baseline
Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the Investigators judgment, make the patient inappropriate for this study
Known hypersensitivity to any component of the investigational product, required combination therapy, or loperamide
Unable or unwilling to swallow tablets
Unable or unwilling to complete study procedures such as research biopsies or imaging
Any medical condition that in the judgement of the co-investigator would impair the patients ability to complete the planned study therapy
