Trial Title:
Neoadjuvant Neratinib in Stage I-III HER2-Mutated Lobular Breast Cancers
NCT ID:
NCT05919108
Condition:
Anatomic Stage I Breast Cancer
Anatomic Stage II Breast Cancer
Anatomic Stage III Breast Cancer
Invasive Breast Lobular Carcinoma
Conditions: Official terms:
Breast Neoplasms
Carcinoma, Lobular
Neratinib
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Endocrine Therapy
Description:
Undergo endocrine therapy
Arm group label:
Treatment A (endocrine therapy)
Arm group label:
Treatment B (endocrine therapy, neratinib)
Intervention type:
Procedure
Intervention name:
Biopsy of breast
Description:
Undergo breast biopsy
Arm group label:
Treatment A (endocrine therapy)
Arm group label:
Treatment B (endocrine therapy, neratinib)
Intervention type:
Drug
Intervention name:
Neratinib
Description:
Taken by mouth
Arm group label:
Treatment A (endocrine therapy)
Arm group label:
Treatment B (endocrine therapy, neratinib)
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo collection of blood samples
Arm group label:
Treatment A (endocrine therapy)
Arm group label:
Treatment B (endocrine therapy, neratinib)
Intervention type:
Procedure
Intervention name:
Mammogram
Description:
Undergo Mammogram
Arm group label:
Treatment A (endocrine therapy)
Arm group label:
Treatment B (endocrine therapy, neratinib)
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo breast Magnetic Resonance Imaging
Arm group label:
Treatment A (endocrine therapy)
Arm group label:
Treatment B (endocrine therapy, neratinib)
Intervention type:
Procedure
Intervention name:
Breast Surgery
Description:
Undergo Breast Surgery
Arm group label:
Treatment A (endocrine therapy)
Arm group label:
Treatment B (endocrine therapy, neratinib)
Intervention type:
Procedure
Intervention name:
Ultrasound
Description:
Undergo Ultrasound
Arm group label:
Treatment B (endocrine therapy, neratinib)
Summary:
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.
Detailed description:
PRIMARY OBJECTIVE:
I. Determine efficacy of neoadjuvant neratinib in combination with endocrine therapy.
SECONDARY OBJECTIVES:
I. Determine additional efficacy outcomes of neoadjuvant neratinib in combination with
endocrine therapy.
II. Compare the safety and tolerability of neratinib plus endocrine therapy.
CORRELATIVE OBJECTIVE:
I. Establish HER2-mutant invasive lobular carcinoma (ILC) organoids.
OUTLINE: Patients are randomized to 1 of 2 treatments.
TREATMENT A: Patients receive standard of care endocrine therapy over 4 weeks for 1
cycle. Patients undergo breast tissue biopsy during the lead-in window/cycle 1. Patients
then endocrine therapy and neratinib orally (PO) daily for 20 weeks in the absence of
disease progression or unacceptable toxicity. Patients undergo breast surgery during
weeks 24-25. Patients undergo collection of blood samples every 4 weeks while on
treatment, at weeks 4 and 24, and at time of surgery. Patients undergo mammogram,
ultrasound, or breast magnetic resonance imaging (MRI) prior to surgery.
TREATMENT B: Patients receive standard of care endocrine therapy and neratinib PO over 4
weeks for 1 cycle. Patients undergo breast tissue biopsy during the lead-in window/cycle
1. Patients then continue endocrine therapy and neratinib PO daily for 20 weeks in the
absence of disease progression or unacceptable toxicity. Patients undergo breast surgery
during weeks 24-25. Patients undergo collection of blood samples every 4 weeks while on
treatment, at weeks 4 and 24, and at time of surgery. Patients undergo mammogram,
ultrasound, or breast MRI prior to surgery.
After completion of study treatment, patients are followed up for 4 weeks after study
drugs interruption.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
Each patient will be entered into this study only if all of these criteria are met:
- Subjects aged 18 years or older at signing of informed consent.
- New diagnosis of clinical stage I-III 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 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 (see Appendix A) 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 ≥1.5 cm by US, mammogram, MRI imaging, or clinical breast exam
- ECOG performance status 0 or 1
- Patients must have adequate hematologic, hepatic, and renal function. All laboratory
tests must be obtained within 1 month of study entry. This includes:
- Estimated glomerular filtration rate of ≥50 mL/min
- Albumin ≥ 2.5 g/dL
- ANC ≥1500/mm^3
- Platelet count ≥100,000/mm^3
- HgB ≥ 9 g/dL
- Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a
total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
- AST and ALT ≤ 3 x ULN
- Pre-, peri-, or post-menopausal, confirmed by history or laboratory testing as
needed
- Diagnostic biopsy tissue availability with sufficient tumor to permit 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 low user dependency consistently and
correctly.
Note: The effects of neratinib on 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;
abstinence) 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 FISH (HER2:CEP17 ratio >2.0) or 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,
Crohn's 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 Investigator's 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
patient's ability to complete the planned study therapy
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Emory University/ Winship Cancer Institute
Address:
City:
Atlanta
Zip:
30322
Country:
United States
Status:
Not yet recruiting
Investigator:
Last name:
Kevin Kalinsky, MD
Email:
Principal Investigator
Facility:
Name:
University of Pittsburgh Medical Center
Address:
City:
Pittsburgh
Zip:
15213
Country:
United States
Status:
Not yet recruiting
Investigator:
Last name:
Adam Brufsky, MD
Email:
Principal Investigator
Facility:
Name:
Vanderbilt University/Ingram Cancer Center
Address:
City:
Nashville
Zip:
37203
Country:
United States
Status:
Recruiting
Contact:
Last name:
Vanderbilt-Ingram Service for Timely Access
Phone:
800-811-8480
Email:
cip@vumc.org
Investigator:
Last name:
Laura Kennedy, MD, PhD
Email:
Principal Investigator
Facility:
Name:
University of Texas, Southwestern
Address:
City:
Dallas
Zip:
75390
Country:
United States
Status:
Not yet recruiting
Investigator:
Last name:
Carlos Arteaga, MD
Email:
Principal Investigator
Facility:
Name:
Baylor College of Medicine
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Not yet recruiting
Investigator:
Last name:
Bora Lim, MD
Email:
Principal Investigator
Start date:
September 30, 2024
Completion date:
April 30, 2031
Lead sponsor:
Agency:
Vanderbilt-Ingram Cancer Center
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Collaborator:
Agency:
Puma Biotechnology, Inc.
Agency class:
Industry
Source:
Vanderbilt-Ingram Cancer Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05919108
