Study Groups:
If participant is found to be eligible to take part in this study, participant will be
assigned to 1 of 3 study groups based on participant's screening results:
- If participant is in Group A or B, participant will receive neratinib, paclitaxel,
pertuzumab, and trastuzumab. The difference between these 2 groups is that the dose of
neratinib and paclitaxel may be different for participants in Group A, but all
participants in Group B will receive the same dose.
- If participant is in Group A, participant will be assigned to a dose level of neratinib
based on when participant joins this study. Up to 5 dose levels of neratinib will be
tested. Up to 20 total participants will be enrolled in Group A. The first group of
participants will receive the lowest dose level. Each new group will receive a higher
dose than the group before it, if no intolerable side effects were seen. This will
continue until the highest tolerable dose of neratinib is found. Participant will
receive 4 cycles of the study treatment. At the completion of the 4th cycle, depending
on participant's response, participant's doctor may decide to continue up to 4
additional cycles of the study therapy or start another treatment.
- If participant is in Group B, participant will receive doxorubicin and cyclophosphamide
after receiving 4 cycles of the drugs listed above.
- If participant is in Group C, participant will receive neratinib and paclitaxel followed
by doxorubicin and cyclophosphamide.
Study Drug Administration:
All participants will take neratinib 1 time a day by mouth for the first week as a 1-week
"pre-cycle". After that, all study cycles will be 21 days long and participant's drug
administration schedule will depend on what group participant is in.
If participant is in Group A:
- Participant will take neratinib tablets 1 time a day by mouth with food at the same time
each day (in the morning, if possible) during Cycles 1-4 (or up to 8 cycles). The study
doctor will tell participant how many tablets participant needs to take every day.
- Participant will receive paclitaxel by vein over about 1-3 hours on Days 1, 8, and 15 of
Cycles 1-4 (or up to 8 cycles).
- Participant will receive pertuzumab by vein over about 1 hour on Day 1 of Cycles 1-4.
- Participant will receive trastuzumab by vein over about 1-2 hours on Day 1 of Cycles 1-4
(or up to 8 cycles).
If participant is in Group B:
- Participant will take neratinib tablets 1 time a day by mouth with food at the same time
each day (in the morning, if possible) during Cycles 1 - 4. The study doctor will tell
participant how many tablets participant needs to take every day.
- Participant will receive paclitaxel by vein over about 1-3 hours on Days 1, 8, and 15 of
Cycles 1-4.
- Participant will receive pertuzumab by vein over about 1 hour on Day 1 of Cycles 1-4.
- Participant will receive trastuzumab by vein over about 1-2 hours on Day 1 of Cycles
1-4.
- Participant will receive standard-of-care doxorubicin and cyclophosphamide by vein over
about 90 minutes on Day 1 of Cycles 5 - 8.
If participant is in Group C:
- Participant will take neratinib tablets 1 time a day by mouth with food at the same time
each day (in the morning, if possible) during Cycles 1 - 4. The study doctor will tell
participant how many tablets participant needs to take every day.
- Participant will receive paclitaxel by vein over about 1 - 3 hours on Days 1, 8, and 15
of Cycles 1 - 4.
- Participant will receive standard-of-care doxorubicin and cyclophosphamide by vein over
about 90 minutes on Day 1 of Cycles 5 - 8.
If participant is in Group B or C, participant will have standard-of-care surgery after
participant finishes receiving doxorubicin and cyclophosphamide. Participant will receive a
separate consent form for the surgery that describes the procedure and its risks.
Participant will have a medication diary to record the information about taking neratinib.
Participant should bring this diary and the medication bottles with the leftover drug to the
clinic at the beginning of each cycles.
Length of Study:
Participant will receive up to 8 cycles of study drugs. Participant will no longer be able to
take the study drugs if the disease gets worse, if intolerable side effects occur, or if
participant is unable to follow study directions.
Participation on the study will be over after the follow-up period.
Study Visits:
Before participant receives study drug, at the end of the "pre-cycle", and then after Cycle
4, blood (about 3 teaspoons) will be drawn for research purposes, including genetic research.
If participant is in Group A:
- Before Day 1 of Cycle 1, participant will have a breast core biopsy to collect tissue
for biomarker testing.
- Blood ( about 3 teaspoons) will be collected for research purposes, including genetic
research.
- Before Day 1 of each cycle, and then before participant begins the next treatment,
participant will have a physical exam including a breast and lymph node exam.
- Before Day 1 of Cycle 1 and then before participant begins the next treatment after
Cycle 4, the study doctor will take pictures of both of participant's breasts.
- On Days 1, 8, and 15 of each cycle and before participant begins the next treatment
after Cycle 4, blood (about 1-3 tablespoon) will be drawn for routine tests.
- Before Day 1 of Cycle 1, and then before participant begins the next treatment after
Cycle 4, participant will have a mammogram of the involved breast and an ultrasound of
the involved breast and lymph nodes, or breast MRI if the doctor thinks it is needed.
- Participant will have a CT scan or PET CT scan or bone scan or chest X-ray after every 3
cycles if participant's doctor think it needed
- After Cycle 4, participant will have a MUGA scan or echocardiogram (ECHO) to check
participant's heart function.
- After Cycle 4 and participant still has breast tumor, participant will have another
biopsy to collect tissue for biomarker testing.
If participant is in Group B or C:
- Before Day 1 of Cycle 1, participant will have a breast core biopsy to collect tissue
for biomarker testing.
- Blood ( about 3 teaspoons) will be collected for research purposes, including genetic
research.
- Before Day 1 of each cycle and before surgery, participant will have a physical exam
including a breast and lymph node exam.
- Before Cycle 1 and Cycle 5, and then before surgery, the study doctor will take pictures
of both of participant's breasts.
- On the day of each cycle participant is receiving chemotherapy and then before surgery,
blood (about 1-3 tablespoon) will be drawn for routine tests.
- Before Day 1 of Cycle 1, before participant begins receiving doxorubicin and
cyclophosphamide, and then before surgery, participant will have a mammogram of the
involved breast and an ultrasound of the involved breast and lymph nodes, or breast MRI
if the doctor thinks it is needed.
- After Cycle 4, participant will have a MUGA scan or echocardiogram (ECHO) to check
participant's heart function. Participant may have a MUGA scan or ECHO every 3 months
thereafter if the doctor thinks it is needed.
- During surgery, breast tissue samples will be collected to identify tumors for routine
testing and for biomarker testing. No additional breast tissue will be removed in
addition to what would already be removed during surgery.
Follow-Up:
If participant is in Group A:
°About 1 month after the last dose of study drug, participant will be asked about
participant's health and any side effects participant may have had. Participant may be asked
during a routine clinic visit or participant may be called by a member of the study staff. If
participant is called, each call should last about 2 minutes.
If participant is in Group B or C:
- About 1 month after surgery, participant will be asked about participant's health and
any side effects participant may have had. Participant may be asked during a routine
clinic visit or participant may be called by a member of the study staff. If participant
is called, each call should last about 2 minutes.
- Then participant will be followed every 6 months for 2 years for disease status.
Participant may be asked during a routine clinic visit or participant may be called by a
member of the study staff. If participant is called, each call should last about 2
minutes.
Inclusion Criteria:
1. Histological confirmation of breast cancer
2. 18 years of age or older
3. Able to provide written informed consent for the trial
4. Performance status of </= 1 on the ECOG performance scale
5. Able to swallow oral medication
6. LVEF assessment by 2-D echocardiogram or MUGA scan performed within 90 days prior to
registration must be >/= 50%
7. 7. Adequate organ function as determined by the following laboratory values: Absolute
neutrophil count >/= 1,500 /uL, Platelets >/= 100,000 / uL, Hemoglobin >/=9 g/dL,
Creatinine clearance >/= 50 ml/min, Total bilirubin </= 1.5 X ULN, for patients with
congenital unconjugated hyperbilirubinemia (Crigler-Najjar syndrome type 1 and 2,
Gilbert syndrome) that transient hyperbilirubinemia can occur due to physiological
condition, as long as there is clear documentation of diagnosis, allowed to be
enrolled if direct (conjugated) bilirubin is ≤ 1.5 X ULN, Alanine aminotransferase and
aspartate aminotransferase </= 2.5 X ULN except in patients with AST/ALT elevation
that is declared to be caused due to liver metastasis, they are allowed to be enrolled
as long as <5 x ULN.
8. Subject of Childbearing potential should is willing to use effective methods of birth
control or be surgically sterile, or abstain from heterosexual activity during study
and at least 4 months after the last dose of study drug. Subject of childbearing
potential is defined as has not been surgically sterilized or free from menses for > 1
year.
9. Subject of childbearing potential is willing to use effective methods of birth control
include: 1) Use of hormonal birth control methods: pills, shots/injections, implants
(placed under the skin by a health care provider), or patches (placed on the skin); 2)
Intrauterine devices (IUDs); 3) Using 2 barrier methods (each partner must use 1
barrier method) with a spermicide. Males must use the male condom (latex or other
synthetic material) with spermicide. Females must choose either a Diaphragm with
spermicide, or Cervical cap with spermicide, or a sponge (spermicide is already in the
contraceptive sponge). Female patients of childbearing potential must have a negative
urine pregnancy test no more than 21 days prior to starting study drug; 4) For male
participant, they must agree and commit to use a barrier method of contraception while
on treatment and for 3 months after the last dose of investigational product.
10. Cohort 1: Phase 1b: Subject must have HER2 + (regardless of hormonal receptor status)
primary metastatic or locally advanced breast cancer (IBC or Non-IBC). HER2 positive
status is defined as strongly positive (3+) staining score by IHC, or gene
amplification using FISH, if performed. If IHC is equivocal (2+), assays using FISH
require gene amplification based on recent ASCO-CAP guideline: dual-probe HER2/CEP17
ratio is >/=2.0 and/or an average HER2 copy number >/= 6.0 signals/cell. IBC is
determined by using international consensus criteria: Onset: Rapid onset of breast
erythema, edema and/or peau d'orange, and/or warm breast, with/without an underlying
breast mass. Duration: History of such findings no more than 6 months. Extent erythema
occupying at least 1/3 of whole breast. Pathology: Pathologic confirmation of invasive
carcinoma
11. Cohort 1: Phase II: Patient must have HER2+ (regardless of hormonal receptor status)
stage III IBC.
12. Cohort 2 Patient must have HER2-/HR+ stage III IBC. HER2 negative status, which
determined by assays using IHC require negative (0 or 1+) staining score. If IHC is
equivocal (2+) staining score, assays using FISH require the absence of gene
amplification: dual-probe HER2/CEP17 ratio is < 2.0 and an average HER2 copy number
<4.0 signals/cell. If HER2 testing result is confirmed at MDACC, it does not require
centralized repeat testing. Hormone receptor (HR) positivity is determined by ER
>/=10% and /or PR >/=10% by IHC staining.
Exclusion Criteria:
1. Excisional biopsy or lumpectomy for the current breast cancer.
2. Any other previous malignancies (except for cervical in situ cancers treated only by
local excision, and basal and squamous cell carcinomas of the skin) within 5 years.
3. Any other previous antitumor therapies for the current cancer event. This exclusion
does not apply to phase Ib part of cohort 1.
4. Breast-feeding at screening or planning to become pregnant during the course of
therapy.
5. History of active or known autoimmune disease that can cause diarrhea like (but not
limited to) Addison's Disease, Celiac Disease/Gluten Intolerance/Irritable Bowel
Syndrome, Scleroderma.
6. Active infection or chronic infection requiring chronic suppressive antibiotics.
7. Known hepatitis B or hepatitis C with abnormal liver function tests.
8. Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of
the stomach or small bowel, or other disease or condition significantly affecting
gastrointestinal function.
9. Persistent >/= grade 2 diarrhea regardless of etiology.
10. Sensory or motor neuropathy >/= grade 2
11. Conditions that would prohibit intermittent administration of corticosteroids for
paclitaxel premedication. However, corticosteroid can be dropped after confirming of
no asthma like reaction to paclitaxel after 3 doses.
12. Uncontrolled hypertension defined as a systolic BP > 150 mmHg or diastolic BP > 90
mmHg, with or without anti-hypertensive medications.
13. Cardiac disease (history of and/or active disease) that would preclude the use of any
of the drugs included in the treatment regimen. This includes but is not confined to:
(A)Active cardiac diseases including: • symptomatic angina pectoris within the past
180 days that required the initiation of or increase in anti-anginal medication or
other intervention; • ventricular arrhythmias except for benign premature ventricular
contractions; • supraventricular and nodal arrhythmias requiring a pacemaker or not
controlled with medication; • conduction abnormality requiring a pacemaker; • valvular
disease with documented compromise in cardiac function; and • symptomatic
pericarditis. (B) History of cardiac disease: • myocardial infarction documented by
elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV
function; • history of documented CHF; and • documented cardiomyopathy.
14. If you are pregnant, you will not be enrolled on this study
