PRIMARY OBJECTIVES:
I. To evaluate invasive disease free survival (iDFS) of multi-epitope HER2 vaccine versus
(vs.) placebo in combination with ado-trastuzumab emtansine (TTT-DM1) in patients with stage
II-III HER2 positive (+) breast cancer (BC) with residual disease post-neoadjuvant
chemotherapy.
II. To evaluate the safety of multi-epitope HER2 vaccine given concurrently with
ado-trastuzumab emtansine (T-DM1) maintenance therapy.
SECONDARY OBJECTIVES:
I. To evaluate immunogenicity of multi-epitope HER2 vaccine in combination with T-DM1
maintenance therapy.
II. To evaluate the immune-related tissue and blood biomarkers for complete pathological
response in patients with stage II-III HER2+ BC receiving neoadjuvant chemotherapy.
CORRELATIVE RESEARCH OBJECTIVES:
I. To determine host immune factors which are critical to prevent disease recurrence in HER2+
BC patients.
Ia. To determine if the development of T cell immunity, as assessed by IFN-gamma
enzyme-linked immunospot (ELISpot), to HER2 correlates with improved iDFS.
Ib. To determine the distribution of the helper T cell response among helper T cell
differentiation states.
Ic. To determine if augmenting CD4 helper T cell immunity augments HER2-specific antibody
immunity induced by trastuzumab.
Id. To determine if human leukocyte antigen (HLA) genotypes are associated with antibody
responses before and after neoadjuvant therapy and vaccination.
Ie. To determine gene expression levels in tumors from patients who did not achieve complete
pathological response (pCR) that are associated with recurrence.
II. To determine tumor intrinsic genotyping and phenotyping features associated with
therapeutic failure to HER2 immune-based approaches.
IIa. To determine whether HER2 monoclonal antibody therapy induces HER2 loss and modulation
of HER2-specific adaptive immune responses.
IIb. To determine loss-of-function mutations in breast tumor that associate with lack of pCR
and lack of immune response to HER2+ neoadjuvant treatment.
OUTLINE:
pCR AFTER NEOADJUVANT CHEMOTHERAPY AND SURGERY: Patients receive standard of care maintenance
therapy with trastuzumab and pertuzumab for 1 year in the absence of disease progression or
unacceptable toxicity.
NO pCR AFTER NEOADJUVANT CHEMOTHERAPY AND SURGERY: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive standard of care maintenance therapy with trastuzumab emtansine and
receive TPIV100 intradermally (ID) and sargramostim ID on day 1. Treatment repeats every 21
days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Patients then receive two additional booster injections of TPIV100 ID and sargramostim ID at
3 and 12 months after completion of trastuzumab emtansine maintenance therapy.
ARM II: Patients receive standard of care maintenance therapy with trastuzumab emtansine and
receive placebo ID and sargramostim ID on day 1. Treatment repeats every 21 days for up to 6
cycles in the absence of disease progression or unacceptable toxicity. Patients then receive
two additional booster injections of placebo ID and sargramostim ID at 3 and 12 months after
completion of trastuzumab emtansine maintenance therapy.
After completion of study treatment, patients with pCR are followed up at 30 days and 24
months. Patients with no pCR followed up at 30 days and at 3, 4, 12, 13, and 24 months. All
patients are then followed up every 6 months for up to 5 years.
Inclusion Criteria:
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Histologically confirmed
adenocarcinoma of the breast stage >= T2 OR >= N1 based on the 7th edition of tumor,
node, metastases (TNM) staging system from the American Joint Committee on Cancer
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Any estrogen receptor (ER)
or progesterone receptor (PR) but HER2 positive defined as 3+ staining intensity (on a
scale of 0 to 3) by means of immunohistochemistry (IHC) analysis OR gene amplification
on fluorescence in situ hybridization (FISH) ratio >= 2.0
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Patients must have
adequate pretreatment biopsy sample available
- NOTE: Adequate tissue samples defined as core needle biopsy or incisional biopsy
or excisional samples that can provide >= 3 core needle biopsies with at least 14
gauge (G) needle with 12 unstained sections of 5 micron thickness. Fine needle
aspiration (FNA) sample alone is not sufficient
- NOTE: Patients without adequate pretreatment biopsy samples must be agreeable to
have an additional research biopsy prior to neoadjuvant therapy
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Eastern Cooperative
Oncology Group (ECOG) performance status (PS) 0, 1, 2
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Willing to employ adequate
contraception from the time of pre-registration through 6 months after the final
vaccine cycle
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Willing to receive a
tetanus vaccination if subject has not had one =< 1 year prior to pre-registration
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Provide written informed
consent
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Willing to return to
enrolling institution for follow-up (during the Active Monitoring Phase of the study)
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Willing to provide
mandatory tissue and blood samples for correlative research purposes
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Negative pregnancy test
done =< 7 days prior to pre-registration, for persons of childbearing potential only
- NOTE: If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required
- REGISTRATION (SAFETY LEAD-IN): Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained
=< 28 days prior to registration)
- REGISTRATION (SAFETY LEAD-IN): Platelet count >= 75,000/mm^3 (obtained =< 28 days
prior to registration)
- REGISTRATION (SAFETY LEAD-IN): Hemoglobin >= 9.0 g/dL (obtained =< 28 days prior to
registration)
- REGISTRATION (SAFETY LEAD-IN): Direct bilirubin < 1.5 x upper limit of normal (ULN)
(obtained =< 28 days prior to registration)
- REGISTRATION (SAFETY LEAD-IN): Aspartate transaminase (AST) =< 3 x ULN (obtained =< 28
days prior to registration)
- REGISTRATION (SAFETY LEAD-IN): Creatinine =< 2 x ULN (obtained =< 28 days prior to
registration)
- REGISTRATION (SAFETY LEAD-IN): Prothrombin time (PT)/international normalized ratio
(INR)/ partial thromboplastin time (PTT) =< 1.5 x ULN OR if patient is receiving
anticoagulant therapy and PT or PTT is within therapeutic range of intended use of
coagulant (obtained =< 28 days prior to registration)
- REGISTRATION (SAFETY LEAD-IN): Completed planned curative breast surgeries (not
including any future breast reconstructive surgery) and any radiation therapy >= 30
days prior to registration
- REGISTRATION (SAFETY LEAD-IN): Completed last cycle of chemotherapy >= 90 days prior
to registration
- NOTE: Prior to randomization, patients must not receive >= 6 cycles of T-DM1
maintenance therapy after surgery
- REGISTRATION (SAFETY LEAD-IN): Have residual disease with >= 1 cm residual tumor in
the breast (>= ypT1c) and/or persistent lymph node positivity after trastuzumab +/-
pertuzumab based neoadjuvant chemotherapy
- REGISTRATION (SAFETY LEAD-IN): Adequate tissue specimens from both pre-treatment
biopsy and surgery must be submitted. Adequate tissue samples defined as core needle
biopsy or incisional biopsy or excisional samples that can provide >= 3 core needle
biopsies with at least 14G needle with 12 unstained sections of 5 micron thickness
- NOTE: Fine needle aspiration (FNA) sample alone is not sufficient
- REGISTRATION (SAFETY LEAD-IN): Negative pregnancy test done =< 7 days prior to
registration, for persons of childbearing potential only
- NOTE: If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required
- REGISTRATION (SAFETY LEAD-IN): ECOG performance status (PS) 0, 1, 2
- REGISTRATION (SAFETY LEAD-IN): Willing to employ adequate contraception from the time
of registration through 6 months after the final vaccine cycle
- REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): ECOG
performance status (PS) 0, 1, 2
- REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Absolute
neutrophil count (ANC) >= 1500/mm^3 (obtained =< 28 days prior to registration)
- REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Platelet
count >= 75,000/mm^3 (obtained =< 28 days prior to registration)
- REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Hemoglobin >=
9.0 g/dL (obtained =< 28 days prior to registration)
- REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Direct
bilirubin < 1.5 x upper limit of normal (ULN) (obtained =< 28 days prior to
registration)
- REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Aspartate
transaminase (AST) =< 3 x ULN (obtained =< 28 days prior to registration)
- REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Calculated
serum creatinine clearance of >= 50 mL/minute (min.) (obtained =< 28 days prior to
registration)
- REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): PT/INR/PTT =<
1.5 x ULN OR if patient is receiving anticoagulant therapy and PT or PTT is within
therapeutic range of intended use of coagulants (obtained =< 28 days prior to
registration)
- REGISTRATION - FOR PATIENTS WITH NO RESIDUAL DISEASE (pCR) - (PHASE II): Negative
pregnancy test done =< 7 days prior to registration, for person of childbearing
potential
- NOTE: If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Absolute neutrophil count (ANC)
>= 1500/mm^3 (obtained =< 28 days prior to randomization)
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Platelet count >= 75,000/mm^3
(obtained =< 28 days prior to randomization)
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Hemoglobin >= 9.0 g/dL (obtained
=< 28 days prior to randomization)
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Direct bilirubin < 1.5 x upper
limit of normal (ULN) (obtained =< 28 days prior to randomization)
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Aspartate transaminase (AST) =< 3
x ULN (obtained =< 28 days prior to randomization)
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Creatinine =< 2 x ULN (obtained
=< 28 days prior to randomization)
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): PT/INR/PTT =< 1.5 x ULN OR if
patient is receiving anticoagulant therapy and PT or PTT is within therapeutic range
of intended use of coagulant (obtained =< 28 days prior to randomization)
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Completed last cycle of
chemotherapy >= 90 days prior to randomization
- NOTE: Prior to randomization, patients must not receive >= 6 cycles of T-DM1
maintenance therapy after surgery
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Have residual disease with >= 1
cm residual tumor in the breast (>= ypT1c) and/or persistent lymph node positivity
after trastuzumab +/- pertuzumab based neoadjuvant chemotherapy
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Adequate tissue specimens from
both pre-treatment biopsy and surgery must be submitted. Adequate tissue samples
defined as core needle biopsy or incisional biopsy or excisional samples that can
provide >= 3 core needle biopsies with at least 14G needle with 12 unstained sections
of 5 micron thickness
- NOTE: Fine needle aspiration (FNA) sample alone is not sufficient
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Negative pregnancy test done =< 7
days prior to randomization, for persons of childbearing potential only
- NOTE: If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): ECOG performance status (PS) 0,
1, 2
- RANDOMIZATION - PATIENTS WITH RESIDUAL DISEASE POST NEOADJUVANT TRATUZUMAB +/-
PERTUZUMAB BASED CHEMOTHERAPY (NO pCR) - (PHASE II): Willing to employ adequate
contraception from the time of randomization through 6 months after the final vaccine
cycle
Exclusion Criteria:
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Any of the following
because this study involves an investigational agent whose genotoxic, mutagenic and
teratogenic effects on the developing fetus and newborn are unknown:
- Pregnant person
- Nursing person unwilling to stop breast feeding
- Person of child bearing potential who are unwilling to employ adequate
contraception from the time of registration through 6 months after the final
vaccine cycle
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Clinical evidence of local
recurrence or distant metastases
- NOTE: All patients must have either a positron emission tomography (PET)/computed
tomography (CT) or CT chest, abdomen, and pelvis with bone scan to rule out
distant metastases =< 90 days prior to preregistration. If any of these is
concerning, follow-up imaging or biopsy should be performed if indicated rule out
distant metastases
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Co-morbid systemic
illnesses or other severe concurrent disease which, in the judgment of the
investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Immunocompromised patients
including patients known to be human immunodeficiency virus (HIV) positive or those on
chronic steroids
- NOTE: Must be off systemic steroids at least 14 days prior to pre-registration.
However, topical steroids, inhalants or steroid eye drops are permitted
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Uncontrolled intercurrent
illness including, but not limited to, ongoing or active infection, symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Uncontrolled acute or
chronic medical conditions including, but not limited to the following:
- Active infection requiring antibiotics
- Congestive heart failure with New York Heart Association class III or IV;
moderate to severe objective evidence of cardiovascular disease
- Myocardial infarction or stroke =< 6 months prior to pre-registration
- Significant cardiac arrhythmia or unstable angina
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Receiving any other
investigational agent
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Other active malignancy at
time of pre-registration or =< 3 years prior to preregistration
- EXCEPTIONS: Non-melanoma skin cancer or carcinoma-in-situ (e.g. of cervix,
prostate)
- NOTE: If there is a history of prior malignancy, they must not be receiving other
specific treatment (cytotoxics, monoclonal antibodies, small molecule inhibitors)
for their cancer
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Known history of
autoimmune disease, including type I diabetes
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Any prior hypersensitivity
or adverse reaction to granulocyte-macrophage colony stimulating factor (GM-CSF)
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): History of
trastuzumab-related cardiac toxicity requiring interruption or discontinuation of
therapy, even if left ventricular ejection fraction (LVEF) fully recovered
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Baseline LVEF < 50%
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Failure to fully recover
from acute, reversible effects of prior chemotherapy regardless of interval since last
treatment
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): History of myocardial
infarction =< 168 days (6 months) prior to pre-registration, or congestive heart
failure requiring use of ongoing maintenance therapy for life threatening ventricular
arrhythmias
- PRE-REGISTRATION FOR ALL PATIENTS (INCLUDE SAFETY LEAD-IN): Patients who received
tamoxifen or raloxifene or another agent for prevention of breast cancer =< 2 months
prior to pre-registration
