This study will look to establish the recommended biologic dose of AE37 in combination with
pembrolizumab that will enhance the tumor-specific immune response and demonstrate efficacy
in patients with advanced triple-negative breast cancer.
This study will take place in two parts. Stage 1 will be the safety cohort (13 patients) to
determine the recommended dose of AE37 vaccine that can safely be administered with
pembrolizumab. Stage 2 will be an expansion cohort (16 patients) that will consist of the
recommended dose of AE37 determined in Stage 1.
The FB-14 is an open label, phase II study using pembrolizumab in combination with AE37
peptide vaccine (AE37) in patients with metastatic triple-negative breast cancer (mTNBC).
This study will have a Simon two-stage design. In Stage I (safety cohort), 13 patients will
receive combination therapy of AE37 vaccine (without granulocyte macrophage-colony
stimulating factor [GM-CSF] adjuvant) 1000 micrograms in two split intradermal injections on
Day 1 of cycles 1 through 5 and pembrolizumab 200 mg intravenous infusion (IV) given Day 1 of
each cycle for 2 years (1 cycle equals 21 days).
All patients (safety and expansion cohorts) will receive two delayed type hypersensitivity
inoculations (DTH): the first within one week prior to beginning study therapy, which must
meet the parameters of negative inoculation site assessment for eligibility as described in
the protocol; and the second approximately 42 days after the last AE37 vaccine dose.
During a safety run-in, the first 3 patients will be closely followed for 6 weeks following
the first dose of study therapy (2 cycles) without further accrual of patients. If one or
less of the first 3 patients experience greater than or equal to Grade 3 systemic dose
limiting toxicity (DLT) attributable to study therapy during the observation period, the
safety run-in portion of the study will proceed with enrollment at the proposed study therapy
dose (AE37 1000 micrograms and pembrolizumab 200 mg IV infusion). If there are two or more
patients in the safety run-in with DLT during Cycle 1, the dose of AE37 will be decreased to
dose level −1 (500 micrograms) to complete stage I accrual. The definition of a DLT is found
in the protocol.
If DLT is observed during the safety run-in or in greater than 25% (4 or more) of patients in
stage I, the AE37 dose will be de-escalated to 500 micrograms (dose level −1) for all
patients to complete stage I accrual. If systemic toxicity occurs in greater than or equal to
3 patients at dose level −1, accrual will be halted and the toxicity reviewed by the study
- Have a performance status of 0 or 1 on the (Eastern Cooperative Oncology Group) ECOG
- Patients must have histologic or cytologic confirmation of the diagnosis of invasive
adenocarcinoma of the breast.
- The primary or metastatic tissue must be triple-negative (ER/PR less than or equal to
9%, HER2-negative [human epidermal growth factor receptor 2] by American Society of
Clinical Oncology (ASCO)/ College of American Pathologists (CAP) guidelines).
- There must be documentation that the patient has evidence of measurable metastatic
breast cancer based on RECIST 1.1. Tumor lesions situated in a previously irradiated
area are considered measurable if progression has been demonstrated in such lesions.
Histologic confirmation of metastatic disease is not required.
- At least 1 of the tumor sites must be amenable to core needle biopsy.
- Patients with treated, stable, asymptomatic metastatic disease to the brain not
requiring chronic corticosteroids are eligible (per discretion of the treating
- Patient must have resolution of toxic effect(s) of the most recent chemotherapy less
than or equal to Grade 1 (except alopecia). If the patient has received major surgery
or radiation therapy of greater than 30 Gy, they must have recovered from the toxicity
and/or complication from the intervention.
- Demonstrate adequate organ function, all screening labs should be performed within two
weeks of treatment initiation.
- ANC (absolute neutrophil count) count greater than or equal to 1,500/mm3
- Platelets greater than or equal to 100,000/mm3
- Hemoglobin greater than or equal to 9 g/dL
- Creatinine less than or equal to 1.5x upper limit of normal (ULN) OR measured or
calculated creatinine clearance (CrCl) greater than or equal to 30mL/min for
patients with creatinine levels greater than 1.5x institutional ULN. (Glomerular
filtration rate (GFR) can also be used in place of creatinine or CrCl.)
- Total bilirubin less than or equal to 1.5x ULN OR Direct bilirubin less than or
equal to ULN for patients with total bilirubin levels greater than 1.5 x ULN.
- AST (SGOT) and ALT (SGPT) less than or equal to 2.5 x ULN OR less than or equal
to 5 x ULN for patients with liver metastases.
- A less than or equal to Grade 2 skin reaction to the first DTH inoculation is required
to begin study therapy.
- International normalized ratio (INR) or prothrombin time (PT) must be less than or
equal to 1.5x ULN unless the patient is receiving anticoagulant therapy as long as PT
or PTT is within therapeutic range of intended use of anticoagulants. Partial
Thromboplastin Time (aPTT) must be less than or equal to 1.5 x ULN unless subject is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of
intended use of anticoagulants.
- Female patients of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
- Study patients of childbearing potential must be willing to use an adequate method of
contraception as outlined in the protocol or be surgically sterile, or abstain from
heterosexual activity for the course of the study through 120 days after the last dose
of study medication. Patients of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for greater than 1 year. Note:
If there is any question that a participant of childbearing potential will not
reliably comply with the requirements for contraception, that participant should not
be entered into the study.
- Greater than 1 line of therapy for metastatic disease. Note: patients presenting with
stage IV disease should have one line of standard therapy.
- Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 4 weeks of the first dose of
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in
dosing exceeding 10mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
The use of physiologic doses of corticosteroids must be discussed with the NSABP
Department of Site and Study Management (DSSM).
- A greater than Grade 2 skin reaction to the first DTH inoculation will exclude that
patient from beginning study therapy.
- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., less than or equal to Grade 1 or at baseline)
from adverse events due to agents administered more than 4 weeks earlier.
- Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2
weeks prior to study Day 1 or who has not recovered (i.e., less than or equal to Grade
1 or at baseline) from adverse events due to a previously administered agent. Note:
Patients with alopecia are an exception to this criterion and may qualify for the
- Blood products (including platelets or red blood cells) or administration of colony
stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 4
weeks prior to beginning study therapy.
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin that has undergone potentially curative therapy, or in situ cancers.
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Patients with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment.
- Has an active autoimmune disease that has required systemic treatment within the past
2 years (i.e., with use of disease modifying agents, corticosteroids, or
immunosuppressive drugs). Note: Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency
and bone anti-resorptive agents etc.) is not considered a form of systemic treatment.
- Has a history of (non-infectious) pneumonitis that required steroids or current
- Has a history of or active interstitial lung disease, autoimmune lung disease, severe
asthma requiring daily medication.
- Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of
the stomach or small bowel, or other disease or condition significantly affecting
- Has an active infection requiring systemic therapy.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with a patient's participation
for the full duration of the trial, or is not in the best interest of the patient to
participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive a child within the projected
duration of the trial, starting with the pre-screening or screening visit through 120
days after the last dose of trial treatment.
- Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic
T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
is not allowed.
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B or Hepatitis C infections or known to be positive for
Hepatitis B antigen (HBsAg)/ Hepatitis B virus (HBV) DNA or Hepatitis C Antibody or
RNA. Active Hepatitis C is defined by a known positive Hep C Ab result and known
quantitative HCV RNA results greater than the lower limits of detection of the assay.
- Has received a live vaccine within 30 days prior to the first dose of trial treatment.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine.
Note: Seasonal influenza vaccines for injection are generally killed virus vaccines and are
allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated
vaccines and are not allowed.
• Has severe (greater than or equal to Grade 3) hypersensitivity to pembrolizumab and/or
any of its excipients.