| Eligibility |
Inclusion Criteria:
- female participant is eligible to participate if she is not pregnant,not
breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP)
- A WOCBP who agrees to follow contraceptive guidance
- WOCBP must agree to use acceptable birth control methods for the duration of the study
and until persistence of the study drug is no longer detected in the peripheral
blood:this may be a period of several years. Methods for acceptable birth control
include: condoms, diaphragm or cervical cap with spermicide, intrauterine device, and
hormonal contraception; it is recommended that a combination of two methods be used.
NOTE: If the risk of conception exists, patients must agree to use highly effective
contraception throughout the study and for at least two years following the last study
treatment administration
- Negative serum and highly sensitive urine pregnancy test(s):
i) within 72 hours prior to study allocation; ii) following initiation of treatment,
pregnancy testing will be performed for WOCBP and interpreted prior to every cycle of
pembrolizumab (Initial Treatment Phase); iii) at the End of Treatment (EOT)
Assessment; and iv) whenever pregnancy is otherwise suspected. Note: In the event that
72 hours have elapsed between the screening pregnancy test and the first dose of study
treatment, another pregnancy test must be performed and must be negative in order for
subject to start receiving study medication.
- Histologically or cytologically confirmed diagnosis of triple negative breast cancer
(TNBC) (estrogen receptor [ER] =< 1%, progesterone receptor [PR] =< 1% HER2 negative)
- HER2 testing should be performed on the invasive component using a validated
immunohistochemistry (IHC) or in situ hybridization (ISH) assay
- IHC staining is defined as:
- IHC 3+ if there is complete and intense circumferential membrane staining
within > 10 percent of tumor cells. All IHC 3+ tumors are considered HER2
positive
- IHC 2+ if there is incomplete and/or weak/moderate, circumferential membrane
staining within > 10 percent of tumor cells. All IHC 2+ tumors are reported
as HER2 equivocal
- IHC 1+ if there is faint or barely perceptible, incomplete membrane staining
within > 10 percent of tumor cells. All IHC 1+ tumors are reported as HER2
negative
- IHC 0 if (1) no staining is observed, or (2) there is faint or barely
perceptible, incomplete membrane staining within < 10 percent of tumor
cells. All IHC 0 tumors are reported as HER2 negative
- Equivocal HER2 testing should trigger reflex HER2 testing using ISH on the
same specimen or a new test (using a different specimen with either IHC or
ISH)
- Results from ISH are defined as the ratio of gene amplification of HER2 and the
chromosome 17 enumeration probe (CEP17). Results are reported as:
- ISH positive if the HER2/CEP17 ratio is >= 2.0, and the HER2 copy number
signals/cell is >= 4
- Definitive diagnosis will be rendered pending further workup in the
following instances:
- If the HER2/CEP17 ratio is >= 2.0 and an average HER2 copy number is <
4.0 signals/cell - negative if confirmed on retesting
- If the HER2/CEP17 ratio is < 2.0 and the average HER2 copy number is >=
6.0 signals/cell positive - if confirmed on retesting
- If the HER2/CEP17 ratio is < 2.0 and an average HER2 copy number is
between >= 4.0 and < 6.0 signals/cell negative - if confirmed on
retesting
- ISH negative if the HER2/CEP17 ratio is < 2.0 and average HER2 copy number
is < 4.0 signals/cell
- Measurable brain disease as per RANO-BM criteria modified to include the cut off point
of 0.5 cm or higher. Have at least one untreated brain metastasis approved by a
research team that meets the following size requirements:
- >= 0.5 cm AND twice the magnetic resonance imaging (MRI) slice thickness; and
- < 3.0 cm, that is asymptomatic and does not require local therapy at the time of
enrollment (i.e. target lesion[s])
- Of note, lesions >= 0.5 cm and < 3 cm may be determined ineligible by the
research team because of location or symptoms. An untreated brain metastasis is
defined as a lesion not present at the time of whole brain radiation therapy or
not included in a stereotactic radiotherapy field (or within 0.5 cm of a treated
lesion), or any lesion that is new or unequivocally progressing since prior
radiation therapy or prior surgery.
- Any brain metastasis >= 3.0 cm or causing symptoms must have previously been treated
with local therapy (i.e. radiation or surgical resection, as clinically appropriate)
prior to study enrollment. Any lesion present at the time of whole brain radiation
therapy (WBRT) or included in the stereotactic radiotherapy field (or within 5 mm of
the treated lesion) will NOT be considered evaluable unless it is new or documented to
have progressed since treatment
- Stereotactic radiosurgery (SRS) and/or prior radiotherapy is permitted >=2 weeks prior
to initial Dendritic Cell (DC) vaccine dose (leaving one or more lesions which are not
radiated and will be used as target lesions) but a follow up brain MRI should be
obtained prior to dendritic cell (DC) vaccine to determine stability of the lesions.
An interval of at least 4 weeks after the end of whole brain radiation or for any
surgical resection of brain lesions is permitted ; an interval of at least 4 weeks or
5 half-lives (whichever is sorter) after the last cytotoxic, targeted,
immunotherapeutic or investigational agent is permitted (prior to the start of DC
vaccine)
- Previous whole brain radiation is allowed if patient has been diagnosed with
recurrent, progressive brain metastasis. Previously irradiated lesions would be
considered non-target lesions
- Previously resected lesions or those treated with SRS would be considered
nontarget lesions. There is no limitation on prior local therapies to other
lesions.
- If subject received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Toxicity that has not recovered to <=Grade 1 is allowed if it meets the inclusion
requirments for lab parameters (Participants with <= Grade 2 neuropathy may be
eligible)
- Patients must have adequate organ and marrow function as defined below (specimens must
be collected within 10 days prior to the start of study treatment):
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L
- Leukocytes: >= 3 x 10^9/L
- Absolute neutrophil count: >= 1.5 x 10^9/L
- Platelets: >= 100 x 10^9/L
- Total bilirubin: =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for
participants with total bilirubin levels > 1.5 x ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]):
=< 2.5 x institutional upper limit of normal (=< 5 x ULN for participants with liver
metastases)
- Creatinine OR Measured or calculated creatinine clearance (Glomerular Filtration Rate
(GFR) can also be used in place of creatinine or CrCl): =1.5 × ULN OR =30 mL/min for
participant with creatinine levels >1.5 × institutional ULN
- International normalized ratio (INR) OR prothrombin time (PT) activated partial
thromboplastin time (APTT) =< 1.5 x ULN unless participant is receiving anticoagulant
therapy as long as PT or aPTT is within therapeutic range of intended use of
anticoagulants
- No evidence of leptomeningeal disease
- If patient is on steroids, they must be on a steroid dose less than or = to an
equivalent prednisone dose of 10 mg daily
- Life expectancy of > 3 months
- Prior checkpoint inhibitors permitted 3 weeks prior to enrollment
- If the disease has progressed on current treatment in the CNS, prior to consent,
patients may continue Her 2 directed antibody treatment (trastuzumab and pertuzumab);
aromatase inhibitor or tamoxifen while on the study; patients with triple negative
breast cancer may continue capecitabine, eribulin or paclitaxel while on study per PI
discretion
- Patients with systemic disease will be managed as detailed in Section 10.1 - Patients
who develop systemic disease progression on the protocol will be managed as detailed
in Section 10.4.2
Exclusion Criteria:
- Any condition which might confound the results of the study, interfere with the
subject's participation for full participation (for the full duration of the study) or
in the Investigator's opinion deems the participant an unsuitable candidate for the
study
- Symptomatic brain metastases. Any neurologic symptoms present must have resolved with
local therapy by the time of administration of study drugs
- May not be receiving any other investigational agents and may not have participated in
a study of an investigational agent or using an investigational device within 4 weeks
of the first dose of DC vaccine treatment
- Has had prior chemotherapy or targeted small molecule therapy (except treatment
mentioned in inclusion criteria 17) within 4 weeks or 5 half-lives (whichever is
sooner) prior to start of treatment (first DC vaccine) or who has not recovered (i.e.,
=< grade 1 or at baseline) from adverse events due to a previously administered agent.
Previous radiation to extracranial sites may be completed at any time prior to
initiation of study drugs (first DC vaccine) with a 2-week washout is required.
- Rapidly progressing systemic disease which might interfere with completion of all the
vaccine doses
- Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment and is allowed
- History of allogenic tissue/solid organ transplantation
- Has an active infection requiring systemic therapy which in the investigator's opinion
will increase risk to the patient
- Has known active hepatitis B or hepatitis C infection (Testing is not mandatory)
- Has known immunosuppressive disease (e.g. human immunodeficiency virus [HIV], acquired
immunodeficiency syndrome [AIDS] or other immune depressing disease). Testing is not
mandatory
- Has received a blood transfusion in the two weeks prior to leukapheresis
- Pregnant or actively nursing (females who agree to stop nursing would be eligible)
participants
- Unwilling or unable to follow protocol requirements
- Brain lesion size with significant midline shift or obstructive hydrocephalus
- The use of corticosteroids to control cerebral edema or treat neurologic symptoms will
not be allowed unless at a low dose, not to exceed 10 mg of prednisone (or equivalent)
per day
- History of stroke or transient ischemic attack within 6 months prior to study
enrollment
- History of (non-infectious) pneumonitis /interstitial lung disease that required
steroids, or has current pneumonitis/ interstitial lung disease
- Presence of leptomeningeal disease
- Any contraindication to MRI (i.e., patients with pacemakers or other metal implanted
medical devices). An MRI safety questionnaire is required prior to MR imaging
- Has received prior radiotherapy within 2 weeks of start of study treatment with
dendritic cell (DC) vaccine and/or has received SRS <2. weeks prior to the
administration of the first DC vaccine dose. Participants must have recovered from all
radiation-related toxicities, not require corticosteroids, and not have had radiation
pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of
radiotherapy) to non-CNS disease
- Has received a live vaccine or live-attenuated vaccine within 30 days prior to the
first dose of study drug. Seasonal influenza vaccines for injection are allowed;
however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines
and are not allowed. Administration of killed vaccines is allowed.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug (DC
vaccine)
- Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
cervical cancer in situ) that have undergone potentially curative therapy are not
excluded
- A WOCBP who has a positive urine or blood pregnancy test within 72 hrs prior to study
allocation.
*Note: in the event that 72 hrs have elapsed between the screening pregnancy test and
the first dose of study treatment, another pregnancy test (urine or serum) must be
performed and must be negative in order for subject to start receiving study
medication
- Known active carcinomatous meningitis
- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial.
|
