Pembrolizumab in Treating Patients With Triple-Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To compare invasive disease-free survival (IDFS) of patients with triple-negative breast
cancer (TNBC) who have either >= 1 cm residual invasive breast cancer and/or positive lymph
nodes (> ypN+) after neoadjuvant chemotherapy randomized to receive 1 year of MK-3475
(pembrolizumab) adjuvant therapy compared to no MK-3475 (pembrolizumab), in both the entire
study population and also in the PD-L1 positive subset.

SECONDARY OBJECTIVES:

I. To compare the effects of MK-3475 (pembrolizumab) on overall survival (OS) and distant
recurrence-free survival (DRFS) between the two randomized arms for the PD-L1 positive
patients and then all patients.

II. To assess the toxicity and tolerability of MK-3475 (pembrolizumab) in this patient
population with or without radiation therapy.

TERTIARY OBJECTIVES:

I. To examine the association between biomarkers of inflammation and quality of life and
patient reported outcomes between the two groups during and at the end of therapy.

II. To examine the long-term and late effects of treatment on patient-reported outcomes.

III. To collect tissue and whole blood for processing and banking in anticipation of future
correlative studies in this patient population.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I (OBSERVATION): Patients receive no treatment but are monitored at standard clinical
intervals during first year after randomization. Patients are examined every 12 weeks for 1
year, and every 6 months for 4 years, then annually for 5 years.

ARM II (PEMROLIZUMAB): Patients receive pembrolizumab intravenously (IV) over 30 minutes on
days 1 and 22. Courses repeat every 42 days for 52 weeks in the absence of disease
progression or unacceptable toxicity.

All patients may undergo radiation therapy within 12 weeks of last breast cancer operation or
after treatment.

After completion of study treatment, patients are followed up to 10 years.

Inclusion Criteria:

- STEP 1 REGISTRATION

- Patients must have histologically confirmed estrogen receptor (ER)-, progesterone
receptor (PR)- and HER2-negative (triple-negative, TNBC) or ER, PR, and HER2 equivocal
status and must not have received and not be planning to receive adjuvant anti-HER2 or
endocrine therapies after completion of neoadjuvant chemotherapy; patients who are
HER2 positive by American Society of Clinical Oncology (ASCO) College of American
Pathologists (CAP) guidelines are ineligible; HER2 negative and HER2 equivocal cases
as per ASCO CAP guidelines that do not receive HER2-targeted therapy are eligible;
patients with weekly ER or PR positive disease, defined as ER and/or PR < 5% by
immunohistochemistry, are eligible if the treating physician considers the patient not
eligible for adjuvant endocrine therapy; residual disease must be >= 1 cm in greatest
dimension, and/or have positive lymph nodes (ypN+) observed on pathologic exam

- NOTE: Immunohistochemistry (IHC)-positive isolated tumor cells in the lymph node
(N0 [i+]) are not considered node-positive and these patients also must have >= 1
cm residual invasive cancer in the breast in order to be eligible

- Patients must not have metastatic disease (i.e., must be M0); patients must not have
locally recurrent disease

- It is preferred that axillary lymph node sampling is performed after completion of
neoadjuvant chemotherapy to allow more accurate assessment of pathologic response;
patients must have a complete axillary lymph node dissection after neoadjuvant
chemotherapy in the following situations (exceptions will be granted for patients
participating in the Alliance A11202 trial):

- Patients had documented pathologic involvement of the axillary nodes (fine needle
aspiration [FNA] or core biopsy) before neoadjuvant chemotherapy and had sentinel
node biopsy after neoadjuvant chemotherapy with positive sentinel node(s)

- Patient had documented pathologic involvement of the axillary nodes (FNA or core
biopsy) before neoadjuvant chemotherapy and had only 1 sentinel lymph node
removed after neoadjuvant chemotherapy

- NOTE: Patients who undergo sentinel node biopsy before starting neoadjuvant
treatment and do not undergo post neoadjuvant assessment of the axillary
nodes or who have negative axillary nodes on post neoadjuvant assessment
must have >= 1 cm residual invasive cancer in the breast after completion of
neoadjuvant chemotherapy

- Patients must have a minimum of five, available unstained slides from the residual
(post-neoadjuvant) invasive tumor in primary site or lymph node; (these will be
submitted to determine PD-L1 expression) the tumor tissue must be adequate for PD-L1
testing, which typically requires a minimum of 100 cancer cells per slide

- NOTE: Initial order for specimen kits should be placed at least two weeks prior
to registering the first patient at each site

- Patients must be offered the opportunity to participate in specimen banking

- Patients must have had neoadjuvant chemotherapy followed by surgery; the recommended
neoadjuvant treatment should include 16-24 weeks of a third generation chemotherapy
regimen as recommended by National Comprehensive Cancer Network (NCCN) guidelines for
triple negative breast cancer (examples include dose dense adriamycin-cytoxan [AC]
followed by dose-dense paclitaxel; weekly paclitaxel x 12 followed or preceded by
cyclophosphamide-adriamycin-fluorouracil [FAC], fluorouracil-epirubicin-cytoxan [FEC],
AC or dose dense AC; docetaxel either followed or preceded by FEC/FAC or AC;
carboplatin-containing neoadjuvant chemotherapy is also allowed); patients who cannot
complete all planned treatment cycles for any reason are considered high risk and
therefore are eligible for the study if they have residual disease; patients must have
resolution of adverse event(s) of the most recent prior chemotherapy to grade 1 or
less, except alopecia and =< grade 2 neuropathy which are allowed

- Patients may receive post-operative (adjuvant) chemotherapy for up to 24 weeks of
duration (e.g. 8 cycles of capecitabine as in the CREATE-X trial) after completion of
surgery at the discretion of the treating physician; patients must have resolution of
adverse event(s) of the most recent prior chemotherapy to grade 1 or less, except
alopecia and =< grade 2 neuropathy which are allowed; patients that have received
adjuvant chemotherapy must be registered to screening within 35 days after completing
treatment

- Patients must have completed their final breast surgery (rendering them free from
disease) with clear resection margins for invasive cancer and DCIS within the
following timelines:

- 90 days prior to screening registration for patients not receiving post-operative
(adjuvant) chemotherapy OR

- 270 days prior to screening registration for patients who have received
post-operative (adjuvant) chemotherapy Patients who receive postoperative
chemotherapy may receive radiation therapy before or after the chemotherapy; a
short course of reduced dose chemotherapy concomitant with radiation for
radiation sensitization is not considered to be adjuvant chemotherapy; positive
margins are allowed only if the surgical team of the patient deems further
resection impossible

- Patients for whom radiation therapy (RT) to the affected breast or chest wall and
regional nodal areas is clinically indicated as per NCCN treatment guidelines, should
receive RT after randomization when possible, and receive MK-3475 (pembrolizumab)
concurrent with RT, if randomized to the experimental arm; however, RT administered,
or initiated, prior to registration is also allowed; pembrolizumab may be added to
ongoing radiation, or started after its completion, if randomized to the experimental
arm, provided there are no > grade 2 radiation-related skin toxicities; patients who
have not yet started radiation must specify at the time of screening registration
whether or not they will receive RT and the extent of intended RT

- Patients must not have had prior immunotherapy with anti-PD-L1, anti-PD-1, anti-CTLA4
or similar drugs; patients must not be planning to receive any of the prohibited
therapies during the screening or treatment phases of the study

- Patients must not be planning to receive concomitantly other biologic therapy,
hormonal therapy, other chemotherapy, surgery or other anti-cancer therapy except
radiation therapy while receiving treatment on this protocol; however, patients
receiving extended adjuvant endocrine therapy for an earlier ER positive breast cancer
treated with curative intent and without recurrence for at least 5 years may continue
with their endocrine therapy

- Patients must have Zubrod performance status =< 2

- Patients must not have a history of (non-infectious) pneumonitis that required
steroids or evidence of active pneumonitis

- Patients must not have an active infection requiring systemic therapy

- Patients must not have active autoimmune disease that has required systemic treatment
in 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

- Patients must not have received live vaccines within 30 days prior to registration;
examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin
(BCG), and typhoid (oral) vaccine; seasonal influenza vaccines for injection are
generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

- Patients must not have known active hepatitis B virus (HBV) or hepatitis C virus (HCV)
infection prior to registration; patients who have completed curative therapy for HCV
are eligible; patients with known human immunodeficiency virus (HIV) infection are
eligible if they meet each of the following 3 criteria:

- CD4 counts >= 350 mm^3

- Serum HIV viral load of < 25,000 IU/ml and

- Treated on a stable antiretroviral regimen

- No other prior invasive malignancy is allowed except for the following: adequately
treated basal (or squamous cell) skin cancer, in situ breast or cervical cancer; stage
I or II invasive cancer treated with a curative intent without evidence of disease
recurrence for at least five years

- Patients must have complete history and physical examination within 28 days prior to
registration

- Patients must be informed of the investigational nature of this study and must sign
and give written informed consent for this protocol in accordance with institutional
and federal guidelines

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system

- STEP 2 REGISTRATION

- Patients must not be registered to step 2 until receiving confirmation from the
Southwest Oncology Group (SWOG) Statistical Center that the patient's tissue specimen
was adequate for PD-L1 testing; patients must be registered within 7 days of receiving
the e-mail notification confirming submission was evaluable for PD-L1 status

- Absolute neutrophil count (ANC) >= 1,500 microliter (mcL), obtained within 28 days
prior to step 2 registration

- Platelets >= 100,000/mcL, obtained within 28 days prior to step 2 registration

- Hemoglobin >= 9 g/dL, obtained within 28 days prior to step 2 registration

- A serum thyroid-stimulating hormone (TSH) must be obtained within 28 days prior to
step 2 registration to obtain a baseline value

- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (except Gilbert's
syndrome, who must have a total bilirubin < 3.0 mg/dL), obtained within 28 days prior
to step 2 registration

- Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
IULN, obtained within 28 days prior to step 2 registration

- Alkaline phosphatase =< 2.5 x IULN, obtained within 28 days prior to step 2
registration

- Serum creatinine =< IULN OR measured or calculated creatinine clearance >= 60 mL/min,
obtained within 28 days prior to step 2 registration

- Women of childbearing potential must have a negative urine or serum pregnancy test
within 28 day prior to registration; women/men of reproductive potential must have
agreed to use an effective contraceptive method for the course of the study through
120 days after the last dose of study medication; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy, bilateral tubal ligation, or vasectomy; however, if at any
point a previously celibate patient chooses to become heterosexually active during the
time period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures; patients must not be pregnant or
nursing

- Site must verify that there is no known change in the step 1 eligibility since initial
registration