Pembrolizumab, Letrozole, and Palbociclib in Treating Postmenopausal Patients With Newly Diagnosed Metastatic Stage IV Estrogen Receptor Positive Breast Cancer

PRIMARY OBJECTIVES:

I. To evaluate the objective response rate (ORR), based on Response Evaluation Criteria in
Solid Tumors [RECIST], version 1.1), of pembrolizumab in combination with letrozole and
palbociclib in patients with newly diagnosed metastatic estrogen receptor (ER)+human
epidermal growth factor receptor (HER)2- breast cancer, and determine if the addition of
pembrolizumab to letrozole and palbociclib combination can achieve an improved response rate
(ORR = complete response [CR] + partial response [PR]) measured from the study baseline,
based on RECIST version 1.1.

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of adding pembrolizumab (200 mg every 3 weeks) to
letrozole (2.5 mg) and palbociclib (125 mg 3 weeks on, one week off) in patients with
metastatic ER+HER2- breast cancer.

II. To evaluate the CR rate.

III. To evaluate progression-free survival (PFS).

IV. To evaluate overall survival (OS).

V. To evaluate duration of response (DOR) using RECIST version 1.1.

VI. To evaluate clinical benefit rate (CBR) using RECIST version 1.1.

VII. To evaluate toxicities (using the National Cancer Institute [NCI] Common Terminology
Criteria for adverse Events [CTCAE], version 4.0) associated with the triple drug combination
(pembrolizumab, letrozole, and palbociclib) in patients with metastatic ER+HER2- breast
cancer.

VIII. To evaluate CR, PR, ORR, PFS, DOR, and CBR using immune-related Response Criteria In
Solid Tumors (irRECIST); time to treatment failure will also be assessed.

TERTIARY OBJECTIVES:

I. To study cellular/humoral immune response by analyzing immune and stromal cell
characteristics before and after treatment that correlate with clinical response; this
includes programmed cell death 1 ligand 1 (PD-L1) expression levels.

II. To study the peripheral serum thymidine kinase (TK) level and its association with
treatment response.

III. To study circulating tumor deoxyribonucleic acid (DNA) (ctDNA) and the effect of
combining pembrolizumab, letrozole, and palbociclib on ctDNA profiles.

IV. To evaluate genomic and phenotypic status of breast tumor.

OUTLINE:

Patients receive letrozole orally (PO) once daily (QD) on days 1-28 and palbociclib PO QD for
3 weeks. Courses with letrozole and palbociclib repeat every 28 days in the absence of
disease progression or unacceptable toxicity. Patients also receive pembrolizumab
intravenously (IV) over 30 minutes on day 1. Courses with pembrolizumab repeat every 21 days
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 6 months for
3 years, and then every 12 months for 1 year.

Inclusion Criteria:

- Willing and able to provide written informed consent/assent for the trial

- Willing and able to comply with all aspects of the treatment protocol

- Postmenopausal women defined by at least one of the following criteria:

- Prior bilateral oophorectomy OR amenorrheic for >= 12 months (if =< 55 years of
age and prior to chemotherapy, or on medical ovarian ablative therapy, OR;

- Previous hysterectomy with one or both ovaries left in place (previous
hysterectomy in which documentation of bilateral oophorectomy is unavailable AND
FSH values consistent with the institutional normal values for the
post-menopausal state; FSH levels must be obtained within 28 days prior to
registration)

- Presence of measurable disease meeting the following criteria: at least 1 lesion of >
10 mm in long axis diameter for non-lymph nodes or > 15 mm in short axis diameter for
lymph nodes that is serially measurable according to RECIST version 1.1 using
computerized tomography, magnetic resonance imaging, or panoramic and close-up color
photography

- *Newly diagnosed (cohort 2) stage IV metastatic ER+HER2- breast cancer histologically
proven per current American Society of Clinical Oncology (ASCO)/College of American
Pathologists (CAP) guidelines; allow up to 30 days prior use of endocrine therapy +/-
CDK4/6 inhibitors for treatment of metastatic ER+ breast cancer

- Life expectancy of >= 3 months

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2

- Willing to provide tissue from a newly obtained core or excisional biopsy of a tumor
lesion; newly-obtained is defined as a specimen obtained up-to 6 weeks (42 days) prior
to initiation of treatment on day 1; subjects for whom newly-obtained samples cannot
be provided (e.g. inaccessible or subject safety concern) may submit an archived
specimen only upon agreement from the study principal investigator (PI)

- Absolute neutrophil count (ANC) >= 1,000 /mcL

- Platelets >= 100,000 /mcL

- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
dependency (within 7 days of assessment)

- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
levels > 1.5 x institutional ULN

- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN
OR =< 5 X ULN for subjects with liver metastases

- Albumin >= 2.5 mg/dL

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants

- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
anticoagulant therapy as along as PT or PTT is within therapeutic range of intended
use of anticoagulants

- Female subjects 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

- Female subjects of childbearing potential should be willing to use two methods of
birth control 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; subjects
of childbearing potential are those who have not been surgically sterilized or have
not been free from menses for > 1 year

- *Cohort 1 (accrual to 6 patients) is for patients who had ongoing stable disease (SD)
on letrozole + palbociclib, enrolled on prior version of eligibility criteria to
receive pembrolizumab after obtaining stable disease on letrozole + palbociclib; these
patients must have been on treatment with letrozole and palbociclib for 6 months with
SD per RECIST 1.1; received up to 3 lines of previous therapy including endocrine
and/or chemotherapy in advanced setting prior to initiation of letrozole and
palbociclib; no grade 3 toxicities except alopecia

Exclusion Criteria:

- Patients currently participating and receiving study therapy or who have participated
in a study of an investigational agent and received study therapy or used and
investigational device within 4 weeks of the first dose of treatment

- Previously received pembrolizumab or other anti-programmed cell death-1 (PD-1) or
anti-PD-L1 immunotherapy

- Does not have measurable disease per RECIST 1.1

- For cohort 2, received > 30 days of prior treatment with endocrine therapy +/- CDK4/6
inhibitors before screening (letrozole is allowed for prior adjuvant endocrine
therapy)

- Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment

- Known history of active TB (Bacillus tuberculosis)

- Hypersensitivity to pembrolizumab or any of its excipients

- Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or has
not recovered (i.e., =< grade 1 or at baseline) for adverse events (AEs) due to agents
administered > 4 weeks earlier

- Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2
weeks prior to stay day 1 or has not recovered (i.e. =< grade 1 or at baseline) from
AEs due to a previously administered agent

- Note: Patients with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study

- Note: If patient received major surgery, she must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting therapy

- Known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer

- 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 4 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; this exception does not include
carcinomatous meningitis, which is excluded regardless of clinical stability

- 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

- History of (non-infectious) pneumonitis that required steroids or current pneumonitis

- History of interstitial lung disease

- Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI)
obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)

- Active infection requiring systemic therapy

- History of significant cardiovascular disease, defined as: congestive heart failure
greater than New York Heart Association (NYHA) class II according to the NYHA
functional classification; unstable angina or myocardial infarction within 6 months of
enrollment; or serious cardiac arrhythmia

- Clinically significant electrocardiogram (ECG) abnormality, including a marked
baseline prolonged QT/corrected QT (QTc) ([QT interval/corrected QT interval], e.g., a
repeated demonstration of a QTc interval > 480 ms), a family or personal history of
long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or
Torsade de Pointes (TdP)

- Concurrent use of drugs that are known to be moderate or strong cytochrome P450,
family 3, subfamily A (CYP3A) inhibitors or inducers or drugs that are known to
prolong the QT interval

- History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the trial, interfere with the patient's participation
for the full duration of the trial, or is not in the best interests of the patient to
participate, in the opinion of the treating investigator

- Pregnant or breastfeeding, or expecting to conceive children 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

- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial

- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)

- Received a live vaccine within 30 days of planned start of study therapy; * Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
attenuated vaccines, and are not allowed