Pembrolizumab and Carboplatin in Treating Patients With Circulating Tumor Cells Positive Metastatic Breast Cancer

PRIMARY OBJECTIVES:

I. Evaluate the impact on progression free survival (PFS) of the combination pembrolizumab -
carboplatin in patients with circulating tumor cells (CTC) positive, HER2 negative metastatic
breast cancer (MBC) previously treated with anthracyclines and taxanes in primary setting.

SECONDARY OBJECTIVES:

I. Evaluate the impact on overall survival (OS) of the combination carboplatin -
pembrolizumab in patients with CTC positive MBC previously treated with anthracyclines and
taxanes in primary setting.

II. To assess the overall response rate or objective response rate (ORR) and clinical benefit
rate (CBR) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria in
patients with carboplatin - pembrolizumab in patients with CTC positive MBC previously
treated with anthracyclines and taxanes in primary setting.

III. To assess immune-related response using tumor response by immune-related RECIST
(irRECIST) as immune-related partial response (irPR) or immune-related complete response
(irCR).

IV. Measure the time to new metastases (TTNM). V. Evaluate ORR and clinical benefit in
relation to PDL-1 expression in tissue and CTCs.

TERTIARY OBJECTIVES:

I. Measure immune biomarkers (PDL-1) in CTCs (CellSearch) and immune cells such as
cancer-associated macrophage-like cells (CAMLs) (CellSieve) and correlate with therapeutic
benefit.

II. Measure cell-free circulating tumor deoxyribonecleic acid (ctDNA) and T-cell receptor
sequencing analysis and correlate them with CTC enumeration and therapeutic benefit.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and carboplatin IV
over 30-60 minutes on day 1 beginning with course 3. Courses repeat every 21 days for 24
months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days, every 9 weeks
for 1 year, and then every 12 weeks.

Inclusion Criteria:

- Patients must have either:

- Hormone receptor (HR) negative and HER-2 negative (triple negative breast cancer
[TNBC]) metastatic breast cancer and have not received prior chemotherapy for
metastatic disease

- Demonstrated HER-2 negative MBC (0 or 1+ by immunohistochemistry [IHC] or
non-amplified by fluorescence in situ hybridization [FISH]) according to American
Society of Clinical Oncology (ASCO)/College of American Pathologists (CAPA)
guidelines

- Or histologically or cytologically confirmed estrogen receptor (ER) positive and
HER-2 negative metastatic breast cancer are eligible if they have progressed on
single agent or combination endocrine therapy (e.g. aromatase inhibitor
[AI]/palbociclib or everolimus) indicating an endocrine-refractory disease

- Patients must be CTC positive (defined as CTCs >= 5)

- Have measurable disease based on RECIST 1.1

- Be willing to provide archival tissue (if available) for correlative studies

- Note: The archived tumor tissue specimens may be from metastatic tumor specimen
(first choice); in alternative, we can consider tissue from prior surgery or from
prior diagnostic biopsy (second choice); unavailability of archived tissue will
not render subject ineligible for study

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance status

- Demonstrate adequate organ function, all screening labs should be performed within 14
days prior to registration

- Absolute neutrophil count (ANC) >= 1,500 /mcL

- Platelet >= 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 (ALT) (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 long as PT or PTT is within therapeutic range of intended use
of anticoagulants

- Female subject of childbearing potential (FOCBP) should have a negative urine or serum
pregnancy within 7 days prior to registration; and must be repeated within 3 days (72
hours) prior to first dose of study drug; if the urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required

- (Note: A FOCBP is any woman [regardless of sexual orientation, having undergone a
tubal ligation, or remaining celibate by choice] who meets the following
criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy

- Has had menses at any time in the preceding 12 consecutive months [and
therefore has not been naturally postmenopausal for > 12 months])

- Female subjects of childbearing potential must be willing to use an adequate method of
contraception as outlined in the appendices; contraception must be used for the course
of the study through 120 days after the last dose of study medication

- Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject

- Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy

- Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject

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

Exclusion Criteria:

- Histologically or cytologically confirmed HER2-positive (3+ by IHC or non-amplified by
FISH) according to ASCO/CAP guidelines

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device < or equal to 28 days of registration

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy =< 7 days prior to registration

- Has a known history of active TB (bacillus tuberculosis)

- Hypersensitivity to pembrolizumab or any of its excipients

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
day 1 or who has not recovered (i.e., =< grade 1 or baseline) from adverse events
(AEs) due to agents administered more than 28 days earlier

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 14 days prior to registration or who has not recovered (i.e., =< grade 1 or at
baseline) from AEs due to a previously administered agent

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

- If subject received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy

- Has known additional malignancy that progressed or required treatment within last 5
years; 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
that has been adequately treated

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least 28 days prior
to registration 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 registration; this exception does not include known carcinomatous
meningitis which is excluded regardless of clinical stability

- Has 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

- Patients who have evidence of active, noninfectious pneumonitis or have a history of
severe pneumonitis that required treatment with steroids are not eligible for this
study

- 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 the subject?s
participation for the full duration of the trial, or is not in the best interest of
the subject 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 or father 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

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

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

- Has 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