The primary objective of this study is to assess the safety and feasibility of the following
two regimens: Cohort A) phased regimen of pembrolizumab in which paclitaxel is followed by
paclitaxel plus pembrolizumab and Cohort B) concurrent regimen of paclitaxel plus
pembrolizumab. The primary safety objective is to evaluate the overall grade 3 or 4
treatment-related adverse event rate for each cohort and compare them to relevant historical
This is an open-label randomized pilot research study to determine if the study drug,
pembrolizumab, is safe to use in combination with a chemotherapy drug called paclitaxel. This
study will have the following two regimens: Cohort A) phased regimen of pembrolizumab in
which paclitaxel is followed by paclitaxel plus pembrolizumab and Cohort B) concurrent
regimen of paclitaxel plus pembrolizumab. A total of 40 evaluable subjects will be enrolled
over an enrollment period of 18-24 months. The study is planned to enroll approximately 20
evaluable subjects in each treatment cohort.
Subjects must meet all of the following criteria:
1. Histologically or cytological confirmed diagnosis of HER2-negative metastatic breast
cancer or locally advanced disease not amenable to resection.
- Available ER and PR status from tumor sample with either hormone receptor
positive or negative tumor(s).
- For subjects with hormone receptor-positive, HER2-negative metastatic breast
cancer, they are eligible if they have already received or been intolerant to at
least two lines of endocrine therapies (including the adjuvant and/or metastatic
setting), or are appropriate candidates for chemotherapy (i.e. large burden of
2. Measurable disease by RECIST 1.1, or evaluable bone disease, i.e., bone lesions that
are lytic or mixed (i.e. lytic + sclerotic) in the absence of measurable lesion. Refer
to section 11 for the evaluation of measurable disease.
3. Male or female age ≥18 years.
4. ECOG performance status 0, 1 or 2.
5. Must have normal organ and marrow function as defined below:
- Hematologic - Absolute neutrophil count ≥1,500/mcL
- Platelets ≥75,000/mcL
- Hemoglobin ≥ 9 g/dL
- Creatinine ≤ 1.5X ULN or
- Measured or calculated creatinine clearance (CrCl) ≥ 30 mL/min for subject
with creatinine levels > 1.5X ULN [CrCl should be calculated per
institutional standard; GFR can also be used in place of creatinine or CrCl]
- Total bilirubin ≤1.5X ULN or for subjects with total bilirubin levels >1.5X
ULN, direct bilirubin ≤ULN
- AST(SGOT)/ALT(SGPT) ≤2.5X ULN
- PT and PTT ≤ 1.5X ULN; subjects receiving anticoagulant therapy are eligible
if PT or PTT is within therapeutic range of intended use of anticoagulants
per investigator discretion.
- INR ≤ 1.5; Patients receiving anticoagulant therapy are eligible if their
INR is stable and within the recommended range for the desired level of
anticoagulation per investigator discretion.
6. Female subjects of childbearing potential must have a negative serum or urine
pregnancy test within 14 days prior to receiving C1D1.
7. Female subjects of childbearing potential must be willing to use an adequate method of
birth control as outlined in Section 8.1.10, be surgically sterile, or abstain from
heterosexual activity for the course of the study and 120 days after the last dose of
study therapy. Subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year. Male subjects of
reproductive potential should agree to use an adequate method of contraception
starting with the first dose of study therapy and 120 days after the last dose of
study therapy. Abstinence is acceptable if this is the established and preferred
contraception for the subject.
8. Has completed the screening requirement of a core or punch biopsy of a tumor lesion
per Section 5 (bone tissue not acceptable). Biopsy of the breast tumor or other
regional areas is acceptable (i.e. lymph nodes, skin lesions).
- Subjects who are unable to meet the screening requirement of a tumor biopsy due
to inaccessible tumor, subject safety concern, or bone-only disease may submit an
archived tumor specimen from primary tumor or metastatic biopsy collected within
12 months from consent.
- Subjects who decline tumor biopsy may submit archived tumor specimen as specified
above (within 12 months from consent) only after Sponsor-Investigator approval.
9. Ability to understand and the willingness to sign the written informed consent
Subjects must not meet any of the following criteria:
1. Prior chemotherapy within 3 weeks, prior targeted small molecule therapy or radiation
therapy within 2 weeks, or prior anti-cancer monoclonal antibody (mAb) for direct
anti-neoplastic treatment within 4 weeks prior to Cycle 1 Day 1.
2. Not recovered (i.e., ≤ Grade 1) from adverse events due to agents previously
o Note: Subjects with ≤ Grade 2 neuropathy or alopecia of any grade are an exception
and may qualify for the study.
3. More than three prior lines of chemotherapy for HER2-negative metastatic disease or
for locally advanced disease that is not amenable to resection.
o Note: Non-Chemotherapy regimens do not count as prior lines (ex: hormonals,
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with an
agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137) or
has participated in Merck MK-3475 trial(s) and received MK-3475 as part of protocol
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to Cycle 1 Day 1
6. Has had major surgery within 3 weeks prior to Cycle 1 Day 1.
7. Has received any other investigational agents within 4 weeks of Cycle 1 Day 1 of study
8. Known active uncontrolled or symptomatic central nervous system (CNS) metastases
and/or carcinomatous meningitis as indicated by clinical symptoms, cerebral edema,
and/or progressive growth.
o Note: Subjects with treated CNS metastases are eligible if they are asymptomatic,
have no requirement for steroids, no requirement for anticonvulsants, and stable CNS
radiographic study showing no significant vasogenic edema ≥ 4 weeks since completion
of radiation and ≥ 2 weeks since discontinuation of steroids.
9. History of known allergic reaction to paclitaxel
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might 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.
11. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 120 days
after the last dose of trial treatment. Pregnant women are excluded from this study
because paclitaxel is an agent with the potential for teratogenic or abortifacient
effects. Because there is an unknown but potential risk for adverse events in nursing
infants secondary to treatment of the mother with paclitaxel, breastfeeding should be
discontinued if the mother is treated with paclitaxel. These potential risks also
apply to pembrolizumab being used in this study.
12. Has a known history of Human Immunodeficiency Virus (HIV) or known acquired
immunodeficiency disorder (AIDS). HIV-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
paclitaxel and pembrolizumab. In addition, these patients are at increased risk of
lethal infections when treated with marrow-suppressive therapy.
13. Has known active infection with hepatitis B or hepatitis C.
14. Has an active autoimmune disease that has required systemic treatment in past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
o Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
15. Has a known additional malignancy that progressed or required active treatment within
the last 5 years.
o Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma
of the skin that has undergone potentially curative therapy, or in situ cervical
16. Has a history of (non-infectious) pneumonitis that required steroids or current
17. Has an active infection requiring systemic therapy.
18. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
19. Has received a live vaccine within 30 days of Cycle 1 Day 1 of study therapy. o 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.