Pilot Study of Paclitaxel Plus Pembrolizumab in Metastatic HER2-Negative Breast Cancer

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 controls.

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.

Eligibility Criteria:
Inclusion Criteria

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 visceral disease).
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
   * Renal

     * Creatinine ≤ 1.5X ULN or
     * Measured or calculated creatinine clearance (CrCl) ≥ 30 mL/min for subject with creatinine levels \> 1.5X ULN \[CrCl should be calculated per institutional standard; GFR can also be used in place of creatinine or CrCl\]
   * Hepatic

     * 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
   * Coagulation

     * 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 document.

Exclusion Criteria

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 administered.

   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, biologics)
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 therapy.
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 therapy.
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 drugs).

    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 cancer.
16. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
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.