Pilot Study of Paclitaxel Plus Pembrolizumab in Metastatic HER2-Negative Breast Cancer
Condition: Breast - Female; Male Breast Cancer
MeSH terms: Breast Neoplasms; Breast Neoplasms, Male
Intervention: Pembrolizumab; Paclitaxel
Intervention description: IV (in the vein) on day 1 of a 21 day cycle; IV (in the vein) on days 1 and 8 of a 21 day cycle
Intervention MeSH terms: Paclitaxel; Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

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.