Trial to Evaluate Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC
Condition: Advanced Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Pembrolizumab; Gemcitabine
Intervention description: Pembrolizumab at a dose of 200mg as an intravenous (IV) 30 minutes infusion on day 1 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. Patients completing 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication will stop pembrolizumab treatment (though may continue with gemcitabine). Subjects who stop pembrolizumab after 24 months may be eligible for up to one year of additional pembrolizumab treatment if they progress after stopping it.; Gemcitabine at a dose of 1,250mg/m2 as an intravenous (IV) 60 minutes infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.
Intervention MeSH terms: Gemcitabine; Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced Breast Cancer; Pembrolizumab; HER2-negative

Summary:

      Study Design and Treatment:

      This is a multicenter phase II trial, with an initial exploratory run-in-phase, to evaluate
      the efficacy and safety of pembrolizumab in combination with gemcitabine in patients with
      HER2-negative ABC that have previously received anthracyclines and taxanes (unless clinically
      contraindicated). In hormone receptor positive patients, previous treatment with 2 or more
      lines of hormone therapy will also be required. Patients must have at least one measurable
      lesion that can be accurately assessed at baseline and is suitable for repeated assessment by
      CT, MRI or plan X-ray. Approximately 53 patients (up to a maximum of 65 patients depending on
      the results of the run-in-phase) will be included in this trial.
    

Eligibility criteria:

        Inclusion Criteria:

          1. The patient has signed and dated the informed consent document and it has been
             obtained before conducting any procedure specifically for the study.

          2. Female ≥ 18 years of age on day of signing informed consent.

          3. Histological/cytological confirmation of breast cancer with evidence of advanced
             disease, not amenable to resection or radiation therapy with curative intent.

          4. Documented luminal A, luminal B (HER2-negative) or triple negative disease by
             immunohistochemistry (IHQ) and/or in situ hybridization (FISH/CISH/SISH) based on
             local testing on the most recent tumour biopsy defined as follows:

             Luminal A: tumour with positive oestrogen receptor (ER) status (≥1% of tumour cells
             with ER expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ
             hybridization defined as a HER2/chromosome enumeration probe 17 (CEP17) ratio < 2 or
             for single probe assessment a HER2 copy number < 4) and high progesterone receptor
             (PgR) (≥ 20% of tumour cells with PgR expression) and low Ki67 (< 14%).

             Luminal B (HER2-negative): tumour with positive ER status (≥1% of tumour cells with ER
             expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ
             hybridization defined as a HER2/CEP17 ratio < 2 or for single probe assessment a HER2
             copy number < 4) and either low or negative PgR (< 20% of tumour cells with PgR
             expression) and/or high Ki67 (≥ 14%).

             Triple negative: tumour with negative hormone receptor status (<1% of tumour cells
             with ER and PgR expression) and HER2-negative status (IHQ score 0/1+ or negative by in
             situ hybridization defined as a HER2/CEP17 ratio < 2 or for single probe assessment a
             HER2 copy number < 4).

          5. Have at least one unidimensionally measurable lesion by RECIST 1.1.

          6. Patient agrees to the collection of a metastatic tumor sample (biopsy) at the time of
             inclusion and at progression (whenever possible).

          7. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group
             (ECOG) Performance Scale.

          8. Demonstrate adequate organ function as follows (all screening labs should be performed
             within 7 days of study treatment initiation):

             Bone marrow:

             Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/l) Platelets ≥ 100,000/mm3
             (100x109/l) Hemoglobin ≥ 9g/dl or ≥ 5.6 mmol/l without transfusion or erythropoietin
             (EPO) dependency (within 7 days of assessment)

             Hepatic:

             Serum total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) Alkaline Phosphatase ≤ 2.5 x
             ULN Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGPT)
             ≤ 2.5 x ULN or ≤ 5 x ULN for patients with liver metastases Albumin ≥ 2.5 g/dl

             Renal:

             Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 ml/min for patients with
             creatinine levels > 1.5 x ULN

             Coagulation:

             International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULN unless
             patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic
             range of intended use of anticoagulants.

             Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless patient is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants.

          9. Prior treatment with anthracyclines and taxanes (unless clinically contraindicated)
             and two or more prior lines of hormone therapy in hormone receptor positive disease.

         10. At least 3 months life expectancy.

         11. Patient of childbearing potential should have a negative urine or serum pregnancy
             within 72 hours prior to receiving the first dose of study drug/medication. If the
             urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
             be required.

         12. Patients of childbearing potential (see section 4.4. for definition) must be willing
             to use an adequate method of contraception as outlined in Section 4.4. -
             Contraception, 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.

         13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
             tests and other study procedures.

        Exclusion Criteria:

          1. HER2-positive disease by immunohistochemistry or in situ hybridation (FISH-SISH-CISH).

          2. Patient is currently participating or has participated in a study of an
             investigational agent and received study therapy or used an investigational device
             within 4 weeks of the first dose of study drug/medication.

          3. 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 at baseline) from adverse events
             due to agents administered more than 4 weeks earlier.

          4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at
             baseline) from adverse events 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, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting
                  therapy.

          5. Has received prior therapy with an anti-Programmed death-1 (PD), anti-PD-L1, or
             anti-PD-L2 agent.

          6. Has received a live vaccine within 30 days of planned start 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.

          7. Has hypersensitivity to pembrolizumab, gemcitabine or any of theirs excipients.

          8. Has 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 four weeks
             prior to the first dose of trial treatment and all 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.

          9. Has a 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 study
             drug/medication.

         10. Has an 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.

         11. Has a current or prior malignancy within the previous 5 years (other than breast
             cancer or adequately treated basal cell or squamous cell carcinoma of the skin or
             in-situ carcinoma of the cervix).

         12. Has a history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis.

         13. Has an active infection requiring systemic therapy.

         14. Has a known history of active Tuberculosis Bacillus (TB) or Human Immunodeficiency
             Virus (HIV) (HIV 1/2 antibodies) or a known active Hepatitis B (e.g., HBsAg reactive)
             or Hepatitis C (e.g., hepatitis C virus (HCV) RNA [qualitative] is detected).

         15. Has a 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 interest of
             the patient to participate, in the opinion of the treating investigator.

         16. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         17. Patient is pregnant or breastfeeding, or expecting to conceive within the projected
             duration of the trial, starting with the baseline visit through 120 days after the
             last dose of trial treatment.