Clinical Trials /

Pembrolizumab And Tamoxifen Among Women With Advanced Hormone Receptor Positive Breast Cancer And Esr1 Mutation

NCT03879174

Description:

Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) designed to directly block the interaction between PD-1 and its ligands and enable the T cell to remain active and co-ordinate an attack on tumor cells. We hypothesise that the Clinical Benefit Rate (CBR) and progression free survival (PFS) of metastatic breast cancer patients who have ESR1 mutation will improve following administration of a combination of pembrolizumab and tamoxifen.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab And Tamoxifen Among Women With Advanced Hormone Receptor Positive Breast Cancer And Esr1 Mutation
  • Official Title: A Phase II Study of Pembrolizumab And Tamoxifen Among Women With Advanced Hormone Receptor Positive Breast Cancer And Esr1 Mutation

Clinical Trial IDs

  • ORG STUDY ID: AN.MCME.CR.12
  • SECONDARY ID: MISP # 55574
  • NCT ID: NCT03879174

Conditions

  • Breast Cancer Female

Interventions

DrugSynonymsArms
Pembrolizumab + TamoxifenPembrolizumab + Tamoxifen

Purpose

Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) designed to directly block the interaction between PD-1 and its ligands and enable the T cell to remain active and co-ordinate an attack on tumor cells. We hypothesise that the Clinical Benefit Rate (CBR) and progression free survival (PFS) of metastatic breast cancer patients who have ESR1 mutation will improve following administration of a combination of pembrolizumab and tamoxifen.

Detailed Description

      3.4.1 Pharmaceutical and Therapeutic Background The importance of intact immune surveillance
      in controlling outgrowth of neoplastic transformation has been known for decades.
      Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in
      cancer tissue and favorable prognosis in various malignancies. In particular, the presence of
      CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to
      correlate with improved prognosis and long-term survival in many solid tumors.

      The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune
      control. The normal function of PD-1, expressed on the cell surface of activated T-cells
      under healthy conditions, is to down-modulate unwanted or excessive immune responses,
      including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member
      related to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor
      signaling upon engagement of its ligands (PD-L1 and/or PD L2). The structure of murine PD-1
      has been resolved. PD-1 and family members are type I transmembrane glycoproteins containing
      an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail
      which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1
      contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif
      (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell
      stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within
      its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ,
      PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade. The mechanism by which
      PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both
      molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed
      on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and
      Natural Killer cells. Expression has also been shown during thymic development on CD4-CD8-
      (double negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands
      for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of
      cell types, including non-hematopoietic tissues as well as in various tumors. Both ligands
      are type I transmembrane receptors containing both IgV- and IgC-like domains in the
      extracellular region and contain short cytoplasmic regions with no known signaling motifs.
      Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell
      receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably
      on vascular endothelium, whereas PD-L2 protein is only detectably expressed on
      antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2
      is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to
      dampen unwarranted T-cell function in peripheral tissues. Although healthy organs express
      little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of
      this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in
      subjects with melanoma (MEL). This suggests that the PD-1/PD-L1 pathway plays a critical role
      in tumor immune evasion and should be considered as an attractive target for therapeutic
      intervention.

      Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the
      IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands,
      PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has been approved in the United States for the
      treatment of patients with unresectable or metastatic melanoma and disease progression
      following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. KeytrudaTM
      (pembrolizumab) is also a U.A.E. Ministry of Health registered medication.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + TamoxifenExperimentalPembrolizumab (200mg IV every three weeks) + Tamoxifen (20 mg OD)
  • Pembrolizumab + Tamoxifen

Eligibility Criteria

        Inclusion Criteria:

        In order to be eligible for participation in this trial, the subject must:

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

          2. Be 18 years of age on day of signing informed consent.

          3. Have measurable disease based on RECIST 1.1.

          4. Be willing to provide tissue from a newly obtained core or excisional biopsy of a
             tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days)
             prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples
             cannot be provided (e.g. inaccessible or subject safety concern) may submit an
             archived specimen only upon agreement from the Sponsor.

          5. Have a performance status of 0 or 1 on the ECOG Performance Scale.

          6. Demonstrate adequate organ function as defined in Table 1, all screening labs should
             be performed within 10 days of treatment initiation.

             Table 1 Adequate Organ Function Laboratory Values System Laboratory Value
             Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL
             Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days
             of assessment) Renal Serum creatinine OR Measured or calculated creatinine clearance
             (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal
             (ULN) OR

             ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum
             total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total
             bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR

             ≤ 5 X ULN for subjects with liver metastases Albumin >2.5 mg/dL Coagulation
             International Normalized Ratio (INR) or Prothrombin Time (PT)

             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

             ≤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 aCreatinine clearance
             should be calculated per institutional standard.

        9. Female subject of childbearing potential should have a negative urine or serum pregnancy
        within 72 hours prior to receiving the first dose of study medication. If the urine test is
        positive or cannot be confirmed as negative, a serum pregnancy test will be required.

        10. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an
        adequate method of contraception as outlined in Section 5.7.2 - 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.

        Exclusion Criteria:

        The subject must be excluded from participating in the trial if the subject:

          1. 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 within 4 weeks of the first dose of treatment.

          2. 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 trial
             treatment.

          3. Has a known history of active TB (Bacillus Tuberculosis)

          4. Hypersensitivity to pembrolizumab or any of its excipients.

          5. 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.

          6. 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: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study.

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

          7. Has a known additional malignancy that is progressing or requires active treatment.
             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.

          8. 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 four weeks
             prior to the first dose of trial treatment 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 trial treatment. This exception does not include
             carcinomatous meningitis which is excluded regardless of clinical stability.

          9. 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 (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

         10. Has known history of, or any evidence of active, non-infectious pneumonitis.

         11. Has an active infection requiring systemic therapy.

         12. 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.

         13. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         14. 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.

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

         16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

         18. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival
Time Frame:defined as time from enrollment to disease progression or death, whichever occurred first, assessed for a period of up to 36 months.
Safety Issue:
Description:time from enrollment to disease progression or death, whichever occurred first

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:The length of time from the start of pembrolizumab treatment following which the patients are still alive, assessed for a period of up to 36 months.
Safety Issue:
Description:Overall Survival

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Mediclinic Middle East

Trial Keywords

  • HR Positive Breast Cancer

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