Clinical Trials /

Evaluation of Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated With Metronomic Cyclophosphamide

NCT03139851

Description:

The investigators hypothesize that the administration of pembrolizumab combined to metronomic cyclophosphamide may be an interesting therapeutic option for female patients breast cancer with lymphopenia. Include only patients with breast cancer with lymphopenia is based on the particularly poor prognosis of these patients. The approach suggested here is to deplete and active the immune response of these immunosuppressed patients. The combination of pembrolizumab and cyclophosphamide would provide a higher gain in anti-tumor response in these patients than in those without lymphopenia and in chemotherapy alone. The investigators proposal is to conduct a multicentric, non-comparative, single arm, two-stage, Phase II trial in lymphopenic patients with metastatic breast cancer. The study is divided in 2 parts: - a safety run-in Phase aiming to evaluate the safety of the combination therapy pembrolizumab + metronomic cyclophosphamide based on the occurrence of severe toxicities. - a two-stage Phase II aiming to evaluate the clinical activity of the combination therapy pembrolizumab + metronomic cyclophosphamide. In both parts of the study, patients will receive cyclophosphamide (50 mg/day, daily, per os) and pembrolizumab (200 mg every 3 weeks, intravenously [IV]). The adverse events of the two drugs are well known.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Evaluation of Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated With Metronomic Cyclophosphamide
  • Official Title: CHEMOIMMUNE - A Phase II Study Evaluating an Anti-PD1 Monoclonal Antibody (Pembrolizumab) in Lymphopenic Metastatic Breast Cancer Patients Treated With Metronomic Cyclophosphamide

Clinical Trial IDs

  • ORG STUDY ID: ET16-073
  • SECONDARY ID: 2016-002736-33
  • NCT ID: NCT03139851

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
Cyclophosphamide 50mgCyclophosphamide et pembrolizumab
Pembrolizumab 100 MG in 4 ML InjectionKeytrudaCyclophosphamide et pembrolizumab

Purpose

The investigators hypothesize that the administration of pembrolizumab combined to metronomic cyclophosphamide may be an interesting therapeutic option for female patients breast cancer with lymphopenia. Include only patients with breast cancer with lymphopenia is based on the particularly poor prognosis of these patients. The approach suggested here is to deplete and active the immune response of these immunosuppressed patients. The combination of pembrolizumab and cyclophosphamide would provide a higher gain in anti-tumor response in these patients than in those without lymphopenia and in chemotherapy alone. The investigators proposal is to conduct a multicentric, non-comparative, single arm, two-stage, Phase II trial in lymphopenic patients with metastatic breast cancer. The study is divided in 2 parts: - a safety run-in Phase aiming to evaluate the safety of the combination therapy pembrolizumab + metronomic cyclophosphamide based on the occurrence of severe toxicities. - a two-stage Phase II aiming to evaluate the clinical activity of the combination therapy pembrolizumab + metronomic cyclophosphamide. In both parts of the study, patients will receive cyclophosphamide (50 mg/day, daily, per os) and pembrolizumab (200 mg every 3 weeks, intravenously [IV]). The adverse events of the two drugs are well known.

Detailed Description

      The initiation of different stage of the study depend on the occurrences of severe toxicities
      in safety run-in phase and Clinical Benefit rate after 24 weeks in the two-stage Phase II of
      the study.

      Both study drugs will continue to be administered as long as patient experience clinical
      benefit in the opinion of the investigator or symptomatic deterioration attributed to disease
      progression as determined by the investigator after an integrated assessment of radiographic
      data and clinical status or withdrawal of consent.
    

Trial Arms

NameTypeDescriptionInterventions
Cyclophosphamide et pembrolizumabOtherThe treatments received are: cyclophosphamide (50 mg/day, daily, per os) pembrolizumab (200 mg every 3 weeks, intravenously [IV]). On days 1, cyclophosphamide should be taken first and pembrolizumab infusion initiated within 1 hour after cyclophosphamide intake.
  • Cyclophosphamide 50mg
  • Pembrolizumab 100 MG in 4 ML Injection

Eligibility Criteria

        Inclusion Criteria:

          -  Female patient>=18 years of age on day of signing informed consent.

          -  Histologically proven HER2-negative metastatic breast cancer. HER2-negativity is
             defined as immunohistochemistry (IHC) score 0, 1+ or 2+ and fluorescent in situ
             hybridization (FISH) negative or just FISH negative, whichever was performed.

          -  Patient previously treated with at least one prior line of standard chemotherapy
             either in the adjuvant setting or in the metastatic setting. Patients may be included
             in the first line metastatic setting if they have received anthracycline and/or
             taxane-based therapy in the neoadjuvant/adjuvant setting.

        Note: Patients with ER-positive tumors must have received at least one prior endocrine
        therapy, either in the adjuvant setting or in the metastatic setting.

          -  Documented lymphopenia defined by at least one value of lymphocyte count < 1.5 G/L
             within 15 days before treatment start (C1D1) and following at least 15 days since the
             last administration of chemotherapy.

          -  Biopsiable disease i.e. at least one lesion with a diameter ≥ 10 mm, visible by
             medical imaging and accessible to percutaneous sampling.

          -  Patient willing to undergo 2 tumor biopsies (at inclusion and at C3D1).

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2 and
             minimum life expectancy of 24 weeks.

          -  Documented radiological disease progression at time of study entry.

          -  At least one measurable lesion according to RECIST 1.1.

          -  Adequate end organ and marrow function as defined below: all screening labs should be
             performed within 3 days before treatment start (C1D1).

        Hematological Laboratory Values Absolute neutrophil count (ANC) ≥ 1.5G/L Platelets ≥ 100G/L
        Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L (without transfusion within 7 days of assessment) Renal
        Laboratory Values Serum creatinine ≤ 1.5 X upper limit of normal (ULN) or Calculated
        creatinine clearance as per MDRD or CKD-EPI formula ≥ 60 mL/min /1.73m2 Hepatic Laboratory
        Values 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 LDH ≤ 1.5 ULN Albumin ≥ 25
        g/L Coagulation Laboratory Values International Normalized Ratio (INR) ≤ 1.5 ULN Ratio of
        activated Partial Thromboplastin Time (aPTT) ≤ 1.5 ULN

          -  Absence of prior significant treatment-related toxicity i.e. treatment-related
             toxicity > Grade 1 as per CTCAE v4.03 (Appendix 2), except grade 2 alopecia, grade 2
             neuropathy and biological values as described in I10.

          -  Women of child-bearing potential must have a negative serum pregnancy test within 3
             days before C1D1.

          -  Women of child-bearing potential must agree to use 2 effective forms of contraception
             from the time of the negative pregnancy test up to 120 days after the last dose of
             study drugs. Effective forms are detailed in Appendix 5.

          -  Patient should understand, sign, and date the written voluntary informed consent form
             at the screening visit prior to any protocol-specific procedures performed. Patient
             should be able and willing to comply with study visits and procedures as per protocol.

          -  Patients must be covered by a medical insurance.

        Exclusion Criteria:

          -  Previously treated with more than 3 prior lines of chemotherapy in the metastatic
             setting

          -  Has previously received therapy with an anti-programmed cell death 1 (PD-1),
             anti-programmed cell death 1 ligand 1(PD-L1), anti-PD-L2, anti-CD137 antibody, or
             anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody.

          -  Presenting any contraindication to cyclophosphamide treatment including known
             hypersensitivity to cyclophosphamide, inflammation of the bladder (cystitis), urinary
             outflow obstruction or active infection.

          -  Requiring the use of concomitant medications defined as forbidden in the SPC of
             cyclophosphamide.

          -  Hypersensitivity to pembrolizumab or any of its excipients.

          -  Has a known history of active Bacillus Tuberculosis.

          -  Prior treatment with:

               -  any investigational agent within 4 weeks before C1D1 (or 5 half-lives whichever
                  is shorter with a minimum of 2 weeks);

               -  any systemic corticosteroids at doses higher than 10 mg/d of prednisolone or
                  equivalent or immunosuppressive agent within 4 weeks before C1D1;

               -  any monoclonal antibody within 4 weeks before C1D1;

               -  any chemotherapy, targeted small molecule therapy, radiation therapy, or surgery
                  within 2 weeks prior to C1D1.

        Note: If a patient underwent a major surgical procedure, they must have adequately
        recovered from the toxicity (i.e. wound healing) and/or complications from the intervention
        prior to starting therapy.

        * any 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.

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy.

          -  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 C1D1 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 28 days
             prior to C1D1. This exception does not include carcinomatous meningitis which is
             excluded regardless of clinical stability.

          -  Has active autoimmune disease that has required systemic treatment in the past 3
             months or a documented history of clinically severe autoimmune disease, or a syndrome
             that requires systemic steroids at doses higher than 10 mg/d of methylprednisolone or
             equivalent or immunosuppressive agents.

        Note: Patients with vitiligo or resolved childhood asthma/atopy would be an exception to
        this rule. Patients that require intermittent use of bronchodilators or local steroid
        injections would not be excluded from the study. Patients with hypothyroidism stable on
        hormone replacement or Sjorgen's syndrome will not be excluded from the study.

          -  Has an history of (non-infectious) pneumonitis that required steroids, evidence of
             interstitial lung disease or active non-infectious pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  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.

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

          -  Is pregnant or breastfeeding, or expecting to conceive children within the projected
             duration of the trial, starting with the screening visit through 120 days after the
             last dose of trial treatment.

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or
             active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative]
             is detected).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Severe Toxicities (ST) in Run-In Phase Part
Time Frame:First 6 weeks of treatment
Safety Issue:
Description:Number of severe toxicities occurring during the first 6 weeks of treatment and defined as following events evaluated as related to study drugs, using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4.03: any Grade ≥ 3 non hematological toxicity including in particular events of special interest any Grade ≥4 hematological and non-hematological Adverse Event (AE) including.

Secondary Outcome Measures

Measure:Overall response Rate (ORR) at 24 weeks
Time Frame:24 weeks of treatment
Safety Issue:
Description:The objective response rate (ORR) will be defined as the proportion of patients (described on the efficacy-evaluable population) who achieve complete response (CR) or partial response (PR) as best overall response at 24 weeks of treatment. ORR is based on tumor assessments (measurements according to RECIST 1.1 and irRC criteria).
Measure:Duration of response (DoR)
Time Frame:15 months
Safety Issue:
Description:Calculated from date of first documented objective response (i.e., CR or PR) until date of first documented progression disease (measurements according to RECIST 1.1 and irRC criteria).
Measure:Progression-Free Survival (PFS)
Time Frame:15 months
Safety Issue:
Description:Measured from the date of study drugs start to the date of the first objective radiological disease progression using RECIST 1.1 or death.
Measure:Overall Survival (OS)
Time Frame:15 months
Safety Issue:
Description:Defined as the duration of time from start of treatment to time of death.
Measure:Adverse events reporting
Time Frame:15 months
Safety Issue:
Description:Adverse Events (AE), vital signs, ECG, physical examination, laboratory safety assessments (hematological and biochemical parameters).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Centre Leon Berard

Trial Keywords

  • Solid tumor
  • Breast cancer
  • Metastatic cancer
  • Pembrolizumab
  • Metronomic cyclophosphamide

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