Clinical Trials /

Neoadjuvant Therapy in TRIPle Negative Breast Cancer With antiPDL1

NCT02620280

Description:

This study that aims to evaluate the addition of MPDL3280A (atezolizumab) to carboplatin and nab-paclitaxel in patients with early high-risk and locally advanced triple negative breast cancer. compared to the control arm of carboplatin and abraxane. Half of participants will receive MPDL3280A in combination with carboplatin and abraxane, while the other half will receive only carboplatin and abraxane.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Therapy in TRIPle Negative Breast Cancer With antiPDL1
  • Official Title: Neo-Adjuvant Study With the PDL1-directed Antibody in Triple Negative Locally Advanced Breast Cancer Undergoing Treatment With Nab-paclitaxel and Carboplatin

Clinical Trial IDs

  • ORG STUDY ID: FM-14-B02
  • SECONDARY ID: 2014-005017-23
  • NCT ID: NCT02620280

Conditions

  • Invasive Ductal Breast Carcinoma

Interventions

DrugSynonymsArms
CarboplatinCarboplatin TevaCarbo-abrax, surgery, anthra
Abraxanenab-paclitaxelCarbo-abrax, surgery, anthra
MPDL3280AAtezolizumabCarbo-abrax-MPDL3280A, surgery, anthra
AnthraCarbo-abrax, surgery, anthra

Purpose

This study that aims to evaluate the addition of MPDL3280A (atezolizumab) to carboplatin and nab-paclitaxel in patients with locally advanced triple negative breast cancer. compared to the control arm of carboplatin and abraxane. Half of participants will receive MPDL3280A in combination with carboplatin and abraxane, while the other half will receive only carboplatin and abraxane.

Detailed Description

      Emerging evidence shows that many breast cancers with triple negative and basal like features
      have infiltration by mononuclear cells and lymphocytes. Irrespective of the entity of tumor
      infiltration by mononuclear cells, expression of immune regulatory checkpoints such as PD-1
      and its ligand B7-H1 (or PD-L1) negatively affect the results of treatments. These data
      suggest that a subset of patients have an ongoing immune response within the tumor
      micro-environment, and that PD-L1 expression is an adaptive method of tumor resistance to
      tumor infiltrating lymphocytes, which in turn are needed for response to chemotherapy.
      Overall, the data suggests a role for immune regulation of response to chemotherapy, and
      support the concept that blockade of immune check-points may favor the achievement of durable
      response by immune mechanisms themselves, and in combination with classical chemotherapy.

      MPDL3280A (atezolizumab) is a human monoclonal antibody containing an engineered Fc-domain to
      optimize efficacy and safety that targets PD-L1 and blocks binding of its receptors,
      including PD-1 and B7.1. Based on these considerations, we plan to conduct a study of the
      combination of abraxane and carboplatin with or without PDL1-directed antibody in women with
      locally advanced breast cancer suitable for neoadjuvant therapy with the aim to improve
      event-free survival
    

Trial Arms

NameTypeDescriptionInterventions
Carbo-abrax, surgery, anthraActive ComparatorPatients will receive a combination of carboplatin and abraxane as neoadjuvant treatment. Definite surgery will be performed not later than 6 weeks after the last dose of neoadjuvant therapy. Four cycles of AC or EC or FEC will then be delivered as adjuvant chemotherapy
  • Carboplatin
  • Abraxane
  • Anthra
Carbo-abrax-MPDL3280A, surgery, anthraExperimentalPatients will receive a combination of carboplatin, abraxane and MPDL3280A as neoadjuvant treatment. Definite surgery will be performed not later than 6 weeks after the last dose of neoadjuvant therapy. Four cycles of AC or EC or FEC will then be delivered as adjuvant chemotherapy
  • Carboplatin
  • Abraxane
  • MPDL3280A
  • Anthra

Eligibility Criteria

        Inclusion Criteria:

          1. Female patients aged 18 years or older with locally advanced or inflammatory breast
             cancers

          2. Histologically confirmed unilateral breast cancer with invasive ductal histology not
             otherwise specified (NOS) of high proliferation or grade

          3. HER2 negative disease

          4. Negative estrogen receptor (ER) and progesterone receptor (PgR), both < 1% locally
             assessed

          5. Representative paraffin-embedded (FFPE) tumor block taken at diagnostic biopsy for
             confirmation of HER2, ER and PgR eligibility, for assessment of PDL-1 expression and
             for further exploratory biomarker evaluation is mandatory

          6. ECOG performance status 0 or 1

          7. Written informed consent to participate in the trial (approved by the Institutional
             Review Board [IRB]/ Independent Ethics Committee [IEC]) obtained prior to any study
             specific screening procedures

          8. Willing and able to comply with the protocol

          9. Consent to the collection of blood samples

         10. For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea)
             or surgically sterile (absence of ovaries and/or uterus): agreement to remain
             abstinent or use single or combined contraceptive methods that result in a failure
             rate of < 1% per year during the treatment period and for at least 90 days after the
             last dose of study drug.

        Exclusion Criteria:

          1. Evidence of bilateral breast cancer or metastatic disease (M1)

          2. Cases with an histology different from invasive ductal NOS of high proliferation or
             grade

          3. Patients with HER2-positive disease according to ASCO/CAP guidelines 2013

          4. Pregnant or lactating women. Documentation of a negative pregnancy test must be
             available for premenopausal women with intact reproductive organs and for women less
             than one year after the last menstrual cycle

          5. Previous treatment with chemotherapy, hormonal therapy or an investigational drug for
             any type of malignancy

          6. Previous investigational treatment for any condition within 4 weeks of randomization
             date

          7. Administration of a live, attenuated vaccine within 4 weeks before cycle 1 Day 1 or
             anticipation that such a live attenuated vaccine will be required during the study

          8. Previous or concomitant invasive malignancy of any other type or previous invasive
             breast cancer. Patients with curatively treated basal cell carcinoma of the skin or in
             situ cervix cancer are generally eligible

          9. Pre-existing motor or sensory neuropathy of grade > 1 for any reason

         10. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

         11. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or any component of the MPDL3280A formulation

         12. Patients with prior allogeneic stem cell or solid organ transplantation

         13. History of autoimmune disease including, but not limited to, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's
             syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or
             glomerulonephritis

         14. History of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with
             organizing pneumonia) or evidence of active pneumonitis on screening chest computed
             tomography scan

         15. Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis, cirrhosis, fatty liver, and inherited liver disease

         16. History of HIV infection, active hepatitis B (chronic or acute), or hepatitis C
             infection. Patients with past or resolved hepatitis B infection (defined as having a
             negative HBsAg test and a positive hepatitis B core antigen [anti-HBc] test) are
             eligible.

        Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase
        chain reaction assay (PCR) is negative for HCV RNA 17. Active tuberculosis 18. Severe
        infections within 4 weeks prior to cycle 1 Day 1, including, but not limited to,
        hospitalization for complications of infection, bacteremia, or severe pneumonia. Signs or
        symptoms of significant infection within 2 weeks prior to cycle 1 Day 1 19. Received oral
        or IV antibiotics within 2 weeks prior to Cycle 1 Day 1 20. Other serious illness or
        medical condition including: history of documented congestive cardiac failure; New York
        Heart Association (NYHA) Class II or greater CHF; angina pectoris requiring anti-anginal
        medication or unstable angina within 6 months prior to cycle 1 Day 1; evidence of
        transmural infarction on ECG; myocardial infarction stroke or transient ischemic attack
        (TIA) within 6 months prior to cycle 1 Day 1; poorly controlled hypertension (e.g. systolic
        >180 mm Hg or diastolic >100 mm Hg; however, patients with hypertension which is well
        controlled on medication are eligible); clinically significant valvular heart disease;
        high-risk uncontrolled arrhythmias 21. Patients with a history of uncontrolled seizures,
        central nervous system disorders or psychiatric disability judged by the investigator to be
        clinically significant and precluding informed consent or adversely affecting compliance
        with study drugs 22. Serious uncontrolled infections (bacterial or viral) or poorly
        controlled diabetes mellitus 23. Abnormal baseline hematological values 24. Abnormal
        baseline laboratory tests for serum total bilirubin, liver function tests, alkaline
        phosphatase, serum creatinine, INR and aPTT 25. Baseline left ventricular ejection fraction
        (LVEF) < 50% by echocardiography or multi-gated scintigraphic scan (MUGA) 26. Major
        surgical procedure within 28 days prior to cycle 1 Day 1 or anticipation of need for a
        major surgical procedure during the course of the study 27. Influenza vaccination should be
        given during influenza season only (approximately October to March). Patients must not
        receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to cycle 1
        Day 1 or at any time during the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event Free Survival (EFS)
Time Frame:5 years after the randomization of the last patient
Safety Issue:
Description:To compare EFS (disease progression while on neoadjuvant therapy or disease recurrence after surgery) in the two study arms

Secondary Outcome Measures

Measure:Pathological complete response (pCR)
Time Frame:At surgery, an expected average of 34 weeks after the randomization of the last patient
Safety Issue:
Description:Assess the rate of pCR defined as ypT0-ypTis ypN0 at surgery in the two treatment arms
Measure:Clinical objective response
Time Frame:Participants will be followed for the duration of neoadjuvant therapy, an expected average of 26 weeks
Safety Issue:
Description:Assess the clinical response rate after neoadjuvant therapy
Measure:Distant Event Free Survival (DEFS)
Time Frame:5 years after the randomization of the last patients
Safety Issue:
Description:To compare the DEFS, defined as the occurrence of distant disease progression while on neoadjuvant therapy or distant recurrence after surgery in the two treatment arms
Measure:Number of participants with adverse events as a Measure of Safety and Tolerability
Time Frame:Participants wil be followed for up to 5 years from the last randomized patient
Safety Issue:
Description:Number of participants with Adverse Events and related grade

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fondazione Michelangelo

Trial Keywords

  • Triple Negative Breast Cancer

Last Updated

February 6, 2018