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Evaluate the Clinical Benefit of a Post-operative Treatment Associating Radiotherapy + Nivolumab + Ipilimumab Versus Radiotherapy + Capecitabine for Triple Negative Breast Cancer Patients With Residual Disease

NCT03818685

Description:

To evaluate the clinical benefit of a post-operative adjuvant therapy combining radiotherapy + Nivolumab + Ipilimumab versus radiotherapy + Capecitabine in Triple Negative Breast Cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Evaluate the Clinical Benefit of a Post-operative Treatment Associating Radiotherapy + Nivolumab + Ipilimumab Versus Radiotherapy + Capecitabine for Triple Negative Breast Cancer Patients With Residual Disease
  • Official Title: A Multicenter, Randomised, Open-label Phase II Study to Evaluate the Clinical Benefit of a Post-operative Treatment Associating Radiotherapy + Nivolumab + Ipilimumab Versus Radiotherapy + Capecitabine for Triple Negative Breast Cancer Patients With Residual Disease After Neoadjuvant Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: ET17-093 BreastImmune03
  • NCT ID: NCT03818685

Conditions

  • Breast Cancer
  • Triple Negative Breast Neoplasms

Interventions

DrugSynonymsArms
NivolumabNivolumab + Ipilimumab
IpilimumabNivolumab + Ipilimumab
CapecitabineCapecitabine

Purpose

To evaluate the clinical benefit of a post-operative adjuvant therapy combining radiotherapy + Nivolumab + Ipilimumab versus radiotherapy + Capecitabine in Triple Negative Breast Cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy.

Detailed Description

      This trial is an open-label, randomised, multicentric, comparative, Phase II study aiming to
      evaluate the clinical benefit of a combined treatment associating radiotherapy + Nivolumab +
      Ipilimumab versus radiotherapy + Capecitabine (standard treatment) in early TNBC patients who
      have Residual cancer burden (RCB) III residual disease after neoadjuvant chemotherapy.

      Following validation of eligibility criteria, patients will be randomised (1:1) to receive:

        -  Arm A: Nivolumab (360 mg IV, every 3 weeks) for 8 doses and Ipilimumab (1 mg/kg, IV,
           every 6 weeks or every 2 doses of Nivolumab in case of dose delays) for 4 doses.

        -  Arm B: Capecitabine (1000 mg/m2 twice a day, Bis In Die [BID]), 14 days on / 7 days off
           for 8 cycles.

      In both arms, radiotherapy will be administered as per standard practice and has to be
      initiated one week before C1D1.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab + IpilimumabExperimentalNivolumab (360 mg IV, every 3 weeks) for 8 doses and Ipilimumab (1 mg/kg, IV, every 6 weeks or every 2 doses of Nivolumab in case of dose delays) for 4 doses.
  • Nivolumab
  • Ipilimumab
CapecitabineActive ComparatorCapecitabine (1000 mg/m2 twice a day, Bis In Die), 14 days on / 7 days off for 8 cycles.
  • Capecitabine

Eligibility Criteria

        Inclusion Criteria:

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

          -  Histologically proven TNBC defined as follows : HER2 negativity must be confirmed (by
             one of the following: Fluorescence in situ hybridization (FISH) negative (FISH ratio
             <2.2), or Immunohistochemistry (IHC): 0-1+, or IHC 2-3+ and FISH-negative (FISH ratio
             <2.2)) and less than 1% of cells stained by immunohistochemistry (IHC) for ER and PR
             as per ASCO guidelines.

          -  TNBC previously treated by : Standard neoadjuvant chemotherapy containing
             anthracycline and taxanes and Surgery.

          -  TNBC patients currently treated by post-operative radiotherapy as per standard and/or
             institutional guidelines.

          -  No radiological evidence of metastatic disease documented by a CT-Scan of Chest
             abdomen and pelvis.

          -  Residual disease with RCB of Class III documented before randomisation using the
             surgery specimen.

          -  Availability of a representative formalin-fixed paraffin-embedded (FFPE) tumor block
             from surgery specimen with its histological report.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.

          -  Adequate end organ and bone marrow function as defined in protocol. All screening lab
             tests should be performed within 7 days before C1D1.

          -  Absence of significant treatment-related toxicity i.e. > Grade 1 as per CTCAE v5.0,
             except alopecia (all grades are acceptable), neuropathy (Grade 2 is acceptable) or
             biological values as defined in protocol.

          -  Minimal wash-out period for prior treatments (i.e. minimal delay from last dose of
             prior treatment to C1D1): any investigational agent > 4 weeks (or 5 half-lives
             whichever is longer with a minimum of 2 weeks), any monoclonal antibody > 4 weeks, any
             targeted therapies > 4 weeks, - live vaccine > 4 weeks, systemic steroids at doses
             higher than 10 mg/day prednisone equivalent or other immunosuppressive agents > 3
             weeks, sorivudine or its chemically related analogues such as brivudine > 4 weeks.

          -  Women of child-bearing potential must have a negative serum pregnancy test within 7
             days before C1D1.

          -  Women of child-bearing potential must agree to use 1 effective form of contraception
             from the time of the negative pregnancy test up to 5 months after the last dose of
             study drugs.

          -  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:

          -  Patient has a metastatic TN breast cancer.

          -  Patient has previously received therapy with an anti- PD-1, anti- PD-L1, or anti-CTLA4
             or any other immunotherapies.

          -  Patient 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 curative therapy
             and other completely treated prior malignancy if no evidence of disease for ≥ 2 years.

          -  Patient presents a contraindication to Nivolumab or Ipilimumab treatment as per
             respective SPC including known hypersensitivity to one of these study drugs or severe
             hypersensitivity reaction to any monoclonal antibody.

          -  Patient presents a contraindication to Capecitabine treatment as per SPC including :
             1) History of severe and unexpected reactions to fluoropyrimidine therapy, 2)
             Hypersensitivity to Capecitabine or to any of the excipients listed in SPC or
             fluorouracil, 3) Patients with known complete absence of dihydropyrimidine
             dehydrogenase activity, 4) Treatment with sorivudine or its chemically related
             analogues, such as brivudine, 5) any contraindication listed in respective SPC.

          -  Patient has active autoimmune disease that has required systemic treatment in the past
             3 months before C1D1 or a documented history of clinically severe autoimmune disease,
             or a syndrome that requires systemic steroids at doses higher than 10 mg/d prednisone
             equivalents or immunosuppressive agents.

          -  Patient requires the use of one of the following forbidden treatment during the study
             treatment period: any investigational anticancer therapy other than the protocol
             specified thérapies, any concurrent chemotherapy, immunotherapy, biologic for cancer
             treatment, other than the ones stated in the protocol. Concurrent use of hormones for
             non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement
             therapy) is acceptable, major surger, live vaccines, immunosuppressive agents and
             immunosuppressive high doses of systemic corticosteroids i.e. doses >10 mg/d
             prednisone or equivalent, sorivudine or its chemically related analogues such as
             brivudine and any treatment contra-indicated as per Capecitabine SPC.

          -  History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
             pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic
             organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.

          -  Significant cardiovascular disease, such as New York Heart Association cardiac disease
             (Class II or greater), myocardial infarction within 3 months prior to C1D1 unstable
             arrhythmias or unstable angina, Known Left Ventricular Ejection Fraction (LVEF) < 50%.

          -  Patient has a known history of active Bacillus Tuberculosis.

          -  Patient has an active infection requiring systemic therapy.

          -  Patient has Active hepatitis B (chronic or acute; defined as having a positive
             hepatitis B surface antigen [HBsAg] test at screening), Active hepatitis C (Patients
             positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for
             HCV RNA at screening) or Human Immunodeficiency Virus (HIV) infection (HIV 1/2
             antibodies).

          -  Prior allogeneic bone marrow transplantation or solid organ transplant in the past.

          -  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 5 months after the
             last dose of study drugs.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease free survival (DFS)
Time Frame:At 2 years
Safety Issue:
Description:DFS is defined as the time from randomization until the date of the first relapse (local/regional recurrence or distant metastasis) or death (from any cause) whichever comes firsts and regardless of whether the patient withdraws from randomised study treatment or receives another anti-cancer therapy prior to disease relapse.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Overall survival will be measured from the date of randomization to the date of death from any cause.
Measure:Local-regional recurrence
Time Frame:Up to 2 years
Safety Issue:
Description:Local-regional recurrence (LRR) refers to relapse of the primary tumor site
Measure:Distant metastasis
Time Frame:Up to 2 years
Safety Issue:
Description:Distant metastasis is defined as presence of any non-local metastatic sites.
Measure:Disease recurrence/relapse (local or distant)
Time Frame:Up to 2 years
Safety Issue:
Description:Rate of patients with recurrence at 1 year and 2 year post-randomisation as well as time to recurrence will be analysed.
Measure:Adverse Event
Time Frame:Up to 2 years
Safety Issue:
Description:The assessment of safety will be based mainly on the frequency of adverse events based on the common toxicity criteria (CTCAE-V5.0) grade.
Measure:EORTC QLQ C30
Time Frame:At Baseline, every 12 weeks and 30 days after the last dose
Safety Issue:
Description:Patient reported outcomes and quality of life will be assessed using the validated following questionnaire: The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30). The QLQ-C30 incorporates nine multi-item scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life scale. Several single-item symptom measures are also included. See scoring manual at :https://www.eortc.be/qol/files/SCManualQLQ-C30.pdf.
Measure:Questionnaire EORTC QLQ BR-23
Time Frame:At Baseline, every 12 weeks and 30 days after the last dose
Safety Issue:
Description:Patient reported outcomes and quality of life will be assessed using the validated following questionnaire :The European Organization for Research and Treatment of Cancer Breast-Cancer-Specific Quality of Life Questionnaire. See details at :https://www.eortc.be.
Measure:Questionnaire EORTC QLQ FA-12 Fatigue
Time Frame:At Baseline, every 12 weeks and 30 days after the last dose
Safety Issue:
Description:Patient reported outcomes and quality of life will be assessed using the validated following questionnaire : EORTC QLQ FA-12 Fatigue. The European Organisation for Research and Treatment of Cancer (EORTC) Group has developed a multidimensional instrument measuring cancer-related fatigue to be used in conjunction with the quality of life core questionnaire (EORTC QLQ-C30). The module EORTC QLQ-FA12 assesses physical, cognitive, and emotional aspects of cancer-related fatigue. See details at :https://www.eortc.be.
Measure:Questionnaire patient self-rating mood scale.
Time Frame:At Baseline, every 12 weeks and 30 days after the last dose
Safety Issue:
Description:Patient reported outcomes and quality of life will be assessed using the following questionnaire : patient self-rating mood scale.
Measure:Mutational profiles
Time Frame:At Baseline and in case of disease relapse up to 2 years
Safety Issue:
Description:To define the molecular characteristics of the tumor' patients: Mutational profiles of tumors (Whole Exome seq,)
Measure:Copy Number alterations.
Time Frame:At Baseline and in case of disease relapse up to 2 years
Safety Issue:
Description:To define the molecular characteristics of the tumor' patients: Copy Number alterations.
Measure:Loss of heterozygosity.
Time Frame:At Baseline and in case of disease relapse up to 2 years
Safety Issue:
Description:To define the molecular characteristics of the tumor' patients: loss of heterozygosity.
Measure:Circulating tumor DNA
Time Frame:At Baseline and in case of disease relapse up to 2 years
Safety Issue:
Description:Circulating tumor DNA detection and analysis will be performed on tumor' patients.
Measure:Molecular Subtyping
Time Frame:At Baseline and in case of disease relapse up to 2 years
Safety Issue:
Description:To define Molecular Subtyping of TNBC (RNAseq) on tumor' patients.
Measure:Immune monitoring
Time Frame:At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse
Safety Issue:
Description:To perform Immune monitoring of circulating immune cells and circulating tumor cells on blood sample.
Measure:Circulating growth factors
Time Frame:At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse
Safety Issue:
Description:To assess levels of circulating growth factors and cytokines on blood sample.
Measure:Cytokines
Time Frame:At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse
Safety Issue:
Description:To assess levels of cytokines on blood sample.
Measure:PDL1
Time Frame:At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse
Safety Issue:
Description:To assess the presence in plasma of soluble PDL1.
Measure:PDL2
Time Frame:At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse
Safety Issue:
Description:To assess the presence in plasma of soluble PDL2.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Centre Leon Berard

Trial Keywords

  • Residual disease with RCB of Class III

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