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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 (BreastImmune03)

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ClinicalTrials.gov Identifier: NCT03818685
Recruitment Status : Recruiting
First Posted : January 28, 2019
Last Update Posted : July 7, 2020
Sponsor:
Information provided by (Responsible Party):
Centre Leon Berard

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Breast Cancer Triple Negative Breast Neoplasms Drug: Nivolumab Drug: Ipilimumab Drug: Capecitabine Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 98 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This trial is an open-label, randomised, multicentric, comparative, Phase II study
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 2, 2019
Estimated Primary Completion Date : March 1, 2022
Estimated Study Completion Date : March 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Nivolumab + Ipilimumab
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.
Drug: Nivolumab
Radiotherapy will be maintained in each Arm.

Drug: Ipilimumab
Radiotherapy will be maintained in each Arm.

Active Comparator: Capecitabine
Capecitabine (1000 mg/m2 twice a day, Bis In Die), 14 days on / 7 days off for 8 cycles.
Drug: Capecitabine
Radiotherapy will be maintained in each Arm.




Primary Outcome Measures :
  1. Disease free survival (DFS) [ Time Frame: At 2 years ]
    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 :
  1. Overall survival [ Time Frame: Up to 2 years ]
    Overall survival will be measured from the date of randomization to the date of death from any cause.

  2. Local-regional recurrence [ Time Frame: Up to 2 years ]
    Local-regional recurrence (LRR) refers to relapse of the primary tumor site

  3. Distant metastasis [ Time Frame: Up to 2 years ]
    Distant metastasis is defined as presence of any non-local metastatic sites.

  4. Disease recurrence/relapse (local or distant) [ Time Frame: Up to 2 years ]
    Rate of patients with recurrence at 1 year and 2 year post-randomisation as well as time to recurrence will be analysed.

  5. Adverse Event [ Time Frame: Up to 2 years ]
    The assessment of safety will be based mainly on the frequency of adverse events based on the common toxicity criteria (CTCAE-V5.0) grade.

  6. EORTC QLQ C30 [ Time Frame: At Baseline, every 12 weeks and 30 days after the last dose ]
    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.

  7. Questionnaire EORTC QLQ BR-23 [ Time Frame: At Baseline, every 12 weeks and 30 days after the last dose ]
    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.

  8. Questionnaire EORTC QLQ FA-12 Fatigue [ Time Frame: At Baseline, every 12 weeks and 30 days after the last dose ]

    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.


  9. Questionnaire patient self-rating mood scale. [ Time Frame: At Baseline, every 12 weeks and 30 days after the last dose ]
    Patient reported outcomes and quality of life will be assessed using the following questionnaire : patient self-rating mood scale.

  10. Mutational profiles [ Time Frame: At Baseline and in case of disease relapse up to 2 years ]
    To define the molecular characteristics of the tumor' patients: Mutational profiles of tumors (Whole Exome seq,)

  11. Copy Number alterations. [ Time Frame: At Baseline and in case of disease relapse up to 2 years ]
    To define the molecular characteristics of the tumor' patients: Copy Number alterations.

  12. Loss of heterozygosity. [ Time Frame: At Baseline and in case of disease relapse up to 2 years ]
    To define the molecular characteristics of the tumor' patients: loss of heterozygosity.

  13. Circulating tumor DNA [ Time Frame: At Baseline and in case of disease relapse up to 2 years ]
    Circulating tumor DNA detection and analysis will be performed on tumor' patients.

  14. Molecular Subtyping [ Time Frame: At Baseline and in case of disease relapse up to 2 years ]
    To define Molecular Subtyping of TNBC (RNAseq) on tumor' patients.

  15. 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 ]
    To perform Immune monitoring of circulating immune cells and circulating tumor cells on blood sample.

  16. 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 ]
    To assess levels of circulating growth factors and cytokines on blood sample.

  17. Cytokines [ Time Frame: At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse ]
    To assess levels of cytokines on blood sample.

  18. PDL1 [ Time Frame: At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse ]
    To assess the presence in plasma of soluble PDL1.

  19. PDL2 [ Time Frame: At cycle1 (each cycle is 21 days), cycle 2, cycle 5 and 24 months after randomisation or in case of relapse ]
    To assess the presence in plasma of soluble PDL2.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03818685


Contacts
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Contact: Olivier Tredan, MD + 33 (0)4 78 78 26 44 olivier.tredan@lyon.unicancer.fr

Locations
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France
Institut de Cancérologie de l'Ouest Recruiting
Angers, France, 49055
Contact: Anne PATSOURIS, MD    +33 (0)2 41 35 27 00    anne.patsouris@ico.unicancer.fr   
Principal Investigator: Anne PATSOURIS, MD         
Institut Sainte Catherine Recruiting
Avignon, France
Contact: Julien GRENIER, MD       j.grenier@isc84.org   
Principal Investigator: Julien GRENIER, MD         
CHRU Besançon Recruiting
Besançon, France
Contact: Laura MANSI, MD       lmansi@chu-besancon.fr   
Principal Investigator: Laura MANSI, MD         
Centre Francois Baclesse Recruiting
Caen, France
Contact: Christelle LEVY, MD       c.levy@baclesse.unicancer.fr   
Principal Investigator: Christelle LEVY, MD         
Hopital Prive Jean Mermoz Recruiting
Lyon, France, 69008
Contact: OLFA DERBEL, MD       o.derbelmermoz@gmail.com   
Principal Investigator: Olfa DERBEL, MD         
Centre Léon Bérard Recruiting
Lyon, France, 69373
Contact: Olivier TREDAN, MD    +33 (0)4 78 78 26 44    olivier.tredan@lyon.unicancer.fr   
Principal Investigator: Olivier TREDAN, MD         
Clinique de la Sauvegarde Recruiting
Lyon, France
Contact: Yann MOLIN, MD       dryannmolin@gmail.com   
Principal Investigator: Yann MOLIN, MD         
Institut Paoli Calmettes Recruiting
Marseille, France, 13273
Contact: Anthony GONCALVES, MD    +33 (0)4 91 22 37 89    goncalvesa@ipc.unicancer.fr   
Principal Investigator: Anthony GONCALVES, MD         
Centre Antoine Lacassagne Recruiting
Nice, France, 06189
Contact: Jean Marc FERRERO, MD    +33 (0)4 92 03 11 14    jean-marc.ferrero@nice.unicancer.fr   
Principal Investigator: Jean Marc FERRERO, MD         
Institut Curie Recruiting
Paris, France, 75005
Contact: Jean-Yves PIERGA       Jean-yves.pierga@curie.fr   
Principal Investigator: Jean-Yves PIERGA, MD         
Institut Jean Godinot Recruiting
Reims, France, 51056
Contact: Christelle JOUANNAUD, MD    +33 (0)3 26 50 43 83    christelle.jouannaud@reims.unicancer.fr   
Principal Investigator: Christelle JOUANNAUD, MD         
Institut Curie Recruiting
Saint Cloud, France, 92201
Contact: Jean-Yves PIERGA, MD       Jean-yves.pierga@curie.fr   
Principal Investigator: Jean-Yves PIERGA, MD         
Institut de Cancérologie de l'Ouest Recruiting
Saint-Herblain, France, 44805
Contact: Jean Sébastien FRENEL, MD    +33 (0)2 40 67 99 00    jean-sebastien.frenel@ico.unicancer.fr   
Principal Investigator: Jean Sébastien FRENEL, MD         
Centre Paul Strauss Recruiting
Strasbourg, France, 67065
Contact: Thierry PETIT, MD    +33 (0)3 88 25 24 85    tpetit@strasbourg.unicancer.fr   
Principal Investigator: Thierry PETIT, MD         
Sponsors and Collaborators
Centre Leon Berard
Investigators
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Principal Investigator: Olivier Tredan, MD Centre Leon Berard
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Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT03818685    
Other Study ID Numbers: ET17-093 BreastImmune03
First Posted: January 28, 2019    Key Record Dates
Last Update Posted: July 7, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centre Leon Berard:
Residual disease with RCB of Class III
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Capecitabine
Nivolumab
Ipilimumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological