Clinical Trials /

Adjuvant Treatment for High-risk Triple Negative Breast Cancer Patients With the Anti-PD-l1 Antibody Avelumab

NCT02926196

Description:

Phase III randomized trial of the anti-PD-L1 antibody avelumab as adjuvant or post-neoadjuvant treatment for high-risk triple negative breast cancer patients. The overall protocol-defined patient population will include the following two strata of patients: - Stratum A - Patients who have completed treatment with curative intent including surgery of the primary tumor followed by adjuvant chemotherapy and (if indicated) radiotherapy. - Stratum B - Patients who have completed treatment with curative intent including neoadjuvant chemotherapy followed by surgery of the primary tumor and (if indicated) radiotherapy.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Adjuvant Treatment for High-risk Triple Negative Breast Cancer Patients With the Anti-PD-l1 Antibody Avelumab
  • Official Title: Adjuvant Treatment for High-risk Triple Negative Breast Cancer Patients With the Anti-PD-l1 Antibody Avelumab: A Phase III Randomized Trial. Sponsor: Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Università di Padova

Clinical Trial IDs

  • ORG STUDY ID: A-BRAVE-Trial
  • SECONDARY ID: 2016-000189-45
  • NCT ID: NCT02926196

Conditions

  • Triple Negative Breast Neoplasms

Interventions

DrugSynonymsArms
MSB0010718CAvelumabArm Avelumab

Purpose

Phase III randomized trial of the anti-PD-L1 antibody avelumab as adjuvant or post-neoadjuvant treatment for high-risk triple negative breast cancer patients. The overall protocol-defined patient population will include the following two strata of patients: - Stratum A - Patients who have completed treatment with curative intent including surgery of the primary tumor followed by adjuvant chemotherapy and (if indicated) radiotherapy. - Stratum B - Patients who have completed treatment with curative intent including neoadjuvant chemotherapy followed by surgery of the primary tumor and (if indicated) radiotherapy.

Detailed Description

      -  to determine whether 1 year of adjuvant Avelumab improves disease-free survival (DFS)
           compared to observation in patients with high-risk primary triple negative breast cancer
           (all comers, unselected for PD-L1 status) who have completed treatment with curative
           intent including surgery of the primary tumor, neo- or adjuvant chemotherapy, and (if
           indicated) radiotherapy.

        -  to determine whether 1 year of adjuvant Avelumab improves disease-free survival (DFS)
           compared to observation in PD-L1-positive (as determined by a companion diagnostic test
           under development) patients with high-risk primary triple negative breast cancer who
           have completed treatment with curative intent including surgery of the primary tumor,
           neo- or adjuvant chemotherapy, and (if indicated) radiotherapy.

        -  to determine whether Avelumab improves overall survival (OS) compared to observation in
           patients with high-risk primary triple negative breast cancer who have completed
           treatment with curative intent including surgery of the primary tumor, neo- or adjuvant
           chemotherapy, and (if indicated) radiotherapy.

        -  to assess the overall safety of Avelumab administered as adjuvant treatment in patients
           with high-risk primary triple negative breast cancer who have completed treatment with
           curative intent including surgery of the primary tumor, neo- or adjuvant chemotherapy,
           and (if indicated) radiotherapy.
    

Trial Arms

NameTypeDescriptionInterventions
Arm AvelumabExperimentalAvelumab 10 mg/kg I.V. q2w for 1 year (52 weeks)
  • MSB0010718C
Arm ObservationNo InterventionObservation as per guidelines

    Eligibility Criteria

            Inclusion Criteria Stratum A (Adjuvant patients) & B (Post-neoadjuvant patients)
    
              1. Male or female subjects aged > 18 years
    
              2. Signed written informed consent before any trial-related procedure is undertaken that
                 is not part of the standard patient management
    
              3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
    
              4. Patients must have completed treatment with curative intent including: surgery,
                 adjuvant chemotherapy and (if clinically indicated as per local policy) radiotherapy.
    
              5. Patients must have completed adjuvant chemotherapy including at least 3 courses of an
                 anthracycline agent and 3 courses of a taxane agent. Patients who received dose-dense
                 regimens and those who received carboplatin as part of the adjuvant treatment are
                 eligible.
    
              6. Patients for whom radiotherapy is clinically indicated as per local policy must have
                 completed radiotherapy prior to study enrolment.
    
              7. No more than 8 weeks may elapse between the completion of last adjuvant treatment
                 (adjuvant chemotherapy or radiotherapy when indicated) and randomization.
    
              8. Normal organ and marrow function
    
                   1. White blood count (WBC) greater than or equal to 2.5 x109/L
    
                   2. Absolute neutrophil count (ANC) greater than or equal to 1.5 x109/L
    
                   3. Absolute lymphocyte count greater or equal to 0.5 x109/L
    
                   4. Platelet count greater than or equal to 100 x109/L
    
                   5. Hemoglobin greater than or equal to 9 g/dL
    
                   6. Serum creatinine less or equal to 1.5 x the upper limit of laboratory normal
                      range (ULN)
    
                   7. Adequate hepatic function defined by a total bilirubin level less or equal to 1.5
                      x ULN range and AST and ALT levels less or equal than 2.5 x ULN for all subjects.
                      For patients with known Gilbert's syndrome, total bilirubin levels less or equal
                      than 2 x ULN range (with direct bilirubin less than ULN) will be accepted.
    
              9. Highly effective contraception (i.e. methods with a failure rate of less than 1 % per
                 year) for both male and female subjects if the risk of conception exists (Note: The
                 effects of the trial treatment on the developing human fetus are unknown; thus, women
                 of childbearing potential and men must agree to use highly effective contraception,
                 defined in Appendix A or as stipulated in national or local guidelines. Highly
                 effective contraception must be used 28 days prior to first trial treatment
                 administration, for the duration of trial treatment, and at least for 60 days after
                 stopping trial treatment. Should a woman become pregnant or suspect she is pregnant
                 while she or her partner is participating in this trial, the treating physician should
                 be informed immediately).
    
             10. Ability to understand and willingness to sign a written informed consent.
    
            Inclusion Criteria Stratum A (Adjuvant patients)
    
              1. Non-metastatic, histologically confirmed primary invasive breast carcinoma
    
              2. Triple negative breast cancer: hormone receptor negative (ER < 10% and PgR < 10%) and
                 HER2 negative (IHC 0/1+ or ISH non-amplified), as defined by the local pathology
                 laboratory. In case of discordance between pre-operative core-biopsy and the surgical
                 sample, the receptor assessment performed on the surgical sample has to be considered
                 for inclusion criteria evaluation.
    
              3. Availability of a formalin-fixed, paraffin-embedded block containing tumor tissue or
                 at least 7 unstained tumor slides.
    
              4. Adequately excised: patients must have undergone either breast-conserving surgery or
                 mastectomy/nipple- or skin-sparing mastectomy. The margins of the resected specimen
                 should be free of invasive tumor and ductal carcinoma in situ (no ink on tumor). In
                 the case of breast-conserving surgery patients with margins positive for lobular
                 carcinoma in situ (LCIS) are eligible without additional resection. For patients who
                 undergo mastectomy, patients with a microscopic positive deep margin are eligible,
                 provided they have received radiotherapy on chest wall.
    
              5. Pathological node staging (Union for International Cancer Control-American Joint
                 Committee on Cancer [UICC/AJCC] 7th edition): patients must have had axillary lymph
                 node dissection for evaluation of pathologic nodal status. Only patients with > 4
                 metastatic axillary node will be eligible (>pN2).
    
            Inclusion criteria:
    
            Stratum B (Post-neoadjuvant patients)
    
              1. Non-metastatic histologically confirmed invasive breast carcinoma.
    
              2. Triple negative breast cancer: hormone receptor negative (ER < 10% and PgR < 10%) and
                 HER2 negative (IHC 0/1+ or ISH non-amplified), as defined by the local pathology
                 laboratory. Both the diagnostic core-biopsy performed prior to neoadjuvant
                 chemotherapy and the residual disease assessed on the surgical specimen should show a
                 triple negative receptor status, as defined by the protocol. Patients with discordant
                 triple negative status will not be eligible.
    
              3. Adequately excised: patients should have undergone adequate tumor excision after
                 preoperative chemotherapy, which means surgical removal of all clinically evident
                 disease in the breast and lymph nodes.
    
                   1. Breast surgery: patients must have undergone either breast-conserving surgery or
                      mastectomy/nipple- or skin-sparing mastectomy. The margins of the resected
                      specimen should be free of invasive tumor and ductal carcinoma in situ (no ink on
                      tumor). In the case of breast-conserving surgery patients with margins positive
                      for lobular carcinoma in situ (LCIS) are eligible without additional resection.
                      For patients who undergo mastectomy, patients with a microscopic positive deep
                      margin are eligible, provided they have received radiotherapy on chest wall.
    
                   2. Lymph node surgery:
    
                 i. Axillary dissection without sentinel node evaluation is permitted after
                 preoperative therapy.
    
                 ii. In case of positive results from a fine-needle aspiration, core biopsy, or
                 sentinel node biopsy performed prior to preoperative therapy, additional surgical
                 evaluation of the axilla following preoperative therapy is required.
    
                 iii. If sentinel node biopsy performed before preoperative therapy was negative, no
                 additional surgical evaluation of the axilla is required after preoperative therapy.
    
                 iv. Sentinel node after preoperative therapy is allowed if no evidence of axillary
                 node involvement was documented by ultrasonography at diagnosis. If sentinel node
                 biopsy after preoperative therapy is negative, no further additional surgical
                 evaluation of the axilla is required. If sentinel node biopsy performed after
                 preoperative therapy is positive, additional surgical evaluation of the axilla is
                 recommended.
    
              4. Pathologic evidence of residual invasive carcinoma in the breast and/or axillary lymph
                 nodes on the surgical specimen obtained after preoperative therapy (ypT1micN0,
                 ypT1micN0i+, ypT0N0i+ will be excluded).
    
              5. Clinical stage at presentation: T1-4, N0-3, M0 (Exception: Patients with T1a/bN0
                 tumors at presentation will not be eligible).
    
              6. No more than 8 weeks may elapse between the date of last treatment (surgery or
                 post-surgery radiotherapy if indicated) and the date of randomization. In case of
                 positive margins after the first intervention requiring additional resection, in a
                 patient for whom post-surgery radiotherapy is not indicated, the interval of 8 weeks
                 will be calculated from the date of last surgery.
    
              7. Availability of a formalin-fixed, paraffin-embedded block containing tumor tissue or
                 at least 7 unstained tumor slides (tumor sample from the diagnostic core-biopsy
                 obtained before neoadjuvant chemotherapy). In case only 7 unstained slides from the
                 bioptic sample will be available, the investigator must ensure that the sample
                 contains tumor tissue by performing an hematoxylin and eosin staining.
    
            Exclusion criteria: Stratum A (Adjuvant patients) & B (Post-neoadjuvant patients)
    
              1. Stage IV breast cancer.
    
              2. History of any prior (ipsi- and/or contralateral) invasive breast carcinoma diagnosed
                 within 10 years.
    
              3. Synchronous bilateral breast cancer, unless both tumors confirmed as triple negative
                 disease.
    
              4. History of non-breast malignancies within the 5 years prior to study entry, except for
                 the following: Carcinoma in situ (CIS) of the cervix, CIS of the colon, Basal cell and
                 squamous cell carcinomas of the skin.
    
              5. Prior organ transplantation, including allogeneic stem-cell transplantation.
    
              6. Prior or concomitant treatment with any other investigational agents.
    
              7. Prior therapy with any antibody / drug targeting T-cell coregulatory proteins
                 (immune-checkpoints) such as PD-1, PD-L1, or cytotoxic T-lymphocyte antigen-4
                 (CTLA-4).
    
              8. Concurrent anticancer treatment (for example, cytoreductive therapy, radiotherapy,
                 immune therapy, or cytokine therapy except for erythropoietin)
    
              9. Major surgery for any reason, within 4 weeks of randomization and / or if the subject
                 has not fully recovered from the surgery within 4 weeks of randomization.
    
             10. Concomitant treatment with all herbal (alternative) remedies with immunostimulating
                 properties (for example, mistletoe extract) or known to potentially interfere with
                 major organ function (for example, hypericin).
    
             11. Subjects receiving immunosuppressive agents (such as steroids) for any reason should
                 be tapered off these drugs before initiation of the trial treatment (with the
                 exception of subjects with adrenal insufficiency, who may continue corticosteroids at
                 physiologic replacement dose, equivalent to ≤ 10 mg prednisone daily).
    
             12. Significant acute or chronic infections including, among others:
    
                   1. Known history of testing positive test for human immunodeficiency virus (HIV) or
                      known acquired immunodeficiency syndrome.
    
                   2. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening
                      (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test
                      positive).
    
             13. Active autoimmune disease that might deteriorate when receiving an immunostimulatory
                 agent:
    
                   1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease
                      not requiring immunosuppressive treatment are eligible.
    
                   2. Subjects requiring hormone replacement with corticosteroids are eligible if the
                      steroids are administered only for the purpose of hormonal replacement and at
                      doses ≤ 10 mg or equivalent prednisone per day.
    
                   3. Administration of steroids through a route known to result in a minimal systemic
                      exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.
    
             14. Administration of steroids through a route known to result in a minimal systemic
                 exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.
    
             15. Previous or ongoing administration of systemic steroids for the management of an acute
                 allergic phenomenon is acceptable as long as it is anticipated that the administration
                 of steroids will be completed in 14 days, or that the daily dose after 14 days will be
                 ≤ 10 mg per day of equivalent prednisone.
    
             16. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE
                 v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more
                 features of partially controlled asthma).
    
             17. Clinically significant (that is, active) cardiovascular disease: cerebral vascular
                 accident /stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
                 prior to enrollment), unstable angina, congestive heart failure (New York Heart
                 Association Classification Class ≥ II), or serious uncontrolled cardiac arrhythmia
                 requiring medication.
    
             18. All other significant diseases (for example, inflammatory bowel disease), which, in
                 the opinion of the Investigator, might impair the subject's tolerance of trial
                 treatment.
    
             19. Any psychiatric condition that would prohibit the understanding or rendering of
                 informed consent.
    
             20. Vaccination within 4 weeks of the first dose of avelumab and while on trial is
                 prohibited except for administration of inactivated vaccines (for example, inactivated
                 influenza vaccines).
    
             21. Known alcohol or drug abuse.
    
             22. Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v 4.03 (except for
                 grade 2 radiodermatitis and grade 2 neuropathy).
    
             23. Current pregnancy and/or lactation. Refusal to adopt adequate contraception methods.
    
            Stratum A (Adjuvant patients) 1. 3 or less positive axillary lymphnodes at pathological
            examination of surgical specimen.
    
            Stratum B (Postneoadjuvant patients)
    
            1. No invasive residual disease in the breast and axilla at pathological examination after
            neoadjuvant chemotherapy. ypT1micN0, ypT1micN0i+, ypT0N0i+ will also be excluded.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Disease free survival
    Time Frame:Up to 5 years after randomization
    Safety Issue:
    Description:DFS is defined as the time from randomization to locoregional invasive recurrence, second primary invasive breast cancer, other second primary cancer (excluding in-situ cancers), distant metastasis or death from any cause.

    Secondary Outcome Measures

    Measure:Overall survival
    Time Frame:Up to 5 years after randomization
    Safety Issue:
    Description:Overall survival is defined as the time from randomization to death from any cause
    Measure:Safety profile
    Time Frame:From Baseline up to 5 years after randomization
    Safety Issue:
    Description:Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI -CTCAE), version 4.

    Details

    Phase:Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Istituto Oncologico Veneto IRCCS

    Trial Keywords

    • ER-Negative
    • PR-Negative
    • HER2-Negative

    Last Updated

    June 19, 2017