Phase III Randomized Trial of Adjuvant Avelumab in High-Risk Triple Negative Breast Cancer Post-Curative Treatment

Trial ID: 2024-514515-10-00
Protocol: A-BRAVE-Trial
Sponsor: Universita Degli Studi Di Padova

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Diseases & Conditions

Triple negative breast cancer

Objectives

The primary objective of this study is to evaluate whether one year of adjuvant **Avelumab** improves disease-free survival (DFS) compared to observation in patients with high-risk primary triple-negative breast cancer who have completed treatment with curative intent. This includes patients who have undergone surgery of the primary tumor followed by adjuvant chemotherapy (Stratum A) and those who have received neoadjuvant chemotherapy followed by surgery (Stratum B). The clinical relevance of this objective lies in potentially enhancing DFS, which is a critical endpoint in the management of high-risk triple-negative breast cancer, a subtype known for its aggressive nature and limited treatment options.

Secondary objectives include: - Determining whether one year of adjuvant Avelumab improves DFS compared to observation in patients with high-risk primary triple-negative breast cancer who have completed treatment with curative intent, specifically in Stratum B. - Evaluating the improvement in DFS with Avelumab in PD-L1-positive patients, as determined by a companion diagnostic test under development, who have completed treatment with curative intent including surgery of the primary tumor and neo- or adjuvant chemotherapy. These secondary objectives aim to further delineate the potential benefits of Avelumab in specific patient subgroups, thereby informing personalized treatment strategies.

Participants

The clinical trial involves a total of **24 participants** diagnosed with **breast cancer**, specifically focusing on high-risk primary triple-negative breast cancer. The study population includes both male and female subjects aged over 18 years, with a requirement for normal organ and marrow function. Participants must have completed treatment with curative intent, including surgery and adjuvant chemotherapy, and must not have metastatic disease. The trial population was selected based on specific inclusion criteria, such as having undergone adequate tumor excision and having a non-metastatic, histologically confirmed invasive breast carcinoma. Lifestyle considerations, such as diet and physical activity, are not specified. The trial includes a vulnerable population, and participants are required to use highly effective contraception due to unknown effects of the trial treatment on a developing fetus. The selection criteria ensure that participants have completed necessary preoperative and postoperative treatments, including chemotherapy regimens involving anthracycline and taxane agents.

Plans and Procedures

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the efficacy of **avelumab** as an adjuvant treatment for patients with high-risk triple-negative **breast cancer**. The primary objective is to assess whether one year of adjuvant avelumab improves disease-free survival (DFS) compared to observation in patients who have completed treatment with curative intent, including surgery and chemotherapy. The trial is expected to last until October 2025, with participant recruitment having commenced in June 2016.

Participants will be involved in the study for a maximum treatment period of 52 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The screening visit will ensure that participants meet the inclusion criteria, such as having completed adjuvant chemotherapy and surgery, and having normal organ and marrow function. Follow-up visits will occur at regular intervals to monitor the participants' health status and any potential side effects of the treatment. The end-of-study visit will evaluate the primary and secondary endpoints, including DFS and overall survival (OS).

Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator determines that it is in the participant's best interest to discontinue. The trial will adhere to strict ethical guidelines, ensuring that all participants provide informed consent before any trial-related procedures that are not part of standard patient management. The study aims to provide valuable insights into the potential benefits of avelumab in improving outcomes for patients with high-risk triple-negative breast cancer.

Treatment

The clinical trial involves the administration of **Bavencio** (avelumab), a **concentrate for solution for infusion**. Avelumab is a recombinant human monoclonal IgG1 antibody targeting programmed death ligand-1 (PD-L1). The pharmaceutical form is a solution for infusion, and it is administered via the **intravenous route**. The dosage is set at a maximum of 10 mg/kg, with the treatment period extending up to 52 weeks. The administration schedule is designed to ensure optimal therapeutic exposure while monitoring for any adverse effects. Compliance with the dosing regimen is monitored through regular assessments and documentation of infusion sessions.

In this trial, avelumab is used as an adjuvant treatment for patients with high-risk primary **triple negative breast cancer** who have completed treatment with curative intent, including surgery and chemotherapy. The trial aims to evaluate the efficacy of avelumab in improving disease-free survival compared to observation alone. No additional non-experimental treatments, such as placebo or comparator treatments, are utilized in this study. The trial is structured to ensure rigorous monitoring of participant compliance and response to the treatment regimen.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the evaluation of **disease-free survival (DFS)**. DFS is defined as the time interval between randomization and the occurrence of any of the following events: local, regional, or distant recurrence; second primary breast cancer, excluding in situ carcinoma; other second primary cancer (excluding in-situ cancers); or death before recurrence or second primary cancer. This endpoint will provide a measure of the effectiveness of adjuvant Avelumab in improving DFS compared to observation in patients with high-risk primary triple-negative breast cancer.

Additionally, overall survival (OS) will be evaluated as a secondary efficacy endpoint. OS will be calculated as the time interval between randomization and patient death or last follow-up. These efficacy parameters will be collected and analyzed to determine the impact of the treatment regimen on patient outcomes. The trial is designed to provide robust data on the potential benefits of Avelumab in this patient population, with the aim of improving long-term survival and reducing recurrence rates.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female subjects aged > 18 years
Signed written informed consent before any trial-related procedure is undertaken that is not part of the standard patient management
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Non-metastatic, histologically confirmed primary invasive breast carcinoma
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.
Availability of a formalin-fixed, paraffin-embedded block containing tumor tissue or at least 7 unstained tumor slides.
Patients must have completed treatment with curative intent including: surgery and adjuvant chemotherapy.
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.
Patients must have had axillary lymph node dissection for evaluation of pathologic nodal status. Only patients in one of the following stage categories will be eligible: ‒ if 4 or more metastatic lymph nodes, any pT ‒ if 1 to 3 metastatic lymph nodes, pT >2 cm ‒ if no metastatic lymph nodes, pT >5 cm
Patients must have had adjuvant chemotherapy after surgery. The recommended adjuvant treatment should have included at least 3 courses of an anthracycline agent and 3 courses of a taxane agent. Patients who cannot complete all planned treatment cycles for any reason are considered high risk and therefore are eligible for the study. Patients who received dose-dense regimens and those who received carboplatin as part of the adjuvant treatment are eligible.
No more than 10 weeks may elapse between the completion adjuvant chemotherapy and randomization.
Normal organ and marrow function a. White blood count (WBC) greater than or equal to 2.5 x109 /L b. Absolute neutrophil count (ANC) greater than or equal to 1.5 x109 /L c. Absolute lymphocyte count greater or equal to 0.5 x109 /L d. Platelet count greater than or equal to 100 x109 /L e. Hemoglobin greater than or equal to 9 g/dL f. Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) g. 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.
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 B 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 30 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).
Ability to understand and willingness to sign a written informed consent
Male or female subjects aged > 18 years.
Signed written informed consent before any trial-related procedure is undertaken that is not part of the standard patient management.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Non-metastatic histologically confirmed invasive breast carcinoma
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 the pre-treatment diagnostic core-biopsy and the surgical sample, the receptor assessment performed on the surgical sample has to be considered for inclusion criteria evaluation
Patients must have completed treatment with curative intent including: neoadjuvant chemotherapy and surgery.
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. a. 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. b. 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.
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).
Clinical stage at presentation: T1–4, N0–3, M0 (Exception: Patients with T1a/bN0 tumors at presentation will not be eligible).
Patients should have completed neoadjuvant chemotherapy before surgery. The recommended neoadjuvant treatment should have included at least 3 courses of ananthracycline agent and 3 courses of a taxane agent. Patients who cannot complete all planned treatment cycles for any reason are considered high risk and therefore are eligible for the study. Patients who received dose-dense regimens and those who received carboplatin as part of the adjuvant treatment are eligible.
No more than 10 weeks may elapse between the date surgery and the date of randomization. In case of positive margins after the first intervention requiring additional resection, the interval of 10 weeks will be calculated from the date of last surgery.
Patients with residual invasive breast cancer (as defined in inclusion criteria 8) at pathological examination after neoadjuvant chemotherapy (at least 3 courses of an anthracycline and 3 courses of a taxane agent), who also received additional adjuvant chemotherapy for no more than 6 months, are eligible in Stratum B. Screening procedures must start after the completion of adjuvant chemotherapy. No more than 10 weeks may elapse between the completion of adjuvant chemotherapy and the date of randomization.
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.
Normal organ and marrow function a. White blood count (WBC) greater than or equal to 2.5 x109/L b. Absolute neutrophil count (ANC) greater than or equal to 1.5 x109/L c. Absolute lymphocyte count greater or equal to 0.5 x109/L d. Platelet count greater than or equal to 100 x109/L e. Hemoglobin greater than or equal to 9 g/dL f. Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) g. Adequate hepatic function defined by a total bilirubin level less or equal to 1.5 x ULN 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.
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 B 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 30 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).
Ability to understand and willingness to sign a written informed consent.

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Exclusion Criteria

Metastatic breast cancer
Patients in any of the following stage categories are not eligible: - 1 to 3 metastatic axillary lymph nodes and pT<2cm; -0 metastatic axillary lymph nodes and pT<5cm.
History of any prior (ipsi- and/or contralateral) invasive breast carcinoma diagnosed within 10 years
Synchronous bilateral breast cancer, unless both tumors confirmed as triple negative disease.
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.
Prior organ transplantation, including allogeneic stem-cell transplantation
Prior or concomitant treatment with any other investigational agents.
Prior therapy with any antibody / drug targeting T-cell coregulatory proteins (immunecheckpoints) such as PD-1, PD-L1, or cytotoxic T-lymphocyte antigen-4 (CTLA-4).
Concurrent anticancer treatment (for example, cytoreductive therapy, immune therapy, or cytokine therapy except for erythropoietin). If indicated, radiotherapy to the operated breast/chest wall/locoregional lymph nodes is admitted.
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.
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)
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).
Significant acute or chronic infections including, among others: a. Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. b. 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).
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. b. 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.
Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
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.
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)
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.
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.
Any psychiatric condition that would prohibit the understanding or rendering of informed consent
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).
Known alcohol or drug abuse.
Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v 4.03 (however, alopecia, grade 2 neuropathy and any other grade 2 not constituting a safety risk based on investigator’s judgement are acceptable).
Current pregnancy and/or lactation. Refusal to adopt adequate contraception methods.
Metastatic breast cancer.
No invasive residual disease in the breast and axilla at pathological examination after neoadjuvant chemotherapy. ypT1micN0, ypT1micN0i+, ypT0N0i+ will also be excluded.
History of any prior (ipsi- and/or contralateral) invasive breast carcinoma diagnosed within 10 years.
Synchronous bilateral breast cancer, unless both tumors confirmed as triple negative disease.
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.
Prior organ transplantation, including allogeneic stem-cell transplantation.
Prior or concomitant treatment with any other investigational agents.
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).
Concurrent anticancer treatment (for example, cytoreductive therapy, immune therapy, or cytokine therapy except for erythropoietin). If indicated, radiotherapy to the operated breast/chest wall/locoregional lymph nodes is admitted.
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).
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
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).
Significant acute or chronic infections including, among others: a. Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. b. 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).
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. b. 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.
Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.
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.
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).
Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident /stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication.
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.
Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
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).
Known alcohol or drug abuse.
Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v 4.03 (however, alopecia, grade 2 neuropathy and any other grade 2 not constituting a safety risk based on investigator’s judgement are acceptable).
Current pregnancy and/or lactation. Refusal to adopt adequate contraception methods.