Atezolizumab for HER2-positive breast cancer | Advanced breast cancer

Inclusion criteria

• {"criterion_text":"- Patient eligibility will be reviewed and documented by a suitable member of the Investigator’s study team before the patients are enrolled in the study (section 6.2.2) Any asterisked* are also applicable as an exclusion criterion prior to perform the prescreening PAM50 testing. To perform the PAM50 assay, investigator judgement of patient’s potential eligibility to the study should be assessed as per Table of assessments (section 6.1). All the following criteria must be fulfilled for a patient to be eligible to this study: 1. Written signed Informed Consent for all study procedures in accordance with the local administrative requirements prior to starting the protocol-specific procedures.\n- *Male or female patients. Premenopausal or postmenopausal women.\n- *Age 18 years or older\n- *ECOG performance status 0 to 2 (Appendix A).\n- *Histologically confirmed adenocarcinoma of the breast, metastatic or unresectable locally advanced. a. Patients with locally advanced disease must have recurrent or progressive disease unsuitable for resection with curative intent. Patients with standard curative options available will not be eligible. b. Invasive HER2-positive breast cancer in the last biopsy performed, according to the local laboratory, defined according to the most recent ASCO/CAP criteria. c. In patients with bilateral breast cancer, HER2+ positivity must be demonstrated in both sites or in the last metastatic biopsy. d. Hormone receptor negative according to the local laboratory in the last biopsy performed, defined according to the most recent ASCO/CAP criteria, OR Hormone receptor positive breast cancer in the last biopsy performed according to the local laboratory, defined according to the most recent ASCO/CAP criteria AND centrally confirmed non-luminal intrinsic subtype as per PAM50 analysis (i.e. HER2-E or Basal-like).\n- All patients must have received at least trastuzumab and other anti-HER2 ADCs (including but not limited to T-DM1) in one as follows situation: a. For patients with newly diagnosed HER2+ advanced disease or advanced disease that recurred after 12 months of last dose of adjuvant therapy, must have received at least 2 previous lines of systemic treatment for metastatic disease with trastuzumab +/- pertuzumab and anti-HER2 ADCs. b. For patients who recur during or within 12 months after completing adjuvant therapy with trastuzumab +/- pertuzumab can be enrolled after one line of systemic treatment for metastatic disease with anti-HER2 ADCs. c. For patients who recur during or within 12 months after completing adjuvant treatment with anti-HER2 ADCs and neoadjuvant therapy with trastuzumab +/- pertuzumab can be enrolled directly in the moment of the diagnosis of metastatic disease. d. Previous use of other anti-HER2 treatments, alone or in combination with chemotherapy, is permitted, including lapatinib, neratinib, trastuzumab, tucatinib, other anti-HER2 antibody, anti-HER2 antibody drug conjugates or antiHER2 tyrosine-kinase inhibitors. e. Previous use of any hormone agent or chemotherapy is permitted (except immediately prior line with Vinorelbine or any other vinca alkaloids before initiating study treatment).\n- *Availability of formalin-fixed paraffin-embedded (FFPE) tumor block for biomarker analysis, obtained from metastatic lesions (preferably) or from the primary tumor. a. The tumor tissue should be of good quality based on total and viable tumor content and must be evaluated centrally by PAM50 test (if HR positive) prior to enrolment. Patients whose tumor tissue is not evaluable for prospective PD-L1 expression central testing are not eligible. - Acceptable samples include core needle biopsies for deep tumor tissue (more than one core if clinically feasible) or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. - Fine needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable. - Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable. b. If HR-positive, Non-luminal subtype as per PAM50 analysis confirmed by the designated laboratory. If prior approval has been granted by the Sponsors, centrally confirmed PAM50 non luminal tumor results from a current or previous study identified by the Sponsors⎯ e.g., Study PATRICIA SOLTI-1303 ⎯ can be used to determine eligibility for this study. c. A diagnostic antihuman PD-L1 monoclonal antibody (VENTANA SP142) will be used to stain prospectively for PD-L1 expression on formalin-fixed paraffin-embedded tumor tissue by immunohistochemistry (IHC), as described in published literature 30 , considering: - PD-L1 positive patients: defined as tumors with a PD-L1 in immune cells expression level of IC 1/2/3) - PD-L1 negative patients: defined as tumors with a PD-L1 expression level of IC 0).\n- Measurable disease according to RECIST 1.1 criteria\n- *Adequate organ function, defined as: a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. b. Hemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted). c. Platelets > 100,000/mm3 d. Creatinine ≤ 1.5 x normal value e. AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis) f. Alkaline phosphatase ≤2.5 x ULN. Alkaline phosphatase may be more than 2.5 x ULN only in the case of bone metastases, and AST and ALT less than 5 x ULN. g. Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient has Gilbert's syndrome).\n- *Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic ventriculography (MUGA).\n- *Absence of psychological, family, sociological or geographical conditions that could potentially hinder compliance with the study protocol and follow-up schedule. These situations must be discussed with the patient before she is included in the study.\n- If female of childbearing potential, must have a negative result of serum pregnancy test performed within 7 days prior to first dose of study treatment. Females of childbearing age potential and male subjects with partners of childbearing potential must use highly effective (Appendix H) contraceptive measures (according to CTFG recommendations). According to the clinical trial facilitation group recommendations, a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. Subjects should be informed and accept that these requirements should also extend to: - 5 months after the last dose with Atezolizumab, - 3 months after the last dose with Vinorelbine and - 7 months after the last dose with Trastuzumab.\n- Participants with a history of CNS metastases are eligible, must have one of the following: - Untreated brain metastases not needing immediate local therapy. For patients with untreated CNS lesions > 2.0 cm on screening contrast brain MRI, discussion with and approval from the medical monitor is required prior to enrollment. - Previously treated brain metastases: a) Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator. b) Patients treated with CNS local therapy for newly identified lesions may be eligible to enroll if all of the following criteria are met: i) Time since WBRT is ≥ 21 days prior to first dose of treatment, time since SRS is ≥ 7 days prior to first dose of treatment, or time since surgical resection is ≥ 21 days. ii) Other sites of disease assessable by RECIST 1.1 are present."}

Exclusion criteria

• {"criterion_text":"- Treatment with any investigational anticancer drug within 14 days of the start of study treatment.\n- Patient who has received Vinorelbine or any other vinca alkaloids immediately prior to initiate study treatment are excluded. Patients previously treated with vinorelbine or other vinca alkaloids that afterwards have received at least a subsequent treatment line with a permitted regimen can be enrolled.\n- History of other malignant tumors in the past 3 years, except for adequately treated in situ carcinoma of the cervix, non-melanoma carcinoma of the skin, uterine cancer in stage I or other malignant tumors with an expected curative outcome.\n- *CNS exclusion criteria:a. Known or suspected leptomeningeal disease (LMD) as documented by the investigator.b. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy.\n- Patients who have received radiation therapy for metastases outside the brain carried out in the 21 days prior to inclusion in the study and/or patients who have received radiation to > 30% of the bone marrow.\n- *Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 14 days prior to inclusion in the study. Bisphosphonates or RANKL inhibitor, will be permitted for the prevention of bone events.\n- *History of exposure to cumulative anthracycline doses greater than follows: a. Adriamycin > 400 mg/m2 b. Epirubicin > 720 mg/m2 c. Mitoxantrone > 120 mg/m2 d. Idarubicin > 90 mg/m2 e. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 400 mg/m2 of adriamicin.\n- *Cardiopulmonary dysfunction, defined as: a. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) despite optimum medical treatment. b. Angina pectoris or arrhythmia poorly controlled with optimum medical treatment. c. History of congestive heart failure NCI CTCAE version 5.0 grade ≥ 3 (appendix C) OR NYHA class ≥ 2 (appendix D). d. History of LVEF decrease to < 40% or symptomatic congestive heart failure during prior treatment with trastuzumab. e. Myocardial infarction within 6 months before enrolment. f. Resting dyspnea due to complications of the malignant disease, requiring continuous oxygen therapy.\n- *Any other severe, uncontrolled disease (pulmonary, cardiac, metabolic, or hematological disorder, wound healing disorders, ulcers, bone fractures, infectious processes).\n- Major surgery in the 28 days prior to enrolment or foreseeable during study treatment period.\n- *Infection with HIV or active Hepatitis B and/or Hepatitis C.\n- *History of trastuzumab intolerance, including grade 3-4 infusion reaction or hypersensitivity.\n- *Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary (CHO) cells or any component of the atezolizumab formulation\n- *History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, multiple sclerosis , vasculitis, or glomerulonephritis. (Note: Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.)\n- *Prior allogeneic stem cell or solid organ transplantation\n- *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. (Note: History of radiation pneumonitis in the radiation field [fibrosis] is permitted.)\n- *Active tuberculosis\n- Receipt of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study. Note: Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) within 28 days prior to enrolment, during treatment or within 5 months following the last dose of atezolizumab\n- *Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or immune checkpoint targeting agents\n- Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug (whichever is longer) prior to enrolment\n- *Treatment with systemic immunosuppressive medications (including but not limited to corticosteroids, cyclophosphamide, azathioprine, cyclosporine, methotrexate, thalidomide, and antitumor necrosis factor [TNF] agents) within 2 weeks prior to enrolment, or anticipated requirement for systemic immunosuppressive medications during the trial. a. Patients who have received acute, low-dose (≤ 10 mg oral prednisone or equivalent), systemic immunosuppressant medications may be enrolled in the study. b. Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments performed using MRI. c. The use of corticosteroids (≤ 10 mg oral prednisone or equivalent) for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low dose supplemental corticosteroids for adrenocortical insufficiency are allowed.\n- *Inability, in the opinion of the investigator, to comply with the protocol requirements or any comorbidity that might hinder study follow-up, response evaluation or the informed consent process.\n- *Pregnant or breastfeeding women"}

Primary endpoints

• {"endpoint_text":"- Overall Response rate (ORR) defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR), as per local investigator´s assessment and according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.(see Appendix B).","definition_or_measurement_approach":"Proportion of patients with best overall response CR or PR assessed by local investigator according to RECIST v1.1."}

Secondary endpoints

• {"endpoint_text":"- Overall Response rate (ORR) defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR), as per local investigator´s assessment and according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. (see Appendix B","definition_or_measurement_approach":"ORR assessed by local investigator according to RECIST v1.1."}
• {"endpoint_text":"- Clinical Benefit Rate at 24 weeks (CBR6) as defined by RECIST 1.1 (including patients with Complete response (CR), Partial response (PR),Stable Disease (SD) > 24 week) • Overall survival • Progression free survival • Duration of response • Time to response","definition_or_measurement_approach":"CBR at 24 weeks by RECIST 1.1; overall survival, progression-free survival, duration of response and time to response as standard time-to-event measures (per protocol)."}
• {"endpoint_text":"- ORR according to RECIST to RECIST 1.1 • Clinical Benefit Rate at 24 weeks (CBR6) as defined by RECIST 1.1 • Progression free survival • Overall survival","definition_or_measurement_approach":"Efficacy endpoints assessed according to RECIST v1.1 and standard survival analysis methods."}
• {"endpoint_text":"- AEs according to CTCAE v 5.0.","definition_or_measurement_approach":"Adverse events graded and reported according to CTCAE v5.0."}

Spain

Latest Decision Or Authorization Date

29-07-2024

Number Of Sites

16

Number Of Participants

55

Primary sponsor

Full Name

Solti Group

Organisation Type

Pharmaceutical company

Country Of Registered Address

Spain

Third parties

• {"country":"Spain","full_name":"Roche Farma S.A.","duties_or_roles":"Distribution and Management of PR1","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Azierta Life Sciences & Health Consulting Firm S.L.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}