Study With Atezolizumab in Combination With Trastuzumab and Vinorelbine in HER2-positive Advanced/Metastatic Breast Cancer

Study Overview
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Brief Summary
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Immune checkpoint inhibitors given in monotherapy in advanced breast cancer have shown modest benefit in first-line, but very limited efficacy in later lines. Thus, combination therapies are needed. Response following anti-PD1/PD-L1 monotherapy is associated with large survival benefit in the advanced setting. Previous studies of the intrinsic subtypes have shown that Basal-like and HER2-E are associated with higher expression of immune-related genes or higher infiltration of stromal tumor infiltrating lymphocytes compared to the luminal subtypes. Immune infiltration in BC is associated with chemo/antiHER2 responsiveness and potentially benefit from anti-PD-1/PD-L1 inhibitors. In addition, one emerging biomarker of response to anti-PD-1 therapy is the tumor mutational burden (I.e. the total number of mutations per coding area of a tumor genome). The HER2-E and Basal-like profiles have been associated with high mutational burden. A range of studies have been initiated including several phase II/III studies evaluating atezolizumab in combination with different chemotherapeutic compounds routinely used in breast cancer, but none with predefined biomarker beyond the expression of PD-L1 by IHC

Official Title
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A Phase II With 2 Parallel Cohorts Clinical Trial Targeting Estrogen Receptor Negative or PAM50 Non-luminal Disease With Atezolizumab in Combination With Trastuzumab and Vinorelbine in HER2-positive Advanced/Metastatic Breast Cancer - ATREZZO Study

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Atezolizumab + Trastuzumab + Vinorelbine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female (Premenopausal or postmenopausal women) ECOG 0 to 2 Histologically confirmed adenocarcinoma of the breast, metastatic or unresectable locally advanced. All patients must have received at least trastuzumab and other anti-HER2 ADCs (including but not limited to T-DM1). Measurable disease according to RECIST 1.1 criteria. Adequate organ function Baseline LVEF ≥50% Participants with asymptomatic brain metastases are eligible. Exclusion Criteria: Treatment with any investigational anticancer drug within 14 days of the start of study treatment. Patient has received Vinorelbine or any other vinca alkaloids previously immediately prior to initiate study treatment. History of other malignant tumors in the past 3 years Known or suspected leptomeningeal disease (LMD)/ poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases. Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 14 days prior to inclusion Cardiopulmonary dysfunction Any other severe, uncontrolled Major surgery in the 28 days prior to enrolment Infection with HIV or active Hepatitis B and/or Hepatitis C. History of trastuzumab intolerance, including grade 3-4 infusion reaction or hypersensitivity. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation History of autoimmune disease, Prior allogeneic stem cell or solid organ transplantation History of idiopathic pulmonary fibrosis, 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.) Active tuberculosis Receipt of a live, attenuated vaccine within 4 weeks prior to enrollment Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or immune checkpoint targeting agents 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 prior to enrolment Treatment with systemic immunosuppressive medications within 2 weeks prior to enrolment, or anticipated requirement for systemic immunosuppressive medications during the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is an open-label, single arm, Simon 2-stage, multicenter phase II study evaluating treatment with atezolizumab in combination with trastuzumab and vinorelbine in patients with locally advanced or metastatic PAM50 non-luminal/HER2+ BC refractory to trastuzumab based therapy and anti-HER2 ADC treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab in combination with Trastuzumab and Vinorelbine<br> | Drug: Atezolizumab + Trastuzumab + Vinorelbine<br>* Atezolizumab IV 1200 mg in combination with Trastuzumab sc 600mg or IV 6mg/kg every 3 weeks and Vinorelbine 25 mg/m² IV or 60 mg/m2 PO on days 1 and 8, every 3 weeks during the first cycle and if there are no toxicity signs dose will be increased to 80 mg/m2 PO o 30 mg/m2 IV.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response rate | 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 | until disease progression or up to 2 years after treatment ends | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response rate in PD-L1+ patients | 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 | until disease progression or up to 2 years after treatment ends | 
| Clinical Benefit | Clinical Benefit Rate at 24 weeks | 24 weeks | 
| Overal survival | Time from the date of allocation to the date of death due to any cause. | Until analysis data cutoff, 2 years | 
| Progression free survival | Survival witouth observed progression | 24 weeks | 
| Duration of response | time from first documented response until progression | 24 weeks | 
| Time to response | time until first documented response | 24 weeks | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | AEs according to CTCAE v 5.0. | until end of treatment / through study completion, an average of 1 year | 
| Overall Response rate in patients with brain metastases at baseline | Patients with a history of brain metastases, current brain metastases, or equivocal brain lesions at baseline | Until disease progression or up to 2 years after treatment ends | 
| Clinical Benefit in patients with brain metastases at baseline | Clinical Benefit Rate at 24 weeks in patients with a history of brain metastases, current brain metastases, or equivocal brain lesions at baseline | 24 weeks | 
| Progression free survival in patients with brain metastases at baseline | Survival without observed progression in patients with a history of brain metastases, current brain metastases, or equivocal brain lesions at baseline | 24 weeks | 
| Overal survival in patients with brain metastases at baseline | Time from the date of allocation to the date of death due to any cause. | Until analysis data cutoff, 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, breast cancer