Breast Cancer
Conditions
Keywords
cancer, breast cancer
Brief summary
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
Interventions
DRUGAtezolizumab + Trastuzumab + Vinorelbine
* 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.
Sponsors
Roche Pharma AG
SOLTI Breast Cancer Research Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response rate | until disease progression or up to 2 years after treatment ends | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit | 24 weeks | Clinical Benefit Rate at 24 weeks |
| Overal survival | Until analysis data cutoff, 2 years | Time from the date of allocation to the date of death due to any cause. |
| Progression free survival | 24 weeks | Survival witouth observed progression |
| Duration of response | 24 weeks | time from first documented response until progression |
| Time to response | 24 weeks | time until first documented response |
| Overall Response rate in PD-L1+ patients | until disease progression or up to 2 years after treatment ends | 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 |
| Overall Response rate in patients with brain metastases at baseline | Until disease progression or up to 2 years after treatment ends | Patients with a history of brain metastases, current brain metastases, or equivocal brain lesions at baseline |
| Clinical Benefit in patients with brain metastases at baseline | 24 weeks | Clinical Benefit Rate at 24 weeks in patients with a history of brain metastases, current brain metastases, or equivocal brain lesions at baseline |
| Progression free survival in patients with brain metastases at baseline | 24 weeks | Survival without observed progression in patients with a history of brain metastases, current brain metastases, or equivocal brain lesions at baseline |
| Overal survival in patients with brain metastases at baseline | Until analysis data cutoff, 2 years | Time from the date of allocation to the date of death due to any cause. |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | until end of treatment / through study completion, an average of 1 year | AEs according to CTCAE v 5.0. |
Countries
Spain
Outcome results
None listed