Clinical trial NCT04759248: Study With Atezolizumab in Combination With Trastuzumab and Vinorelbine in HER2-positive Advanced/Metastatic Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
Keywords: cancer
breast cancer
Lead sponsor: SOLTI Breast Cancer Research Group
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
First posted: 2021-02-18
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
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.
Primary purpose: TREATMENT

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


Eligibility criteria: 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.

Primary outcomes:
measure: Overall Response rate
timeFrame: until disease progression or up to 2 years after treatment ends
Secondary outcomes:
measure: Overall Response rate in PD-L1+ patients
timeFrame: until disease progression or up to 2 years after treatment ends
measure: Clinical Benefit
timeFrame: 24 weeks
measure: Overal survival
timeFrame: Until analysis data cutoff, 2 years
measure: Progression free survival
timeFrame: 24 weeks
measure: Duration of response
timeFrame: 24 weeks
measure: Time to response
timeFrame: 24 weeks
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: until end of treatment / through study completion, an average of 1 year
measure: Overall Response rate in patients with brain metastases at baseline
timeFrame: Until disease progression or up to 2 years after treatment ends
measure: Clinical Benefit in patients with brain metastases at baseline
timeFrame: 24 weeks
measure: Progression free survival in patients with brain metastases at baseline
timeFrame: 24 weeks
measure: Overal survival in patients with brain metastases at baseline
timeFrame: Until analysis data cutoff, 2 years
Other outcomes:
Locations:
city: Granada
country: Spain
facility: H. Clínico San Cecilio de Granada
state: Andalucía
city: Hospitalet de Llobregat
country: Spain
facility: Institut Català d'Oncologia Hospitalet
state: Barcelona
city: Tenerife
country: Spain
facility: Hospital Universitario de Canarias
state: Islas Canarias
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña (CHUAC)
state: La Coruña
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d' Hebron
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcántara
city: León
country: Spain
facility: Hospital de León
city: Madrid
country: Spain
facility: Hospital Universitario 12 de octubre
city: Palma De Mallorca
country: Spain
facility: Hospital Son Espases
city: Reus
country: Spain
facility: Hospital Universitari Sant Joan de Reus
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
Study officials:
References: