Newly diagnosed, non-metastatic early triple negative or HER2+ breast cancer MedDRA version: 20.0 Level: PT Classification code 10075566 Term: Triple negative breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 23.0 Level: PT Classification code 10065430 Term: HER2 positive breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: TECENTRIQ
Product Code: RO5541267
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: ATEZOLIZUMAB
Other descriptive name: RO5541267
Concentration unit: mg/ml m
Sponsors
Gustave Roussy
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Patient should understand, sign, and date the written informed consent form (including the consent to collect tissue, blood and stool samples, as specified by the protocol) prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol. - Female patients aged 18 years or older - ECOG performance status 0-1 - Female patients with histologically confirmed breast cancer with no evidence of metastatic spread - Candidate to surgery upfront or patients with an indication of neoadjuvant chemotherapy, assuming chemotherapy starts after the completion of the pre-operative immunotherapy treatment, biopsies are undertaken before the start of the systemic chemotherapy and the decision to administer neoadjuvant chemotherapy is made before randomization - At least 11 mm in tumor size as determined by breast ultrasound - ER, PR and HER2 will be locally assessed and defined as per ASCO/CAP guidelines o For the TNBC cohort, ER 1,500 cells/µl o Platelet count => 100,000/µl o Haemoglobin = 9.0 g/dL (90 g/L) o Serum albumin => 2.5 g/dL o Creatinine = 1.5 x ULN o Bilirubin = 1.5 x ULN, AST or ALT < 3 x ULN, ALP < 2.5 x ULN (patients with known Gilbert disease who have serum bilirubin level = 3 × the institutional ULN may be enrolled) o For patients not receiving therapeutic anticoagulation: INR or aPTT = 1.5 x ULN. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen. - Patients of child-bearing potential are eligible, provided they have a negative serum ß-HCG pregnancy test within 2 weeks or urine pregnancy test within 48 hours prior to the first dose of study treatment, and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacuzimab and 7 months for the last dose of pertuzumab and/or trastuzumab. - A woman is considered of childbearing potential following menarche and until becoming post-menopausal (= 12 months of non-therapy-induced amenorrhea) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral oophorectomy and bilateral salpingectomy. -Sexually active women of childbearing potential must agree to use a highly effective method of contraception supplemented by a barrier method, or to abstain from sexual activity during the study and for at least 5 months after discontinuation of atezolizumab treatment, 6 months after the last dose of bevacizumab, 6 months after the last dose of ipatasertib and 7 months after the last dose of pertuzumab and trastuzumab. Female subjects should also refrain from breastfeeding throughout this period. - A highly effective birth control method is a one, which can achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include: combined (estrogen and progestogen containing) hormonal contraception; progestogen-only hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized
Exclusion criteria
Exclusion criteria: - Evidence of metastatic breast cancer - HR+ and/or HER2+ (for the TNBC cohort) and HER2- (for the HER2+ cohort) - Any systemic therapy (...) or radiotherapy for current breast cancer disease before study entry - Previous systemic treatment for other neoplasms within 1 year prior to randomization - Active malignancy (except for non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in-situ) within the past 36 months prior to study entry - Known intolerance to any of the study drugs or any of their excipients - Patients with prior allogeneic stem cell or solid organ transplantation - Administration 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 or within 5 months after the last dose of atezolizumab - Treatment with systemic immunostimulatory agents (...) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment - Treatment with systemic immunosuppressive medication (...) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: (...) - Active or history of autoimmune disease or immune deficiency, with the exception of history of treated autoimmune-related hypothyroidism and Type 1 diabetes mellitus on insulin regimen - History of idiopathic pulmonary fibrosis (including pneumonitis or interstitial lung disease), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis (history of radiation pneumonitis in the radiation field (fibrosis) is permitted). - History of HIV infection - Patients with active hepatitis infection (...) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (...) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA -Active tuberculosis -Current treatment with anti-viral therapy for HBV -Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies -Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol -Participation in another clinical study with an investigational product during the last 28 days and while on study treatment -Currently known to have a history or ongoing serious retinopathy and/or history of retinal vein occlusion -History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins -Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation or to any component of the other drugs on the study -Severe infection within 4 weeks prior to initiation of study treatment (...) -Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment -Significant cardiovascular disease, such as (...) -Uncontrolled hypertension defined by systolic pressure > 150 and/or diastolic pressure > 110 mmHg, with or without anti-hypertensive medication. Patients with initial blood pressure elevations are eligible if initiation or adjustment of anti-hypertensive medication lowers blood pressure to
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine, using immunohistochemistry (IHC) on biopsies and surgically removed tumor if short-treatment immunotherapy is associated with increase of activated GzmB+ CD8+ T cells levels from baseline to post treatment sample;Secondary Objective: • To determine, using immunohistochemistry (IHC) on biopsies pre and post-treatment if short-treatment immunotherapy is associated with an increase in immunogenicity as determined by increase ratio of GzmB/CD8, CD8/FoxP3, CD8/CD68 ratio, as compared to control arm • To assess the safety and tolerability of study treatments in this population • To determine the effect of short-term immunotherapy treatment in pCR at surgery • To assess the effect of immunotherapy alone or in combination with other therapies in tumor cell proliferation • To determine modifications of different immune biomarkers under treatment vs baseline including but not limited to CD8, PDL-1 and MHC-I • To assess changes in immune-related gene expression, in tumor tissue prior to and after study treatment as performed by RNA-seq • To assess the effect of immunotherapy on pCR in patients treated with neoadjuvant chemotherapy ;Primary end point(s): • Two-fold increase in GzmB+ CD8+ T cell levels from baseline to post-treatment window;Timepoint(s) of evaluation of this end point: See Above | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Changes in CD8+, PDL-1 and % of Ki67 expression from baseline (pre-study) to end of study-treatment biopsies • Changes from baseline in PD-L1 and MHC-I levels to end-of study-treatment • Changes from baseline tumor tissue to end of treatment in immune infiltrates, immune-related gene expression • Incidence, nature and severity of Adverse Events graded according to NCI-CTCAE v5.0 collected during treatment and up to 4 weeks post-surgery • Clinical response after experimental therapy, defined as a > 30% decrease in tumor diameter from baseline breast ultrasound based on investigator assessment • pCR defined as the absence of any residual invasive cancer based on histological evaluation of the resected specimen during definitive breast cancer surgery. ;Timepoint(s) of evaluation of this end point: See above | — |
Countries
France
Contacts
Public ContactSponsor CRA
Gustave Roussy
Outcome results
None listed