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About
The aim of this study is to determine, using immunohistochemistry (IHC) on biopsies and surgically removed tumor if short-treatment immunotherapy with atezolizumab monotherapy or in combination with other biologic agents (ipatasertib / Bevacizumab / Trastuzumab / Pertuzumab) is associated with increased levels of activated GzmB+ CD8+ T cells from baseline to post treatment sample.
Moreover, from baseline to post treatment sample, evolution of others biomarkers will be studied : GzmB/CD8, CD8/FoxP3, CD8/CD68 in IHC, cell proliferation, PD-L1, MHC-I, change in gene expression (RNA-Seq). Tjis study aim also to assess the safety and tolerability of study treatments in this population and to determine the effect of short-term immunotherapy treatment in pCR at surgery.
Patients will undergo tumor biopsies at screening and 15 days after the beginning of treatment (if they start neoadjuvant chemotherapy) / at surgery, in order to evaluate in IHC evolution of activated GzmB+ CD8+ T cells and evaluate other markers
It targets 2 different cohorts: newly diagnosed, non-metastatic early-stage triple-negative (TNBC) or HER2+ breast cancer. TNBC cohort is composed of 2 open-label, randomized arms, HER2+ of 2 arms.
A maximum of 185 patients will be included in the trial
Tumor evaluation will be performed by clinical examination and Breast echography at baseline and end of treatment visit.
The safety of the product will be assessed at each cycle, through complete clinical exams, biological tests and through the collection of ongoing toxicities or adverse events.
Full description
Cohort 1 In TNBC patients t will be composed of 4 open-label, randomized arms:
Arm 1A: atezolizumab alone, administered as one single IV infusion on day -15 +/- 48 h Arm 1B: atezolizumab and bevacizumab as one single IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of the standard of care neoadjuvant systemic treatment.
Cohort 2 in HER2-positive patients will be composed of 2 arms:
Arm 2A: pertuzumab for one IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of the standard of care neoadjuvant systemic treatment.
Arm 2B: atezolizumab as one single IV infusion in combination with trastuzumab + pertuzumab for one IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of the standard of care neoadjuvant systemic treatment.
Enrollment
Sex
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Volunteers
Inclusion criteria
Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol.
Female or male patients aged 18 years or older
Eastern Cooperative Group (ECOG) Performance Status 0-1
Histologically confirmed female breast cancer with no evidence of metastatic spread
Candidate to surgery upfront or patients with an indication to standard of care neoadjuvant systemic treatment, assuming that systemic treatment starts after the completion of the pre-operative immunotherapy treatment, biopsies are undertaken before the start of the systemic treatment and the decision to administer neoadjuvant systemic treatment 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 the french national guidelines:
Adequate haematologic and organ function defined by the following:
Patients of child-bearing potential are eligible, provided they have a negative serum β-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 bevacizumab, 28 days after the last dose of ipatasertib and 7 months after 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, 28 days after the last dose of ipatasertib and 7 months after the last dose of pertuzumab and/or 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 partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence during the entire period of risk associated with study treatment. To prevent the risk of interaction between the study drug and hormonal contraceptives, hormonal contraceptives should be supplemented with a barrier method (preferably male condom). Following methods are considered as unacceptable methods (non-exhaustive list): periodic abstinence (calendar, symptothermal, post-ovulation methods) and withdrawal (coitus interruptus).
Sexually actives males patients must agree to use condom during the study and for at least 5 months after discontinuation of atezolizumab treatment, 6 months after the last dose of bevacizumab, 28 days after the last dose of ipatasertib and 7 months after the last dose of pertuzumab and/or trastuzumab. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception for the same duration.
Patients must be affiliated to a social security system or beneficiary of the same.
Exclusion criteria
Patients who meet any of the following exclusion criteria will not be eligible for this study.
Evidence of metastatic breast cancer
ER≥10% or PR≥10%and/or HER2+ (for the TNBC cohort) and HER2- (for the HER2+ cohort)
Any systemic therapy (e.g, chemotherapy, targeted therapy, immune-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 (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment
Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate and thalidomide) 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
Symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea
History of idio pathic 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).
Patients who underwent major surgery within 28 days prior to inclusion or until the surgical wound is fully healed
History of HIV infection
Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
Patients with a history cirrhosis
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, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
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 meet entry criteria
History of stroke or transient ischemic attack within 6 months prior to randomisation
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomisation
History of haemoptysis (> 1/2 teaspoon of bright red blood per episode) or other serious haemorrhage or at risk of bleeding (gastrointestinal history of bleeds, gastrointestinal ulcers etc.) within 1 month prior to randomization
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
Pregnant or breastfeeding women
Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.
For the TNBC cohort (exclusion criteria in relation to bevacizumab):
Primary purpose
Allocation
Interventional model
Masking
185 participants in 4 patient groups
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Central trial contact
Joana Mourato Ribeiro, Dr
Data sourced from clinicaltrials.gov
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