Informations générales (source: ClinicalTrials.gov)
Impact of Neoadjuvant Immunotherapy in Early Stage Breast Cancer Before Standard Therapy
Interventional
Phase 2
Gustave Roussy, Cancer Campus, Grand Paris (Voir sur ClinicalTrials)
février 2022
février 2026
27 août 2025
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.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT GUSTAVE ROUSSY | Barbara PISTILLI | 28/06/2024 10:14:21 | Contacter | ||
Critères
Tous
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:
- For the TNBC cohort, ER≤10%, PR≤10% and HER2 not overexpressed/amplified
- For the HER2-positive cohort, presence of a HER2 overexpression and/or
amplification as per ASCO/CAP guidelines
- Adequate haematologic and organ function defined by the following:
- ANC ≥ 1,500 cells/µl
- Platelet count ≥ 100,000/µl
- Haemoglobin ≥ 9.0 g/dL (90g/L)
- Serum albumin ≥ 2.5 g/dL
- Creatinine ≤ 1.5 x ULN
- 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)
- 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 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.
- 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:
- For the TNBC cohort, ER≤10%, PR≤10% and HER2 not overexpressed/amplified
- For the HER2-positive cohort, presence of a HER2 overexpression and/or
amplification as per ASCO/CAP guidelines
- Adequate haematologic and organ function defined by the following:
- ANC ≥ 1,500 cells/µl
- Platelet count ≥ 100,000/µl
- Haemoglobin ≥ 9.0 g/dL (90g/L)
- Serum albumin ≥ 2.5 g/dL
- Creatinine ≤ 1.5 x ULN
- 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)
- 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 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.
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:
- Patients who received acute, low-dose systemic immunosuppressant medication or
a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours
of corticosteroids as premedication for hypersensitivity reaction (e.g., CT
scan premedication)) are eligible for the study after Medical Monitor approval
has been obtained
- Patients who received mineralocorticoids (e.g., fludrocortisone),
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or
low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency
are eligible for the study
- Patients who received intranasal, inhaled, topical or local steroid injections
(e.g., intra articular injection)
- 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:
- History of myocardial infarction, acute coronary syndromes or coronary
angioplasty/stenting/bypass grafting within the past 6 months,
- Congestive Heart Failure (CHF) NYHA class III or IV or history of CHF NYHA
class III or IV, unless an echocardiogram or multi-gated acquisition scan
performed within 3 months day 1 reveals a left ventricular ejection fraction ≥
50%55%
- 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):
- 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
- Currently known to have a history or ongoing serous retinopathy and/or history of
retinal vein occlusion
- History of stroke or transient ischemic attack within 6 months prior to
randomization
- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to randomization
- 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
- History of active inflammatory bowel disease (e.g. Crohn's disease and ulcerative
colitis) or active bowel inflammation ( e.g. diverticulitis)
- Grade ≥ 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia
- Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,
cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic
infections (pneumocystis pneumonia or cytomegalovirus pneumonia)
- Known clinically significant history of liver disease consistent with Child Pugh
Class B or C, including active viral or other hepatitis (e.g., positive for
hepatitis B surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at
screening), current drug or alcohol abuse, or cirrhosis